Current Drug Targets

Urologists are required to manage a wide spectrum of conditions ranging from the typical male patient with uncomplicated lower urinary tract symptoms (LUTS) to advanced malignancies of the urinary tract that require extirpative, debilitating surgery and multidisciplinary team management. Medical and surgical therapy are used either sequentially or complimentary to one another for a variety of urological diseases. Advanced and challenging surgery is necessary in cases where medical therapy fails while on the other hand medical therapy is used to alleviate complications and amend shortcomings of surgical interventions. Recently, unprecedented evolutions in drug development as well as in surgical devices and techniques have created dilemmas as to the optimal management of a variety of urological diseases. This special issue of CDT aims to investigate those interactions between drugs and surgery in the treatment of the most common urological conditions; lower urinary tract symptoms and urological oncology. When it comes to LUTS, medical therapy has historically been considered as the cornerstone of treatment, with ablockers being the choice for first-line therapy either in combination with 5-ARIs or more commonly as sole treatment. Considering that LUTS’s complex pathophysiology is not always related to the enlarged prostate, urologist have come to realize that patients seeking treatment for LUTS are to a different extend bothered by storage and/or voiding symptoms, rendering their therapeutic approach challenging. Since the “one-size-fits-all” rule does not apply to the pharmacological management of LUTS, given the wide heterogeneity in the etiology and phenotype of patients with LUTS it appears inevitable that in clinical practice, most of the patients will be advised to opt for combination therapy of an a-blocker with 5-a-reductase inhibitors (5-ARIs) or antimuscarinics. Furthermore, assuming that BPH will progress for the majority of patients, combination therapy with a-blockers and 5ARIs is a reasonable choice in an effort to lessen the risks of retention and prostate surgery by decreasing prostate size. On the other hand and while the limits of pharmacotherapy for BPH are still not very clear, patients do not stay for long on BPH medications, especially on combination therapies, and this has a negative effect on the rates of hospitalization and BPH surgery. Interestingly, a recent survey has shown that although most men were satisfied with their current medical therapy for BPH, the majority (61%) were willing to participate in an alpha-blocker discontinuation trial. In addition to low adherence to BPH medication, longstanding issues of their long-term efficacy, safety and negative impact on libido, ejaculation and quality of life on sexually active patients further complicate their use. The recent advent of innovative minimally invasive surgical techniques has further fueled the debate as to whether medical treatment should remain the first line therapy for patients with LUTS/BPH and if so for which patients. Minimally invasive surgical therapies (MISTs) including Prostatic Urethral Lift (PUL), transurethral water vapor therapy (Rezūm), iTIND and Aquablation, have started gaining ground over conventional surgical modalities, namely TURP. MISTs confer several inherent advantages, mainly preservation of sexual and ejaculatory function and avoidance of long-term use of drugs targeting patients who opt for a quick, safe, reasonably durable, and less invasive procedure that will improve LUTS with minimal morbidity and negligible side effects. It could be argued that MITSs represent an equally good choice as medical therapy as first line treatments of BPH-related LUTS sparing the drug-related side effects of orthostatic hypotension, asthenia and sexual dysfunction. Although no direct studies exist comparing medical therapy to MISTs, Symeonidis and Sountoulides in the current issue offer a narrative review of the available literature and provide an indirect comparative assessment of drugs versus MISTs for obstructive LUTS. Interestingly improvements in symptoms and QoL favored MISTs over medical therapy, with the majority of drugs failing to demonstrate a clear superiority [1]. Despite these encouraging results, MISTs long-term durability is unknown given the relatively short follow up time (maximum 5 years) of relevant studies. There is no doubt that further clinical studies are required for obtaining solid evidence before definite conclusions are made about the place of MISTs in clinical practice and even more so as first line treatment of BPH-related LUTS. There is a handful of urological conditions where medical therapy is used to alleviate surgical outcomes or manage postoperative side effects or complications. This holds true for persistent LUTS post-radical prostatectomy since bladder dysfunction affects more than a third of the patients undergoing prostate cancer surgery. Although post-radical prostatectomy overactive bladder (post-RP OAB) has a non-negligible incidence ranging from 15.2-37.8% with a negative effect on patient’s quality of life, few studies have been conducted in order to evaluate response of post-RP OAB to pharmacotherapy. Sakalis and Gkotsi in the present issue have presented an excellent and detailed overview of the available evidence on the challenging management of post-RP OAB. Given the lack of relevant studies, current practice in post-RP OAB is mostly driven by the outcomes of medical treatment of the general population with OAB symptoms. A stepwise management algorithm is proposed starting with lifestyle modifications, behavioral therapy and pelvic floor muscle exercises which can result in up 50% improvement in symptoms. There is evidence that post-RP OAB may respond well to intravesical Botox injection provided that the patient is aware of the increased risk for the need of intermittent self-catheterization [2]. Although there are no studies on the efficacy of oral medications on the specific subgroup of patients with post-RP OAB symptoms, anticholinergics and PDE-5 inhibitors are used in this scenario. Also no studies in the post-RP OAB setting have examined the role of mirabegron, even though its efficacy in the general population with OAB appeared to be comparable to that of anticholinergics [2]. Duloxetine, a serotonin-noradrenaline reuptake inhibitor effective for SUI post RP, is known to suppress bladder activity in animal studies however no studies have examined its efficacy in storage LUTS post-RP. The few patients with refractory post-RP OAB should seek more invasive and complicated surgical procedures, namely urinary diversion or augmentation cystoplasty. This issue of CDT also deals with the management of patients with OAB refractory to bladder training and pharmacotherapy. Despite the availability of different classes of anticholinergics and recently b3-agonists, patient adherence to medical treatment of OAB remains low. According to a recent real world study on OAB patients on oral medications patient adherence was low after 1 year of treatment with adherence being better for mirabegron than for anticholinergics. The cause of this low adherence to therapy can be attributed to a number of reasons including patient’s unreasonable expectations from treatment, low compliance due to side effects and reduced efficacy of drugs over time. Several minimally invasive surgical procedures are available for patients with drug-resistant OAB. These therapies include intravesical botulinum toxin type A, posterior tibial nerve stimulation, and sacral neuromodulation without any clear superiority of one over another. The treatment algorithm for refractory OAB is dependent on several factors, including age, comorbidity, patient preference, surgical expertise, and financial concerns. However intravesical Botox injections is usually the first choice in cases of failure of medical therapy as the procedure is more familiar to the average urologist and requires less expertise and training. Therefore, as Botox injections for refractory to oral medications OAB are increasingly gaining ground in every day urological practice, Apostolidis et al. in the current issue of CDT have presented a very interesting and updated overview of the current indications, precautions, outcomes and reasons for failure of intravesical Botox injections [3]. According to Apostolidis et al. preoperative patient assessment is key for the identification of the best candidates for Botox as well as for appropriate patient consultation. Patients scheduled for Botox injections should be made aware of the risk of urinary tract infections, incomplete bladder emptying or even urinary retention and hence will need to be prepared and trained for the possibility of the need of, even temporary, intermittent self-catheterization. Although the definition of Botox failure is not clear Apostolidis et al. have proposed measures to avoid Botox failure by increasing the dose or shortening of injection intervals, particularly in neurogenic patients, switching to a different toxin or adding- on anticholinergics or b-3 agonists. In case of persistent non response, treatment with percutaneous tibial nerve stimulation or sacral neuromodulation are the next steps in the treatment algorithm [3]. Research in the field should focus on identification of pathogenetic mechanisms of failure, while clinical questions to be answered include the effect of previous anticholinergic treatment on Botox efficacy as well as whether repeated treatments result in a progressive decline or shorter duration in Botox efficacy. The last article published in the current issue discusses the interactions between medical and surgical therapy in advanced renal cancer. Cytoreductive nephrectomy is no longer the standard of care for patients with mRCC and intermediate-poor prognosis following the results of two major RCTs, namely the CARMENA and SURTIME trials. Modern era targeted therapy with TKIs, mTOR inhibitors and recently, immune checkpoint inhibitors should be the first option for the management of patients with mRCC with cytoreductive surgery reserved for cases with either local symptoms from the tumor or following adequate response to systematic treatment. Greco et al. discuss the evolution of medical therapies for mRCC from the era of interleukin- 2 and IFN-a to targeted therapies and towards immunotherapy [4]. There is evidence that treatment with a combination of immunotherapeutic agents, ipilimumab and nivolumab, is optimal to sunitinib for intermediate and poor risk patients. In this scenario, the role of cytoreductive nephrectomy may be expected to change again. The authors also provide insights into the current treatment algorithm for mRCC relevant to the optimal role, indications and sequencing of cytoreductive nephrectomy with medical therapy [4].

