Current Drug Targets - Volume 24, Issue 2, 2023

Nephropathy has become the most common reason for end-stage renal disease worldwide. The progression of end-stage renal disease occurs caused by decreased glomerular filtration rate, damage to capillaries in renal glomeruli or a higher risk of cardiovascular morbidity and mortality in diabetic patients. The involvement of mechanism in the development of nephropathy via generation of AGEs, the elevation of growth factors, altered hemodynamic and metabolic factors, inflammatory mediators, oxidative stress and dyslipidaemia. The prevalence of chronic kidney disease in India will rise from 3.7 million in 1990 to 7.63 million in 2020 becoming the main cause of mortality and morbidity. The pathogenesis of nephropathy mediates by various molecules that cause alterations in the structure and function of the kidney like growth factors, endothelins, transforming growth factor (TGF-β), and Angiotensin-converting enzymes (ACE), fibronectin and proinflammatory cytokines, mast cells and dyslipidemia. Growth factors like VEGF, IGFs, PDGF, EGFR and TGF-β contribute to excessive extracellular matrix accumulation, together with thickening of the glomerular and tubular basement membranes and an increase in the mesangial matrix, leading to glomerulosclerosis and tubulointerstitial fibrosis. Oxidative stress and inflammation factors like TNF-α, IL-1 and IL-6 are hypothesized to play a role in the development of pathological changes in nephropathy like renal hyperfiltration and hypertrophy, thickening of the glomerular basement membrane (GBM), glomerular lesion and tubulointerstitial fibrosis. Dyslipidemia is involved in the progression of nephropathy by impaired action of lipoprotein lipase, lecithincholesterol acyltransferase (LCAT) and cholesteryl ester transferase protein (CETP) resulting in the increased level of LDL-C, Triglyceride level and decrease HDL-C that enhance macrophage infiltration, excessive extracellular matrix production and accelerate inflammation with the development of proteinuria. Interruption in the RAS, oxidative stress and dyslipidemia have yielded much better results in terms of reno-protection and progression of nephropathy. In this review, we would focus on various factors that have been shown to contribute to renal injury in many experimental models of nephropathy.

Epidemiological evidence continues to accumulate on the effect of stress and depression on cancer initiation and progression. Depression has been introduced as an independent predictor of increased cancer mortality. At the same time, early intervention for depression increases the survival rate. Even some evidence has given prognostic value for depression to predict cancer recurrence and mortality. This article presents current evidence on the correlations of molecular mechanisms of cancer and depression through; I. The evidence shows the role of pre-existing depression and anxiety in the development and progression of cancer. II. The Immune system performs a crucial role in stress, depression, and cancer. III. The role of stress and depression-induced inflammation. IV. The evidence has proposed that cancer may result in depression and the effect of depression on cancer outcomes. In conclusion, the importance of preventive interventions to monitor patients’ mental health during cancer treatment is very significant and should not be underestimated. In other words, the initial interventions can improve depressive symptoms and increase cancer survival. On the other hand, by identifying key biomarkers of depression, physicians can identify cancer patients at risk for depression or those who may not respond to routine treatments. Revealing the molecular mechanism of the cancer microenvironment in the development of comorbidities promises innovative therapeutic options for cancer. Identifying these mechanisms opens a new avenue in identifying cancer patients at risk for depression and can also provide considerable potential in identifying depressive patients prone to cancer.

Alzheimer's disease (AD) has become the fourth leading cause of death in the world. Due to its complex pathogenesis, there is still a lack of effective drug treatments. Studies have found that the metal dyshomeostasis is closely related to other pathogeneses of AD such as oxidative stress, β-amyloid protein deposits, etc. Therefore, it becomes an important target to find the appropriate metal chelating agents to regulate the metal homeostasis. At the same time, because of the complex pathogenesis, single target drugs cannot achieve good effects. Therefore, current studies are mainly focused on exploring multi-target therapy for AD. In this work, the multi-target studies based on metal chelators and other targets with synergistic anti-AD activities were reviewed. The structural characteristics of different chelating agents were summarized and the structure-activity relationship was analyzed, which provided some valuable clues for the subsequent development of anti-AD multi-target drugs based on metal chelating agents.

Melanocortins are tiny protein molecules formed by the post-translational cleavage of proopiomelanocortin. These are bioactive peptides that are responsible for human and lower animal pigmentation patterns, energy homeostasis, and sexual function modulation. These peptides regulate numerous physiological functions by being generated in the central nervous system and peripheral tissues. Melanocortins elicit their varied biological effects by binding to a separate family of G protein, two primary proteolytic enzymes, proconvertases 1 and 2, according to recent research. These breakthroughs have opened up new avenues for research into the role of melanocortins, antagonists, and receptors in a number of physiological activities.

