Targeting GPCRs & their Signaling as a Therapeutic Option in Melanoma

G protein-coupled receptors (GPCRs) serve prominent roles in melanocyte lineage physiology, with an impact at all stages of development, as well as on mature melanocyte functions. GPCR ligands are present in the skin and regulate melanocyte homeostasis, including pigmentation. The role of GPCRs in the regulation of pigmentation and, consequently, protection against external aggression, such as ultraviolet radiation, has long been established. However, evidence of new functions of GPCRs directly in melanomagenesis has been highlighted in recent years. GPCRs are coupled, through their intracellular domains, to heterotrimeric G proteins, which induce cellular signaling through various pathways. Such signaling modulates essential cellular processes of melanomagenesis, such as proliferation and migration. GPCR-associated signaling in melanoma can be activated by the binding of paracrine factors to their receptors or directly by activating mutations. In this review, we present melanoma-associated alterations of GPCRs and their downstream signaling and discuss the various preclinical models used to evaluate new therapeutic approaches against GPCR activity in melanoma. Recent striking advances in our understanding of the structure, function, and regulation of GPCRs will undoubtedly broaden treatment options in melanoma in the future.

Effects of treatment with SGLT-2 inhibitors on arginine-related cardiovascular and renal biomarkers

Background In patients with type 2 diabetes (T2D) sodium-glucose cotransporter 2 (SGLT-2) inhibitors improve glycaemic control as well as cardiovascular and renal outcomes. Their effects on l-arginine (Arg) related risk markers asymmetric and symmetric dimethylarginine (ADMA and SDMA) and the protective biomarker L-homoarginine (hArg) linking T2D to cardiovascular and renal disease have not yet been reported. Methods Plasma and 24-h urine samples taken before and after 6 weeks of treatment were available from two prospective, randomized, double-blind, placebo-controlled, cross-over trials with empagliflozin (71 patients analyzed, NCT02471963) and dapagliflozin (59 patients analyzed, NCT02383238). In these samples, concentrations of hArg, Arg, ADMA, SDMA, and creatinine were determined by liquid-chromatography coupled to tandem mass-spectrometry. Additionally, intraindividual changes of the biomarkers in plasma were correlated with intraindividual changes of clinical parameters. Results Treatment with empagliflozin and dapagliflozin was associated with a reduction of plasma hArg by 17.5% and 13.7% (both p < 0.001), respectively, and increase in plasma SDMA concentration of 6.7% and 3.6%, respectively (p < 0.001 and p < 0.05), while plasma Arg and ADMA concentrations were not significantly altered. 24-h urinary excretion of ADMA was reduced by 15.2% after treatment with empagliflozin (p < 0.001) but not after dapagliflozin treatment, while excretion of the other markers was not significantly altered. Renal clearance of SDMA was reduced by 9.1% and 3.9% for both drugs (both p < 0.05). A reduction in ADMA clearance was observable after empagliflozin treatment only (− 15.5%, p < 0.001), but not after dapagliflozin. Renal clearance of hArg and Arg was not significantly altered. Treatment effects on l-arginine related biomarkers were not constantly correlated with effects on glycated hemoglobin, fasting plasma glucose, body mass index, and systolic blood pressure. Conclusions Treatment with SGLT-2 inhibitors has divergent effects on Arg-related biomarkers and could affect risk estimates associated with these markers. The observed effects are unlikely to explain the known cardiovascular and renal benefits of treatment with empagliflozin or dapagliflozin but still may indicate new therapeutic approaches in patients treated with SGLT-2 inhibitors. Trial registrationhttp://www.clinicaltrials.gov: NCT02471963 (registered 15th June 2015, retrospectively registered) and NCT02383238.

The role of advanced glycation end products in patogenesis of diabetic nephropathy

Diabetes mellitus (DM) and chronic kidney disease are the diseases that have exceeded epidemic thresholds in terms of prevalence all over the world. That made it possible to classify them as non-communicable epidemics of the XXI century. Diabetic nephropathy (DN) is implicated with high levels of disablement and mortality. Advanced glycation end products (AGE) play a key role in the progression of DN. Increased formation of AGE occurs due to hyperglycemia under the conditions of diabetes. Moreover, there are additional factors in DN that increase the elaboration of AGE, such as high levels of oxidative stress and decreased renal clearance which slows down the AGE excretion. Both immediate effects of AGE and interaction of AGE with its cell-bound receptor (RAGE) result in a сascade of events that lead to further progression of DN. Thus, the research of the new therapeutic approaches targeted on the AGE-RAGE system is of great interest to slow progression of DN and improve the prognosis.

Emerging actionable targets to treat therapy-resistant colorectal cancers

In the last two decades major improvements have been reached in the early diagnosis of colorectal cancer (CRC) and, besides chemotherapy, an ampler choice of therapeutic approaches is now available, including targeted and immunotherapy. Despite that, CRC remains a “big killer” mainly due to the development of resistance to therapies, especially when the disease is diagnosed after it is already metastatic. At the same time, our knowledge of the mechanisms underlying resistance has been rapidly expanding which allows the development of novel therapeutic options in order to overcome it. As far as resistance to chemotherapy is concerned, several contributors have been identified such as: intake/efflux systems upregulation; alterations in the DNA damage response, due to defect in the DNA checkpoint and repair systems; dysregulation of the expression of apoptotic/anti-apoptotic members of the BCL2 family; overexpression of oncogenic kinases; the presence of cancer stem cells; and the composition of the tumoral microenvironment and that of the gut microbiota. Interestingly, several mechanisms are also involved in the resistance to targeted and/or immunotherapy. For example, overexpression and/or hyperactivation and/or amplification of oncogenic kinases can sustain resistance to targeted therapy whereas the composition of the gut microbiota, as well as that of the tumoral niche, and defects in DNA repair systems are crucial for determining the response to immunotherapy. In this review we will make an overview of the main resistance mechanisms identified so far and of the new therapeutic approaches to overcome it.