A systematic analysis published just recently [1] shows that the prevalence of inflammatory bowel diseases (IBD) increased considerably from 1990 to 2017 in many regions of the world. Moreover, the number of IBD cases worldwide has reached nearly 7 million. Along come millions of dollars spent on anti-IBD drug development, as well as patient care. Altogether, IBD has become a major social and economic burden for healthcare systems globally. Coping with the matter needs better diagnosis and treatment, which require primarily better understanding of the disease. This special issue discusses diagnostic and therapeutic potential of a wide range of molecules and approaches, from in vitro engineered stem cells to nutritional support, which may visualize IBD or affect its pathogenesis at the earliest stages possible. The issue starts with a review of the role of free fatty acid receptors in IBD and colitis-associated colorectal cancer [2]. Next, Binienda et al. [3] focus on the immune and epithelial stem cells, in view of both, their diagnostic and therapeutic potential. Tarasiuk and Eibl [4] examine the possible value of probiotics, prebiotics and symbiotics as well as nutritional support in treatment of IBD. Then, Stavely et al. [5] study bilateral relationships between the enteric nervous system and inflammation, including the effects and mechanisms of inflammation-induced enteric neuronal loss and plasticity. Additionally, they explore the role of enteric neurons in preventing antigenic/pathogenic insult and immunomodulation. Zatorski and Nakov [6] explain the principles and methodology in fecal microbiota transplantation used as a treatment of IBD and verify its efficacy. In the paper of Wang et al. [7], the concept of exosomes as a cell-free therapeutic approach is given full focus. The issue concludes with the paper by Makaro et al. [8], who discuss the current state of knowledge regarding genetic differences between sporadic and colitis- associated colorectal cancer and analyze the data from studies regarding the correlations between colitis-associated colorectal cancer and the presence of Single Nucleotide Polymorphisms. As of today, IBD is as seen a chronic and relapsing disease and it may still take several decades to cope with successfully. However, articles presented in this Special Issue give hope to patients that finding early detection options and an efficient cure is possible.

In 1994, The American Journal of Pathology published a key article reporting that hypoxic retina produces vascular endothelial growth factor (VEGF), sug- gesting a role for VEGF in ocular neovascularization [1]. Subsequently, several studies have demonstrated that VEGF is not only necessary but also sufficient to induce new vessels growth in the eye [2]. Based on these robust scientific data, Napoleone Ferrara at Genentech (South San Francisco, CA) developed the first humanized anti-VEGF antibody designed to block all VEGF isoforms (bevacizumab). This antibody was approved by the Food and Drug Administration (FDA) in 2004 for the treatment of colon cancer in combination with chemotherapy. In the same year, FDA also approved an RNA aptamer that binds and neutralizes VEGF165 (Pegaptanib - Macugen) for the treatment of neovascular age-related macular degeneration (nAMD). Afterwards ranibizumab (Lucentis) in 2006 and aflibercept (Eyelea) in 2011 were approved for the same disease. Moreover, bevacizumab, although licensed only for treating different types of cancers, has been used off-label in ophthalmology worldwild. With time, the use of these drugs was extended to many ocular conditions, including pathologic myopia, diabetic retinopathy, retinal vein occlusions, neovascular glaucoma, retinopathy of prematurity, idiopathic choroidal and corneal neovascularization. Anti-VEGF therapy has improved visual outcomes in many eye diseases and has changed the standard of care in ophthalmology in the last 15 years. The aim of this thematic issue is to retrace the story of anti-VEGF therapy for ocular diseases, showing the results obtained both in clinical trials and real life: • Battaglia Parodi M. et al. discuss the use of anti-VEGF molecules to treat two important complications of retinal dystrophies: choroidal neovascularization and macular edema [3]; • Vilela M.A.P reviews the results of anti-VEGF therapy in retinal vein occlusions [4]; • Giannaccare G. et al. highlight the efficacy and safety of the adoption of anti-VEGF agents into the daily clinical practice for the management of corneal neovascularization [5]; • Sorrentino F.S. et al. review recent advances by artificial intelligence for individualized anti-VEGF therapy in several eye diseases [6]. • The last paper (Campa C.) 5 new anti-VEGF drugs in an advanced stage of clinical development (conbercept, brolucizumab, port delivery system with ranibizumab, abicipar pegol and faricimab) are presented [7]. Finally, we are grateful to the Editor in Chief Prof. Francis J. Castellino and editorial manager K.M. Qamar of Current Drug Targets (Bentham Science Publishers) for their valualbe support to publish this thematic issue.