Various drugs are not able to reach the market due to their poor bioavailability and poor solubility in aqueous media. Hence, several approaches are used to enhance the solubility of poorly water-soluble drugs. Co-crystallization is one of the approaches used to enhance the solubility of poorly water-soluble drugs. Co-crystals are solid crystalline substances consisting of two or more ingredients in a stoichiometric ratio in which one of the ingredients is an active pharmaceutical ingredient (API) and the other is a co-former. API and co-former mix with one another in a co-crystal through intermolecular interactions. This review represents an overview of co-crystals, a comparison of co-crystals and other solid forms, mechanisms of solubility enhancement by co-crystals in brief, techniques of co-former selection, a list of co-formers used during various co-crystals formation and a list of marketed co-crystals formulation, method of co-crystals preparation and characterization techniques of co-crystals.

More than 150 million people have significant fungal diseases that greatly impact health care and economic expenditures. The expansion of systemic fungal infections and invasive mycoses is being driven by an increase in the number of immunocompromised patients and the recent COVID-19 patients, especially severely ill. There have been numerous cases of fungal infections linked to COVID-19, with pulmonary aspergillosis dominating at first but with the subsequent appearance of mucormycosis, candidiasis, and endemic mycoses. Candida spp. is the most frequent pathogen, with approximately 1 billion infections yearly, among other species causing the most prevalent invasive fungal infections. The importance of recognizing the epidemiological shifts of invasive fungal infections in patient care cannot be overstated. Despite the enormous antifungal therapies available, these infections are difficult to diagnose and cause high morbidity and mortality rates. Treatment choices for systemic fungal infections are severely limited due to the limitations of conventional therapy effectiveness and drug toxicities. So the researchers are still looking for novel therapeutic options, such as carrier-based approaches that are convenient and cost-effective with high and long-lasting fungal infection cure rates with reduced toxicities. The focus of this study is on summarizing the nanotechnology, immunotherapy methods and the drugs under clinical trials that have been employed in treatment as carrier-based antifungal formulations. Most of these have been reported to be promising strategies with broad-spectrum antifungal action and the potential to overcome antibiotic resistance mechanisms. We speculate that this review summarized the current knowledge to its best that will help the future developments of new antifungal therapies.

Background: One of the major indications for digoxin use is the treatment of heart failure (HF). Although the clinical application of digoxin in long-term outcomes in patients with HF and reduced ejection fraction (HFrEF) patients is well explained, the association between digoxin therapy and outcomes in patients with HF and preserved ejection fraction (HFpEF) is not very clear. Objectives: The aim of this study was to show the clinical efficacy of digoxin on long-term outcomes in subjects with HFpEF. Methods: PubMed, Embase, Scopus and Web of Science (ISI) electronic databases were searched until May 2021 to obtain relevant studies. The primary outcome was all-cause mortality attributed to treatment with digoxin. The secondary outcomes were “all-cause hospitalization”, “hospitalization because of HF” and “all-cause mortality or hospitalization of HF”. Results: Seven studies with more than 23000 patients with HFpEF, of which more than 4900 were treated with digoxin, fulfilled the eligibility criteria and were included in this meta-analysis. Treatment with digoxin was associated with a neutral effect on all-cause mortality (HR 1.04, 95 % CI 0.91-1.20, I2 = 57.9 %), all-cause hospitalization (HR 0.97, 95 % CI 0.88-1.07, I2 = 0.0 %), HFhospitalization (HR 0.96, 95 % CI 0.90-1.02, I2 = 41.4 %), and all-cause mortality or HFhospitalization (HR 1.07, 95 % CI 0.91-1.26, I2 = 81.2 %). In subgroup meta-analyses based on ejection fraction (EF), treatment with digoxin did not significantly alter these outcomes in each subset of patients. Conclusion: The results of this meta-analysis suggest that digoxin does not have any significant effect on long-term outcomes of HFpEF patients, including “all-cause mortality”, “all-cause hospitalization”, “hospitalization because of HF” and “all-cause mortality or hospitalization of HF”.

Introduction: Diseases caused by protozoa are one of the leading causes of death worldwide, especially in tropical regions such as Brazil. Chagas disease, leishmaniasis, and malaria are responsible for around 234 million cases and more than 400,000 deaths worldwide. Despite this scenario, drugs for these diseases have several limitations, which justifies the search for new treatments. Iron superoxide dismutase is a promising target for the drug design to treat patients with these diseases. It is a validated target and protects against oxidative stress. Aim: Thus, this systematic review aimed to synthesize evidence on the importance of superoxide dismutase in the drug design to treat patients with this protozoosis. Methods: A search was performed for in vitro and in vivo studies, without publication and language restrictions, in MEDLINE (PubMed), LILACS (BVS), Science Direct, and EMBASE (Elsevier). Studies that pointed to the relationship between the reduction or increase in superoxide dismutase activity and the diseases were included. 23 studies were selected for the qualitative synthesis. Results: The results showed that the inhibition or reduction of the enzyme activity decreases the degree of infection and reinfection and improves the results in treating these diseases. In contrast, the increase in activity caused a high degree of survival and resistance of the parasites. Conclusion: However, the overall quality of evidence is low and more studies with methodological rigor are provided.