Current Medicinal Chemistry - Volume 28, Issue 36, 2021

Mucous epithelia are protected by complex mucus barrier layers, which are part of the innate immune defense. Trefoil factor family peptides TFF1, TFF2, and TFF3 have lectin activities and are predominantly co-secreted together with mucins from these epithelia. TFF1 and TFF2 are mainly expressed in the gastric mucosa, whereas TFF3 is widely secreted from most mucous epithelia and their glands. TFF1 and TFF3 consist of a single TFF domain and an additional free 7th cysteine residue, whereas TFF2 contains two TFF domains. Systematic analyses of the molecular forms of TFFs gave new insights into their diverse molecular functions. TFF1 mainly exists as a monomer with an unusual free thiol group and only minor amounts form a disulfide-linked homodimer as well as heterodimers with gastrokine-2 and IgG-Fc-binding protein (FCGBP). TFF3 mainly forms a heterodimer with FCGBP in vivo, but also binds Deleted in Malignant Brain Tumors/gp340 (DMBT1^gp340) in vitro. In contrast, TFF2 binds as a lectin to a conserved O-linked carbohydrate moiety of the mucin MUC6. Both FCGBP and DMBT1^gp340 are secreted by most mucous epithelia and their glands and are involved in mucosal innate immunity. Thus, a new picture emerged pointing to functions of TFF3-FCGBP (and TFF1-FCGBP) for mucosal innate immune defense, e.g. supporting the clearing of the microorganisms. Such a function could be well be supported by DMBT1^gp340. In contrast, the TFF2/MUC6 lectin complex probably physically stabilizes the inner adherent gastric mucus layer. Furthermore, there are indications that TFF3- FCGBP might also play a role in the blood vessels.

Background: Hypertrophic Cardiomyopathy (HCM) is the most common inherited Cardiomyopathy. The hallmark of HCM is myocardial fibrosis that contributes to heart failure, arrhythmias and sudden cardiac death. Objective: Currently, there are no reliable serum biomarkers for the detection of myocardial fibrosis, while cardiac magnetic resonance (CMR) is an imaging technique to detect myocardial fibrosis. MicroRNAs (miRNAs) have been increasingly suggested as biomarkers in cardiovascular diseases. However, in HCM there is as yet no identified and verified specific circulating miRNA signature. Methods: We conducted a review of the literature to identify the studies that indicate the possible roles of miRNAs in HCM. Results: From studies in transgenic mice with HCM, miR-1, -133 may identify HCM in the early asymptomatic phase. Human miR-29a could be used as a circulating biomarker for detection of both myocardial hypertrophy and fibrosis in HCM, while it could also have a possible additional role in discrimination of hypertrophic obstructive cardiomyopathy from non-obstructive HCM. Additionally, miR-29a-3p is associated with diffuse myocardial fibrosis in HCM, while miR-1-3p could discriminate end-stage HCM from dilated cardiomyopathy and left ventricle dilation. Another role of miRNAs could also be the contribution in the differential diagnosis between HCM and phenocopies. Moreover, miRNA- targeted therapy (miR-133 mimics) is promising in inhibiting cardiac hypertrophy, but this is still in the early stages. Conclusion: A more reliable and specific signature of miRNAs is expected with forthcoming studies in samples from HCM patients and correlation of miRNAs with CMR and serum markers of fibrosis may implicate novel diagnostic and therapeutic pathways.

Considerable evidence has proved that disturbed cholesterol metabolism played a crucial role in diabetic kidney disease. Besides, massive cholesterol depositions were found in intrinsic renal cells of diabetic kidney disease patients and animal models, causing cytotoxicity and affecting renal function. Statins could alleviate cholesterol depositions, podocyte injury, and microalbuminuria of diabetic kidney disease. In this review, we summarized the process of disturbed cholesterol metabolism and discussed how it induced kidney dysfunction in diabetic kidney disease.

Cardiovascular disease (CVD) remains the primary cause of global morbidity and mortality. CVD includes various life-threatening conditions such as myocardial infarction, stroke and peripheral arterial diseases. In this context, atherosclerosis continues to play the principal role in the pathogenesis of these conditions. Atherosclerosis emanates from a set of modifiable and non-modifiable risk factors that include age, male gender, family history, obesity, smoking, diabetes mellitus and hypertension. Recent evidence classifies atherosclerosis as a latent disease affecting all-sized arteries with a predilection for arterial branching points of decreased or absent blood supply. Atherosclerosis is not only a lipid metabolism disorder, but is also a chronic inflammatory one. This review providesa synoptic discussion of the underlying pathological mechanisms of atherosclerosis andthe currently applied therapeutic interventions. We then discuss the classical lipid-lowering therapies as well as the newly discovered therapies. For the classical therapies, we point out the importance of statins and ezetimibe in reducing plasma cholesterol levels by virtue of their effects on synthesis, reuptake and intestinal absorption of cholesterol. We also discuss the role of fibrates in modulating lipid metabolism and improving the ratio of high-density to low-density density lipoproteins. This study focuseson the more recent molecular and genetic interventions exemplified by proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies, evinacumab, and microRNA inhibitors. Special attention is also given to clinical trials involving these therapies.