Epigenetics is defined as heritable changes in gene expression that do not result from an alteration in the DNA sequence itself [1]. DNA/RNA modification, histone variants and modifications, and nucleosome positioning work together to determine the epigenetic landscape of a cell. Until now, there is a growing awareness that epigenetic dysregulation plays a significant role in many types of diseases, and that is fueling an increasing number of studies into drugs that target epigenetic regulators, and several epigenetic targeted drugs have entered into clinic trials, including DNA methyltransferase inhibitor, bromo domain reader inhibitor, histone acetylase or deacetylase inhibitor, histone methyltransferase or demethylase inhibitor, deubiquitinase inhibitor or neddylation inhibitor. Among these modifiers, several of them have been approved for clinical use. For examples, DNMT inhibitors 5-azacytidine (5azaC) and 5-aza-2’-deoxycytidine (5azadC) have been approved for clinical use in haematological malignancies as myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML) and chronic myelomonocytic leukaemia (CMML) [2], vorinostat (Zolinza, SAHA) earned FDA approval for the treatment of cutaneous T-cell lymphoma (CTCL) as histone deacetylase (HDAC)1, 2, 3 and 6 inhibitor, panobinostat (Farydak) is the first HDAC inhibitor to gain approval for a nonlymphoma cancer, a unique natural product Romidepsin isolated from the bacterium Chromobacterium violaceum gained approval to treat both CTCL and peripheral T-cell lymphomas (PTCL) [3], tazemetostat (Tazverik, EPZ-6438, E7438) is the first epigenetic therapy to gain FDA approval in a solid tumor by targeting the S-adenosylmethionine (SAM, AdoMet) binding pocket of H3K27 methyltransferase Enhancer of zeste homolog 2 (EZH2) for epithelioid sarcoma treatment [4], et al. All these FDA approved drugs indicate that epigenetic modifications are promising therapeutic targets for solid tumors and hematological malignancies. Due to the fast-growing number of epigenetics and epigenetic targeted drugs, it is becoming a hot area in drug discovery for cancer therapy. This thematic issue aims to review about epigenetic modification related drug target, drug discovery, assay development, biological function, molecular modeling, target structure analysis, showing the progress of epigenetic modifications as therapeutic targets. Finally, we are grateful to the Editor in Chief Prof. Francis J. Castellino and editorial manager K.M. Qamar of Current Drug Targets (Bentham Science Publishers) for their valualbe support to publish this thematic issue.

Research on gynecological cancers particularly breast and tubo-ovarian cancers is evolving. Every year, randomized and controlled trials in the area of women’s cancer provide considerable improvements in survival outcomes. Moreover, previously known aggressive gynecological malignancies with poor outcomes are now reconsidered for novel treatments. However, drug resistance is a serious challenge for this significant progress. Notably, predictive and prognostic biomarkers are increasingly used to offer therapeutic decision-making in gynecological cancers especially with the remarkable advances in targeted therapies in the last decade such as antiangiogenics, poly-ADP-ribose polymerase (PARP) inhibitors and immune-checkpoint blockers [1-4]. With the emergence of precision medicine, the role of cancer biomarkers is promising as they enable the selection of the best treatment options for the right patients. FDA-approved predictive biomarkers such as BRCA mutational status and programmed death-ligand 1 (PD-L1) assays are enthusiastic examples of successful development of companion diagnostics. In this special issue and as a part of the scientific activities of our recently launched Cancer Biomarkers Working Group, many basic and clinical scientists from different countries were invited to participate in the review writing and share their experiences with this hot topic. Various areas in cancer biomarkers were covered, including proteomic biomarkers, liquid biopsy, genomic signatures, and other emerging biomarkers for several gynecological malignancies including breast cancer, ovarian cancer, endometrial cancer, and other types. Biomarkers that have potential impact on predicting prognosis, survival, and therapy response are discussed based on recently published findings from clinical trials and real-world studies. We strongly believe that our thematic issue will provide clinically actionable information for evidence-based practice in modern cancer management and potential perspectives for further research in gynecologic oncology. In the present thematic issue of Current Drug Targets, we were fortunate to team up reputed scientists from clinical, translational, and basic cancer research on gynecologic neoplasms to highlight important advances in this field of oncology: 1. Le Page et al. reviewed recent progress in biomarkers for serous ovarian cancer, particularly those who lead to new therapeutic strategies encompassing PARP inhibitors, immunotherapy and antiangiogenic drugs and provided potential perspectives for implementing personalized care in the future [5]. 2. Lengyel et al. summarized the role of and clinical impact of PI3K-AKT-mTOR signaling in ovarian and endometrial cancers and therefore, providing a rationale for further drug development in human clinical trials [6]. 3. Tazzite et al. reviewed the genomic predictors of outcomes in triple-negative breast cancer with a special focus on platinumbased chemotherapy which is the cornerstone in the management of this aggressive woman cancer [7]. 4. Souid et al. reviewed predictive biomarkers for a promising marine-derived anticancer drug (trabectedin) that showed clinical activity in various gynecological cancers with poor outcomes [8]. The authors focused their discussion on the mechanisms of action of trabectedin on multiple cancer hallmarks as well as the potential clinical outcomes from clinical trials and the genomic predictors of therapy response. 5. Gouri et al. discussed the prediction of late recurrence and distant metastasis in early-stage breast cancer based on current and emerging molecular signatures encompassing serum biomarkers and multigene profiling scores [9]. 6. The last paper (El Bairi et al.) from our team aimed to discuss the potential of the human epididymis protein 4 (HE4) as a promising prognostic biomarker for detecting recurrent epithelial ovarian cancer. This topic is highly important since the detection of early recurrence considerably impacts the survival outcomes of this aggressive woman’s cancer [10]. Finally, we would like to express our sincere appreciation to the Editor in Chief Prof. Francis J. Castellino, editorial manager K.M. Qamar, authors, reviewers, copy-editors and the entire editorial team of Current Drug Targets (Bentham Science Publishers) for their professionalism and providing support to publish this thematic issue on this emerging topic in modern oncology.