ДОСВІД ВИКОРИСТАННЯ ШКАЛИ ЗАГАЛЬНОЇ ОЦІНКИ ФУНКЦІОНУВАННЯ ДЛЯ ДІАГНОСТИКИ І ПЛАНУВАННЯ ПСИХОТЕРАПІЇ В НАРКОЛОГІЧНІЙ ПРАКТИЦІ

Significant consequences of alcohol abuse give grounds to classify alcohol dependence as a medical and social pathology that poses a danger to society. The number of patients registered in medical dispensaries in Ukraine reaches 1 million. Recurrences of the disease during the year after treatment are observed in 60-75% of patients with alcohol dependence. The problem is exacerbated by the medical and social consequences of alcohol abuse in the form of increased mental and physical illness, trauma, suicide attempts and aggressive behavior, criminal acts. This renders the search for new therapeutic approaches to the treatment of alcohol dependence relevant. The aim of the study was to examine the feasibility and effectiveness of using the global assessment of functioning scale (GAFS) to diagnose the dynamics of social functioning of patients with alcohol dependence. The study of the dynamics in the level of general functioning with the use of GAFS in the main and control groups yielded the following results. There was a significant increase in psychological, social and professional functioning in 74.0% of patients in whom a system of treatment and prophylactic measures was applied as compared to 46.7% of patients in the comparison group (χ2 = 6.062, p <0.05). A follow-up study showed that the number of persistent remissions was by 2 times higher in the main group than in the comparison group, 54.0% and 23.3%, respectively (p <0.001).

Envisioning Post-pandemic Digital Neurological, Psychiatric and Mental Health Care

The SARS-Cov-2 pandemic placed a dramatic burden on managed healthcare and perhaps nowhere as evident as in neurological and psychiatric disease care. This said, the duration of the pandemic mandated adaptability of the entire care system and the oft-vaunted benefits of telehealth and telemedicine were subjected to deep scrutiny at scale. Positive experiences were reported by both patients and providers from routine check-ups, to use of cognitive behavioral therapy associated with mental disorders, and management of complex diseases such as multiple sclerosis and other neurological and psychiatric conditions. Integration into standard care looks likely in the post pandemic era with many healthcare systems moving to expand reimbursement categories and develop equitable incentive models for developers and providers. In this commentary we share perspective on how the future of care may evolve through hybrid delivery models, and the advent of new therapeutic approaches which can address pain points identified during the pandemic.

Diabetic kidney disease in children and adolescents: an update

Diabetic kidney disease (DKD), previously encountered predominantly in adult patients, is rapidly gaining center stage as a childhood morbidity and one that pediatric nephrologists are likely to encounter with increasing frequency. This is in large part due to the obesity epidemic and the consequent rise in type 2 diabetes in children and adolescents, as well as the more aggressive diabetes phenotype in today’s youth with more rapid β-cell decline and faster development and progression of diabetes-related complications along with lower responsiveness to the treatments used in adults. DKD, an end-organ complication of diabetes, is at the very least a marker of, and more likely a predisposing factor for, the development of adverse cardiovascular outcomes and premature mortality in children with diabetes. On an optimistic note, several new therapeutic approaches are now available for the management of diabetes in adults, such as GLP1 receptor agonists, SGLT2 inhibitors, and DPP4 inhibitors, that have also been shown to have a favorable impact on cardiorenal outcomes. Also promising is the success of very low-energy diets in inducing remission of diabetes in adults. However, the addition of these pharmacological and dietary approaches to the management toolbox of diabetes and DKD in children and adolescents awaits thorough assessment of their safety and efficacy in this population. This review outlines the scope of diabetes and DKD, and new developments that may favorably impact the management of children and young adults with diabetes and DKD.

Potential Approaches Versus Approved or Developing Chronic Myeloid Leukemia Therapy

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of patients with chronic myeloid leukemia (CML). However, continued use of these inhibitors has contributed to the increase in clinical resistance and the persistence of resistant leukemic stem cells (LSCs). So, there is an urgent need to introduce additional targeted and selective therapies to eradicate quiescent LSCs, and to avoid the relapse and disease progression. Here, we focused on emerging BCR-ABL targeted and non-BCR-ABL targeted drugs employed in clinical trials and on alternative CML treatments, including antioxidants, oncolytic virus, engineered exosomes, and natural products obtained from marine organisms that could pave the way for new therapeutic approaches for CML patients.

Modulation of Hair Growth Promoting Effect by Natural Products

A large number of people suffer from alopecia or hair loss worldwide. Drug-based therapies using minoxidil and finasteride for the treatment of alopecia are available, but they have shown various side effects in patients. Thus, the use of new therapeutic approaches using bioactive products to reduce the risk of anti-hair-loss medications has been emphasized. Natural products have been used since ancient times and have been proven safe, with few side effects. Several studies have demonstrated the use of plants and their extracts to promote hair growth. Moreover, commercial products based on these natural ingredients have been developed for the treatment of alopecia. Several clinical, animal, and cell-based studies have been conducted to determine the anti-alopecia effects of plant-derived biochemicals. This review is a collective study of phytochemicals with anti-alopecia effects, focusing mainly on the mechanisms underlying their hair-growth-promoting effects.