The integrity of skeleton homeostasis is preserved by a balance maintaining between the activity of osteogenesis and osteoclastogenesis. Document factors and stimuli have been determined involved in these two processes over the past century, however, further understanding for exploring the physiological and pathological cellular processes are imperative requirement. Here, in the current special theme issue, we have organize experts in the relevant fields to contribute novel understanding of osteoclastogenesis, potential detective and therapeutic targets for skeleton diseases. Five reviews included from the experts in the medical research and clinical therapeutic practice provided the novel understanding for osteoclastogenesis relevant disease development and detection, osteoclastic cellular functional regulating, intercellular signaling cascades and potential therapeutic natural compounds studies. Wang et al. [1] comprehensively reviewed various diagnostic targets for its role diagnosis rate of spinal tuberculosis. In this review, authors specifically presented the current novel progression of laboratory, imaging and gene detection in the diagnostic process of spinal tuberculosis last several years. Integrins in bone homeostasis, especially in osteoclastogenesis, have been taken as the novel and promising therapeutic drug target for bone loss diseases, such as: osteolysis. However, its cellular mechanism is still elusive. Kong et al. [2] collected and reviewed several novel studies on integrin and its sub-molecules ICAM-1 on bone homeostasis. Specifically, authors have focused on the ICAM-1 which might play dual effects on osteoclastognesis by directly affecting the adhesion of mature osteoclast and indirectly participates in the RANKL/RANK induced osteoclastic precursors differentiation. Although these results are still conducted by a series of studies for further demonstration, exploring the role of ICAM-1 in osteoclastogenesis will definitely provide promising therapeutic targets for treating bone loss diseases. Besides that, inflammation is the most common pathology in many orthopedic diseases, such as: rheumatoid arthritis (RA), osteoarthritis (OA) and inflammatory osteolysis. The leading factor of inflammation was considered as the differentiation of monocyte and the polarization of macrophage. However, various cytokines and different cell models could regulate this progress in some aspect. Liu et al. [3], therefore reviewed several cytokines and cell models, which lead to inflammatory orthopedic diseases via regulating monocytes and macrophages. This review extensively explored the potential therapeutic and drug targets for inflammatory induced bone diseases. Liu et al. [4] reviewed the current novel research progress of RANKL and its downstream signaling pathways in bone cells, and as an important drug target for its role in bone loss diseases. In this review, the authors also briefly introduced the current application of several natural compounds for treating RANKL-mediated osteoclastic activation by modulating the RANKL signaling pathway and their effects on the treatment and prevention of osteoporosis, OA and RA. Finally, Wang et al. [5] extensively reviewed the naturally occurring compounds with less or no side effects, for their role in the present clinical and fundamental study in osteoclastogenesis. We hope this thematic issue will be beneficial for the vast readers and could serve as a good source of literature for scholars in relevant study fields.

In continuation with computational advances in chronic diseases diagnostics and therapy – I [1], this part II consists of articles which contribute to develop new ideas, algorithm design and rational drug discovery techniques to antiviral drug targets of single-stranded ribonucleic acid (RNA) viruses, homeostasis in the cardiovascular system, ion channels as therapeutic targets for type 1 diabetes mellitus and amyloid beta (Aβ) in Alzheimer's disease (AD). Dinesh et al. [2] demonstrated that antiviral drug targets of single-stranded ribonucleic acid (RNA) viruses cause chronic human diseases. RNA containing viruses associated with chronic diseases in humans are major threats to public health causing high mortality globally. Extremely high mutation rates of RNA viruses make them deadliest and thus difficult to design an effective drug. Chronic infections caused by human immunodeficiency virus (HIV-1) and hepatitis virus (HBV and HCV) lead to acquired immunodeficiency syndrome (AIDS) and hepatocellular carcinoma, respectively, they are the primary cause of human deaths. Effective preventive measures to limit chronic and re-emerging viral infections are absolutely necessary; and remains a challenging issue. Antivirals usually inhibit different stages of the virus life-cycle, instead of killing them as in the case of the bacterial antibiotics. Most often antiviral drugs are targeted against specific viral and host protein, whereas a few broadspectrum drugs are available for targeting multiple viruses. In the recent past, an exponential increase in the number of available three-dimensional protein structures and advancements in the in silico approaches, have paved the way to design and develop several novel, highly specific small molecule inhibitors against protein drug targets. The present review briefly discussed about selected single-stranded (ss) RNA genome containing human pathogenic viruses, causing chronic infections and are of special importance for e.g. HIV-1, HCV, Flaviviruses, Ebola etc., their selected viral target proteins and an update about the available small-molecule inhibitors or antivirals acting against them have also been discussed. Singh and Karnik [3] clearly summarized homeostasis in the cardiovascular system maintained by physiological functions of the renin angiotensin aldosterone system (RAAS). In pathophysiological conditions, over activation of RAAS leads to an increase in the concentration of angiotensin II (AngII) and over activation of angiotensin type 1 receptor (AT1R) resulting in vasoconstriction, sodium retention and change in myocyte growth. In the heart, it causes cardiac remodeling which results in left ventricular hypertrophy, dilation and dysfunction which eventually leads to heart failure (HF). Inhibition of RAAS using angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) has shown to significantly reduce morbidity and mortality due to HF. ACEi have been shown to have higher drug withdrawal rates due to discomfort when compared to ARBs; therefore, ARBs are the preferred choice of physicians for the treatment of HF in combination with other antihypertensive agents. Out of eight FDA approved ARBs, irbesartan and telmisartan are shown to have PPARϒ agonistic properties resulting in improved insulin intolerance. Olmesartan treatment also improves insulin sensitivity and produces antiatherogenic and anti-inflammatory effects in patients with diabetic nephropathy. All the ARBs demonstrate beneficial effects similar to ACEi in the treatment of HF except the lower doses of losartan which leads to increase mortality in HF patients. Valsartan in combination with sacubitril therapy has shown to be a promising therapy for HF. Eprosartan has an effect on the sympathetic nervous system when compared to other ARBs and it is also able to reduce catecholamine release in animal models. Therefore, eprosartan therapy may have an additional beneficial effect in the treatment of heart failure. However, eprosartan has the shortest bioavailability (< 6 hours) when compared to other ARBs. Large numbers of studies that show beneficial effects on animals have been reported but there are limited studies on humans. Hence, more human studies are warranted. Recently, crystal structures of AT1R in inactive and active state structure have been solved. Using these crystal structures and cheminformatics tools, exploring structures similar to eprosartan with an increase in bioavailability and affinity may enhance the treatment of HF. The review of Selvaraj et al. [4] demonstrated ion channels as therapeutic targets for type 1 diabetes mellitus. Ion channels are integral proteins expressed in almost all living cells involved in muscle contraction and nutrient transport. It plays a critical role in the normal function of the excitable tissues of the nervous system and regulates the action potential and contraction events. Dysfunction of genes, which encodes ion channel proteins that disrupt the channel function, leads to a number of diseases, which include type 1 diabetes mellitus (T1DM). Therefore, to understand the complex mechanism of ion channel receptors it is necessary to facilitate the diagnosis and management of treatment. In this review, we summarizes the mechanism of important ion channels involved in T1DM and the role in the regulation of insulin secretion along with the limitations for ion channels as therapeutic targets. Furthermore, we discussed the recent investigations of mechanism regulating the ion channels in beta cells, which suggest that ions channels are active participants in the regulation of insulin secretion. Vijayan and C [5] discussed and summarized recent therapeutic strategies of amyloid beta (Aβ) in Alzheimer's disease (AD). AD is one of the most common forms of dementia and has been a global concern for several years. Due to the multifactorial nature of the disease, AD has become irreversible, fatal and imposes a tremendous socio-economic burden. Even though experimental medicines suggested moderate benefits, AD still lacks an effective treatment strategy for the management of symptoms or cure. Among various hypotheses which describe the development and progression of AD, the amyloid hypothesis has been a long-term adherent to the AD due to the involvement of various forms of Aβ peptides in the impairment of neuronal and cognitive functions. Hence, the majority of the drug discovery approaches in the past have focused on preventing the accumulation of Aβ peptides. Currently, there are several agents in the phase III clinical trials that target Aβ or the various macromolecules triggering Aβ deposition. Here, the author discussed some of the state-of-the- art knowledge on the functional aspects of the key players involved in the amyloid hypothesis. Furthermore, authors conferred about anti-amyloid agents present in phase III clinical trials. We hope multidisciplinary topics discussed with the theme issue will promote further discussions between the researchers of computational advances in chronic diseases diagnostics and therapy. As the guest editors, we would like to thank all the authors and co-authors for their excellent contributions. In addition, we would like to thank a group of scientific experts in computation and chronic diseases diagnostics and therapy who offered their strong comments and suggestions to improve the quality of this special issue. Finally, we would like to express our sincere appreciation to the Editor in Chief Prof. Francis J. Castellino, editorial manager K.M. Qamar, copy-editors and all the editorial staff in Current Drug Targets, Bentham Science Publishers for the excellent opportunity, and experience while working with this thematic issue.

Recently, omics data explosion is transforming diagnostics research and healthcare industry, offering both opportunities and challenges. Huge data of chronic disease diagnosis distributes equal IT challenges as in other fields, including data storage, transfer, access control, and management. Another challenge is the computational modeling of complex biological systems. High-throughput RNA-sequencing based transcriptomics, mass spectrometry based proteomics and nuclear magnetic resonance spectroscopy-mass spectra based metabolomics are the most common popular statistical approaches that can be used for biomarker detection of deadly diseases namely cancer, cardiovascular disease, and other chronic diseases, and to find out the composition of material that the cells obtain from their micro-environment. Many recent studies have successfully applied network models for describing and simplifying such complex systems. The proposed articles contribute to develop new ideas, algorithm design and rational drug discovery techniques to chronic diseases (cancer and cardiovascular disease, etc.) diagnostics and therapy. The first article demonstrated the importance of bioinformatics in anti-cancer drug discovery. High-throughput transcriptome data were widely used in biomarker identification and drug prediction by integrating with drug-response data. In addition, biological network theory and methodology were also successfully applied to the anti-cancer drug discovery, such as studies based on protein-protein interaction network, drug-target network and disease-gene network. Moreover, the authors discussed different bioinformatics approaches for predicting anti-cancer drugs and drug combinations based on the multi-omic data includes transcriptomics, toxicogenomics, function genomics and biological network. Further, the authors overviewed the available databases and current computational methods assisting in the development of novel cancer therapy strategies [1]. Loganathan et al. [2] summarized and discussed the computational and pharmacogenomics insights into hypertension treatment towards rational drug design and optimization strategies. Among hypertension-related signaling mechanisms, the reninangiotensin- aldosterone system is the leading genetic target for hypertension treatment. Identifying a single drug that acts on multiple targets is an emerging strategy for hypertension treatment and could be achieved by discovering potential targets with less mutation and highly conserved regions. Expanding pharmacogenomics research to include patients with hypertension receiving multiple antihypertensive drugs could assist in identifying the genetic markers of hypertension. However, available evidence on pharmacogenomics role in hypertension is limited and primarily focused on candidate genes. Genetic association studies have identified single nucleotide polymorphisms affecting drug responses. To understand how genetic traits alter drug responses, computational screening of mutagenesis can be utilized to observe drug response variations at the protein level, which can help identify new inhibitors and drug targets to manage hypertension. Rational drug design facilitates the discovery and design of potent inhibitors. However, further research and clinical validation are required before novel inhibitors can be clinically used as antihypertensive therapies. Fu et al. [3] systematically reviewed in light of this, the label-free quantification proteomics (LFQ) and diabetic marker selection methods have been applied to elucidate the underlying mechanisms associated with insulin resistance, explore novel protein biomarkers, and discover innovative therapeutic protein targets. Firstly, different popular quantification measurements and proteomic quantification tools have been applied to the diabetes studies which are comprehensively discussed. Secondly, a number of popular manipulation methods including transformation, pretreatment (centering, scaling, and normalization), missing value imputation methods and a variety of popular feature selection techniques applied to diabetes proteomic data are overviewed with objective evaluation on their advantages and disadvantage. Finally, the guidelines for the efficient use of the computation- based LFQ technology and feature selection methods in diabetes proteomics are proposed. Finally, the authors have provided guidelines for the researchers who are engaged in proteomics biomarker discovery and by properly applying these proteomic computational advances, more reliable therapeutic targets can be found in the field of diabetes mellitus. Calcium (Ca2+) ion is a major intracellular signaling messenger, controlling a diverse array of cellular functions like gene expression, secretion, cell growth, proliferation, and apoptosis. This review aims to provide the key structural and mechanical insights of stromal interaction molecule (STIM), ORAI1 and other molecular modulators involved in Ca2+ release-activated Ca2+ (CRAC) channel regulation. Understanding the structure and function of the protein is the foremost step towards improving the effective target specificity by limiting their potential side effects. The major mechanism controlling the Ca2+ homeostasis is store-operated CRAC channels. Following Ca2+ depletion in the Endoplasmic reticulum (ER) store, STIM1 interacts with ORAI1 and leads to the opening of the CRAC channel gate and consequently allows the influx of Ca2+ ions. A plethora of studies reported that aberrant CRAC channel activity due to loss-or-gain-of-function mutations in ORAI1 and STIM1 disturbs this Ca2+ homeostasis and causes several autoimmune disorders. Hence, it is clearly defined that the therapeutic target of CRAC channels provides the space for a new approach to treat autoimmune disorders. Herein, the authors mainly focused on the structural underpinnings of the CRAC channel gating mechanism along with its biophysical properties that would provide a solid foundation to aid the development of novel targeted drugs for an autoimmune disorder. Finally, the immune deficiencies caused due to mutations in CRAC channel and currently used pharmacological blockers with their limitations are briefly summarized [4]. The last article discussed about the computational strategy revealing the structural determinant of ligand selectivity towards highly similar protein targets [5]. Poor selectivity of drug candidates may lead to toxicity and side effects accounting for as high as 60% failure rate, thus selectivity is consistently significant and challenging for drug discovery. To find highly specific small molecules towards very similar protein targets, multiple strategies are always employed, including (1) To make use of the diverse shape of binding pocket to avoid steric bump; (2) To increase binding affinities for favorite residues; (3) To achieve selectivity through allosteric regulation of target; (4) To stabilize the inactive conformation of protein target and (5) To occupy dual binding pockets of single target. Here, the authors summarized computational strategies along with examples of their successful applications in designing selective ligands, with the aim to provide insights into ever-diversifying drug development practice and inspire medicinal chemists to utilize computational strategies to avoid potential side effects due to low selectivity of ligands. We hope that multidisciplinary topics discussed with the theme issue will promote further discussion between the researchers of computational advances in diagnostics and therapy of chronic diseases. As the guest editors, we would like to thank all the authors and co-authors for their excellent contributions. In addition, we would like to thank a group of scientific experts in computation and chronic diseases’ diagnostics and therapy, who offered their strong comments and suggestions to improve the quality of this special issue. Finally, we would like to express our sincere appreciation to the Editor in Chief Prof. Francis J. Castellino, editorial manager K.M. Qamar, copy-editors and the entire editorial staff of the Current Drug Targets, Bentham Science Publishers for the excellent opportunity, and the wonderful experience we had while working with this thematic issue.

The incidence and prevalence of Inflammatory bowel diseases (IBD), represented by Crohn's disease (CD) and ulcerative colitis (UC) are globally increasing over the past few decades [1]. Surgery is still needed in a significant number of IBD patients and represents an important therapeutic tool in the management of both diseases [2, 3]. Surgical rates are decreasing over time following the overspread use of biological agents, such as anti-TNFs, anti-IL-23 or anti-integrins [4]. However, proper care and a timely indication for these new agents vary across the world [5]. In parallel, the evolving role of surgery in IBD management is noteworthy [6]. In 2019, management of IBD and its disease complications often require a combined medical and surgical approach. As a consequence, surgical participation interacting with gastroenterologists in the care of IBD patients is essential in the multidisciplinary management of CD and UC. The correct timing of surgical indication in IBD is essential to maximize the benefits for the patients. As an example, it is not uncommon to see patients with fibrotic disease, which can be managed surgically, being treated with medical therapy. This can be observed in centers where there is no interaction between colorectal surgeons and IBD gastroenterologists, where patients sit in an uncomfortable position between both specialties with no proper communication between the specialists. Clearly, the efficacy of medication will be lower in these situations, leading to a delay in surgical indication, with malnourished patients, resulting in higher postoperative complication rates. In this issue of Current Drug Targets, entitled “Medical-surgical approach in inflammatory bowel disease: doing it together!", several specific situations where the joint care of IBD patients including surgeons and gastroenterologists is optimized are discussed in detail. Perioperative therapy with different drugs, as steroids, immunomodulators and biologics, is explored in different scenarios. The evidence clearly demonstrates that preoperative steroids do worsen postoperative outcomes in both CD and UC. Immunomodulators, such as azathioprine, can be safely used in the perioperative period, with no impact on postoperative infections. Evidence with different classes of biologics also demonstrates the controversy regarding these agents, where conflicting evidence exploring the impact of anti-TNFs, anti-integrins and anti-interleukins in postoperative complications demonstrates the need for a tailored approach in a case-by-case basis. When to initiate or re-initiate biologics after surgery in CD? This is also another example of the need for a close relationship between medical and surgical care specialists. Other situations in IBD also benefit from multidisciplinary team (MDT) frequent discussions. A perfect example of that is the management of perianal CD, usually a challenging scenario for patients and health care specialists. Several sequential steps are needed aiming better outcomes to these patients. A proper diagnosis, with adequate imaging tests, followed by early referral for surgical preparation with curettage of fistula tracks, placement of setons and eradication of perianal sepsis before initiation of biological therapy, exemplify different specialties that are involved in the management of this important phenotype of CD. Radiologists, gastroenterologists and surgeons sitting together, having joint clinics, and discussing each case on a multidisciplinary basis, can lead to optimized outcomes by improving patients' quality of life, which is one of the important treatment goals in this scenario. In UC, the need for joint efforts between gastroenterologists and surgeons can also improve the outcomes for patients. Usually, patients are exhausted with multiple medications, with an impaired nutritional status when they finally have referrals for colectomy. This often impacts a change in the surgical strategy, where staging operations and delaying pouch construction can represent a safer alternative, with decreased major postoperative complications. Involvement of surgeons early in admissions for severe colitis, aiming early recognition of complications, such as toxic megacolon and blocked perforations can also contribute for proper timing of surgery. It is known that a delay in colectomy in this specific scenario increases significant morbidity and mortality, and this can be avoided by a proximal relation between specialists in the MDTs. Therefore, discussion regarding the proper timing of surgery and the specific medications used perioperatively can lead to individualized decisions and need to be discussed between different specialties also in UC. (Table 1) summarizes some of the main indications and specific advantages of joint MDT care in IBD.

The 21st century has seen a massive spring up in the applications of nanotechnology. Incorporation of functionalized and modified nanostructures in various biomedical applications has generated significant research interest. The applications of nanotechnology in medicine and biomedical engineering are vast and span areas such as implant and tissue engineering, diagnosis and therapy. There is a need of designing nanotools, which can respond to the needs of health problems and develop more efficient biomedical approaches. The present special issue includes four articles with the goal of reviewing the recent developments in nanobiotechnology with special emphasis on novel tissue engineered scaffolds and the development of nanonetworks as new communication tools for medical approaches. Nanomaterials are also at the leading edge of the rapidly developing field of nanotechnology. In particular, Marzo J.L. et al. started the thematic issue with a very innovative perspective. Marzo J.L. et al. reviewed the IT systems and networks’ role in medical applications and how nanostructures can contribute medical services. As a perspective of IT on medical field, Laromaine, A. and Roig A. reviewed biomedical application by challenging materials, which can help in tissue treatment. In fact, the paper is focused on new developments in organic material such as cellulose to repair epithelial tissues. In their article, Dean D. et al. focused on tissue regeneration as well. However, their focus as not only on materials which are synthetic and not organic, but on new technologies such as 3D printing methods. A combination of materials and technologies has been summarized to rebuilt biomedical implants. Finally, Puig M et al. reviewed the potential of different biocompatible materials such as PCL and PLA to manufacture scaffolds for cell culture. Cell culture in 3D mimics better the human body cells, thus it helps in the cells enrichment, and thus, the cancer cells characterization with the idea of targeting new treatments. Overall, the aim of this issue is to offering new data to investigators to help them realize about the most recent developments in the field of applied nanomaterials in biomedicine from different perspectives. In addition, the safety aspects in the applications of nanotechnology to biomedical practical applications have also been examined. We greatly acknowledge the Editor-in-Chief, Francis J. Costellino and Bentham Science Publisher for their continuous encouragement and professional support throughout the preparation of this special issue. Finally, we would like to thank all the authors and all the referees for their availability and their thorough evaluations of the articles published in this issue.

With the development of high-throughput sequencing techniques, more and more sequencing data is available, including genomics reads, transcriptomes data, and proteomics sequences, which provide us an opportunity for disease treatment and prevention that takes into account individual variability in environment, lifestyle and genes for each person. Thus, it is critical to develop various methods in the identification of drug targets. Application of computational methods in drugs targets discovery is more and more popular because these techniques can extract the essential characteristics of research object and improve accuracies of models, which is needed by all biological scholars. This special issue will focus on various aspects of the development and application of machine learning techniques in drug targets recognition analysis.

The complete perspectives of bio-psycho-social standing of pharmacological agents are the key-features in the observation how a drug act. This thoughtful approach is indeed imperative when managing patient's anticipation and expectation, especially during the disease process and recuperation process. In clinical practice, the core knowledge on the art of prescribing drugs and understanding their current drug targets in vivo and vitro can be very helpful. Hence, it may help the physician to choose the right pharmacological agents in the therapeutic alliance. Research has robustly documented the role of the bio-psycho-social contributing factor, and how they may influence an individual’s experience of receptor targets for the prescribed drugs. The purpose of bio-psycho-social contribution, i.e. relationships between drug-drug interactions are worth to be understood when prescribing antidepressants among patients with erectile dysfunction, as the former is associated with a significant sexual dysfunction. Sexual dysfunction is also seen among women and the role agent to promote sexual desire is considered pivotal in the intimacy-relationship domain. The cognition and emotional states are essential in managing patients with morbid jealousy, the ‘green-eyed monster’. Cognitive-emotion domain is also important in addressing problems of a substance-use disorder. Kratom, one of the prevalent substance-use disorders in South-East Asian countries are an example of the problematic dilemma in an attempt to balance between the side-effects and the benefit as a pain-killers. Another substance-use problem of nicotine dependence will be discussed in this segment of thematic issue, especially in relation to patients with mental-health issues. We also discussed the role of bupropion in helping patients with an Adult Attention Deficit Hyperactive Disorder, besides prescribing a psychostimulant to reward the pleasure centre of the brain. Changes in the body, as the result of menopause also will be outlined on the role of Phytoestrogens, the Thermoregulatory Mechanism.

The holistic standpoint of biopsychosocial importance of mediation is crucial in terms of the perception regarding how the psychopharmacological agent acts. This understanding is indeed important when dealing with patient's expectation and hope, specifically during their illness and recovery process. In clinical setting, the fundamental knowledge of know-how art of prescribing medication and dietary advice can be of great help in the real-world practice of medicine. Subsequently, this manoeuvre may influence the choice of the pharmacological agents, dietary choice of intake and managing the adverse-effect of the existing drug intervention routine. The relationship of the mind-body is well described in the literature especially in the context of pharmacological therapy. The relationship is important in order to be understood for the management of patients in the clinical settings. Research studies have been conducted to ascertain the role of the psychosocial contributing factors, and how they may influence an individual’s experience of drug targets. In this thematic issue, the articles focussed on the role of drug targets, which was augmented by the emotional-cognitive and behavioral mediation in enhancing the effects of biological therapy. Emotionalcognitive determinants may influence the processing of neurochemical actions, e.g. the dopamine-oxytocin-nitric oxide neural pathway in patients who were given treatment in order to improve their sexual intimacy with his or her partner. These determinants are also relevant while elaborating the role of psychopharmacological agents in alleviating the patient’s somatic symptoms. Behavioural modification advice may help patients regain their self-confidence in their journey to recovery, despite petite guidance given by the clinician. The purpose of biopsychopsychological input, i.e. intimacy-relationship, cognition and emotional states is important in helping the patient’s self-esteem with successful treatment of the PDE-5 inhibitors. Selecting the right psychopharmacological agents to reduce the sexual-adverse effect of drugs is essential in patients with both depression and schizophrenia. The roles of new novel antidepressants are portrayed in their multi-modality function to treat depression. Antidepressant’s effect on managing physical symptoms is important. The stress model diathesis of alcohol in mental health was underlined with the perspective of neuronal basis of cognition memory. In the present thematic issue, the association of serotonin selective reuptake inhibitors and female sexual dysfunction was discussed with special emphasis on its treatment. Interesting articles on the antinociceptive effect of Mitragyna speciosa, the phosphodiasterase 5-inhibitors (PDE-5i) for erectile dysfunction, the recent approaches on treatment of alcohol addiction, the neurobiology of hypersexuality and its treatment, role of atypical antipsychotics in sexuality, treatment of anxiety disorders with Vortioxetine and the role of dietary compounds in the treatment of anxiety disorders were highlighted. Last but not the least, the present issue also focused on the use of antidepressants for physical and psychological symptoms in cancer and discussed the dietary issue in the biopsychopsychological context of treatment, which included tocopherol and tocotrienol.

Abdominal aortic aneurysm (AAA) is a common inflammatory cardiovascular disease among the elderly [1]. Since the 1990s, several animal models have been developed and basic researches have been conducted to understand the pathological conditions [2]. Many molecules and drugs that inhibit the activity of MMPs and suppress the formation of aortic aneurysms were found in these animal models [3]. In particular, those which inhibit c-Jun N-terminal kinase and suppress the activity of MMPs, regressed aortic aneurysms in animal models, and were considered as promising therapeutic drugs [4]. However, the pathogenesis of AAA still remains unknown. Therefore, “no” drug treatments of AAA have been approved in clinical practice, so that surgery is currently the only treatment of AAA [2]. The established animal models of AAA have been employed to advance the understanding of the mechanisms in order to identify potential treatment targets [5]. And the models are constructed by inducing inflammatory responses by using substances such as Angiotensin II, CaCl2 and elastase, because inflammation of the medial region and vulnerable vessel walls are recognized as the main cause of AAA development [3]. However, the upstream factor of inflammation associated with the development of AAA remains unknown. More importantly, there is debate that there are discrepancies in the pathological findings between humans and established animal models used in AAA research. Similarities in the pathogenesis between human AAA and animal AAA models are essential for the development of pharmacological treatments. In order to have a better opinion of experimental study using animal model and to introduce novel methodology and tool for AAA samples, we would like to have specials relating to present and future of pharmacological therapy for AAA. At present, there are few clinical trials associated with AAA. However, several pharmaceutical companies are interested in testing therapies for AAA. There are as yet not few researchers studying AAA. I believe that lots of readers take a considerable interest in AAA research through the special feature.

Cardiometabolic syndrome refers to a group of cardiometabolic risk factors that greatly increase the risk for cardiovascular diseases and other health problems. As per the consensus of the National Heart, Lung and Blood Institute (NHLBI) and American Heart Association (AHA), cardiometabolic syndrome is a constellation of 3 or more of the following risk factors: abdominal obesity, high triglycerides, dyslipidemia (low- and high-density lipoprotein cholesterol), hypertension, and elevated fasting blood glucose [1]. At this time, the therapeutic strategies are mainly aimed at the management of individual risk factors including dyslipidemia, hypertension and diabetes [2]. With the ever-rising prevalence of cardiovascular anomalies including cardiac hypertrophy, hypertension, arrhythmias, and heart failure in cardiometabolic diseases [3], it is pertinent to identify and develop novel diagnostic and therapeutic techniques to better manage the cardiovascular risk in cardiometabolic diseases. For example, the recent application of the new class of anti-diabetic drugs sodium glucose co-transporter 2 (SGLT2) inhibitors has greatly improved the cardiovascular benefits for drugs targeting cardiometabolic syndrome [4]. Here we will present this special issue of “Current Drug Target” on “Drug discovery and development in the management cardiometabolic diseases” to discuss a number of new therapeutic options in the field. Our enthusiasm for this topic came from the profound opportunities for novel therapeutic concepts in cardiometabolic diseases. It is essential to broaden our understanding for the precise mechanisms behind these therapeutic modalities in the management of cardiometabolic diseases. In the first review article of this series, Li and colleagues discussed the pivotal role of ubiquitin (Ub) and ubiquitin-like proteins (UBLs)-associated post-translational modification in the regulation of protein function in cardiac cells. Conjugation of Ub or UBLs to target proteins may modulate both physical and physiological properties of protein substrates, thus governing a number of disease processes including cardiac diseases [5]. In the second article, Zhu and Zhang reviewed how the interplay between apoptosis and autophagy controls cell death or proliferation in vascular smooth muscle cells, neointimal hyperplasia and restenosis pathogenesis [6]. In the third article of this series, the authors also shed light on the conservative autophagy process to provide some valuable insights into the potential mechanism of autophagy in the onset and development of rheumatic autoimmune diseases [7]. In the fourth article, the authors discussed the forefront of pancreatic cancer treatment, and the potential role of pargeting autophagy in therapeutics against pancreatic cancer [8]. Autophagy has recently drawn some attention as a novel drug target in the management of cardiovascular and metabolic diseases [9], although the potential of autophagy in drug development may be a daunting process for cardiometabolic and other human disorders. In the fifth review, Janardhanan reported that endocrine disrupting chemicals impair physiological homeostasis, leading to developmental and reproductive abnormalities. Ample evidence has validated the significance of exposure to endocrine disrupting chemicals in cardiometabolic disorders [10]. In the next article, Chen and associates discussed the promises of ApoE4 as a potential target for the management of coronary heart disease and Alzheimer's disease. Carriers of the ApoE4 allele seem to display hypercholesterolemia, which would accelerate the progression of coronary atherosclerosis and Alzheimer’s disease. They have discussed the interconnection between coronary heart disease and the devastating neurodegenerative diseases [11]. In the seventh article, Ceylan and colleagues discussed the SGLT2 inhibitors as the new class of antidiabetic agents, and possible advantages of the new SGLT2 inhibitors over the traditional hypoglycemic agents in the control of body weight, blood pressure and hyperuricemia [12]. In the eighth article, the authors revisited the recent clinical trials on SGLT2 inhibitors including empagliflozin and canagliflozin and highlighted the cardiovascular benefits of these SGLT2 inhibitors in type 2 diabetic patients. They dissected the regulatory roles of SGLT2 inhibitors in energy metabolism and cardiovascular function, and factors that may compromise the therapeutic benefit [13]. In the ninth article, Obradovic and colleagues discussed the potential role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in the treatment of hypercholesterolemia. They also highlighted the potential opportunities and challenges in targeting PCSK9 in the clinical settings [14]. In the next article, Kobayashi and colleagues discussed the role of iron as a risk factor for coronary artery disease, in particularly whether iron is toxic or not in patients with coronary heart diseases [15]. In the last article of this series, Feng and colleagues from Fuwai Hospital reviewed the recent concept and knowledge of non-cardiomyocytes in the regulation of cardiomyocyte proliferation and differentiation during postnatal cardiac regeneration, in an effort to identify potential targets for the treatment of heart failure [16]. Although our special issue has updated some of the recent hot topics in the understanding of cardiometabolic diseases, it leaves behind much more unanswered questions that remain to be explored with intense research effort in future. First, cardiometabolic syndrome is not a disease entity, thus making it rather challenging to formulate a unified therapeutic regimen for a given individual with cardiometabolic diseases. Second, experimental animal or cell culture models for cardiometabolic diseases may not be able to recapitulate the true pathological changes under clinical settings. Therefore, the translation of knowledge from bench-side to the bed-side practice remains a long journey. Third, given the complexity and multiple independent risk factors in the etiology of cardiometabolic diseases, it is almost impossible to rule a particular intervention to be superior than others, letting alone the option of life style modification as a key element in the management of cardiometabolic syndrome (not included in our special issue considering the central theme). We would hope that this special series will help the scientific society to identify novel therapeutic targets or concepts in the management of cardiometabolic diseases.

The holistic perspective of bio-psychosocial dimension of intervention is important to understand how the psychopharmacological agent works. In this thematic issue, we highlight the role of psychological and behavioural intervention to augment the effects of current drug targets. The articles highlight the role of psychological perspective in understanding emotional responses, cognitive-memory and vitality of the biological therapy. The role of psychological input, i.e. psychosexual and intimacy is vital to help the patient regain full recovery with the PDE- 5 inhibitors treatment. Cognitive and counselling will enhance the treatment for women with vaginismus. Vitamin D and hormonal preparation improves the individual's vitality. Regarding cancer patients, methylphenidate have a role for better recovery in the treatment outcome. In addiction and Alzheimer disease, the common pathway for the human memory is better understood. Knowledge of the pharmacokinetic of drug will surely improve the treatment strategy for psychotropic agents in psychosis.

Inflammatory Bowel Disease (IBD) is a frequent, chronic, incurable and disabling condition [1]. Personalized medicine is a unique opportunity to face these health challenges in the new millennium. The use of personalized medicine will allow the physician to select the best treatment protocol and will avoid passing the expense and risks of unnecessary medical treatments that are not properly metabolized nor are the cause of disease complications. The identification of predictors (biomarkers) of efficacy and safety of biologics as well as predictors of disease progression is a prerequisite to the development of strategies tailored to each individual. It is worth noting the quasi-absence of biomarkers of responsiveness to therapies despite the relatively limited success of biologicals available to treat IBD. Identifying predictors of disease progression and of safety/efficacy of biologics is the next step toward personalized medicine before determining the right dose for a patient, helping to avoid hazards. In this issue of Current Drug Targets dedicated to personalized medicine in IBD, we review many aspects of the future of IBD management and discuss whether we can predict disease course with clinical factors [2] and improve the safety profile of drugs [3] using a personalized approach. Non-invasive monitoring of IBD patients and the clinical utility of therapeutic drug monitoring of biologics and serological markers in clinical practice remain a matter of debate in 2016 [4-7]. The final aim of personalized medicine is to improve quality of care of IBD patients. This will lead to evolving treatment algorithms in the preand post-operative setting for these patients [8-11]. Embarking the patient into the management plan is the key to success. In this regard, personalized psychological treatment of IBD patients should be systematically considered in routine practice.

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