Proprotein convertase subtilisin/Kexin type 9 (PCSK9) is a secretory serine protease that plays multiple biological functions in the regulation of physiological and pathological processes. PCSK9 inhibitors decrease the circulating LDL-cholesterol level with well-known preventive and therapeutic effects on atherosclerosis (AS). Still, increasing evidence shows that the direct impact of PCSK9 on the vascular wall also plays an important role in atherosclerotic progression. Compared with other vascular cells, a large proportion of PCSK9 is originated from vascular smooth muscle cells (VSMC). Therefore, defining the effect of VSMC-derived PCSK9 on response changes, such as phenotypic switch, apoptosis, autophagy, inflammation, foam cell formation, and calcification of VSMC, helps us better understand the “pleiotropic” effects of VSMC on the atherosclerotic process. In addition, our understanding of the mechanisms of PCSK9 controlling VSMC functions in vivo is far from enough. This review aims to holistically evaluate and analyze the current state of our knowledge regarding PCSK9 actions affecting VSMC functions and its mechanism in atherosclerotic lesion development. A mechanistic understanding of PCSK9 effects on VSMC will further underpin the success of a new therapeutic strategy targeting AS.

The translation of nanomedicines from the lab level into marketed product faces several challenges, including characterization of physicochemical properties, pharmacodynamics, pharmacokinetics, process control, biocompatibility, and nanotoxicity, scaling-up as well as reproducibility. The challenges of nanomedicine development are in connection with the different requirements from the patient (clinical and therapeutic use), industry (production), and regulatory bodies (authorization process). This paper aims at reviewing the status and regulatory aspects of nano-based drug delivery systems with a focus on the Food and Drug Administration (FDA) and the European Medicine Agency (EMA) regulations. In addition to discussing the risks accompanied by the development of nanomedicine, the potential of following a risk-based methodology from the early stage of the R phase is emphasized here to ensure safety and efficacy when developing novel nano-based dosage forms. The R of nanomedicines is a complex and multidisciplinary approach, and there are still many challenges in their regulation and legislation. In general, the most critical considerations for nanomedicines are the product quality assessment (physicochemical characteristics, quality control, manufacturing process) and product safety assessment (pharmacokinetics, biodegradation, accumulation, and nanotoxicity). The paper presents a promising paradigm in the development and marketing authorization of nanomedicines, namely the Quality by Design (QbD) approach. Sufficient knowledge on the quality, safety, and efficacy of nanomedicines is necessary to obtain a significant focus on establishing robust, standardized methods for evaluating the critical quality attributes of nanomedicines. The QbD-based submission is highly recommended and required by the regulatory authorities, enabling a smooth clinical translation of the novel nanomedicines.

Background: Oxidative stress and free radicals are harmful to human health. Reactive oxygen species are the major source of oxidative stress and are one of the major causes of cancer development. Cancer is one of the leading causes of death worldwide. Prolonged use of synthetic chemotherapeutic due to their low bioavailability leads to systemic toxic side effects. To surmount this problem, the use of antioxidants is recommended as they have the ability to counteract oxidative stress and mitigate its effects on human health. They inhibit various pathways that are involved with the initiation and progression of cancer. Various nanoformulations have been used to deliver these antioxidants (curcumin, mangiferin, quercetin) in the treatment of various cancer for overcoming oxidative stress. Objective: The main focus of this review article is to illustrate various studies performed using nanocarriers of natural bioactives to overcome oxidative stress and cancer associated with it. It also describes pathways associated with the induction, initiation and progression of cancer due to reactive oxidative species. Methods: Research articles that focused on the use of natural bioactives and their nanoformulations for the treatment of various cancers induced due to oxidative stress, were collected from various search engines like PubMed, Science Direct and Google Scholar, using keywords like oxidative stress, antioxidants, cancers, ROS, etc. Conclusion: Natural bioactives have shown great potential in overcoming oxidative stress for the treatment of various cancers. However, extensive research is required so that these antioxidants and their nanocarriers can be used for the welfare of mankind, in the treatment of various cancers, in the near future.

Chagas Disease, also known as American trypanosomiasis, is a Neglected Tropical Disease that affects around seven million people, especially in Latin America. Noteworthy, there has been an increase in the numbers of case reports in non-endemic areas, such as North America, Europe, Japan, and Australia. The disease is a vector-borne disease caused by the pathogen Trypanosoma cruzi being transmitted by infected bugs. It is known that about forty percent of infected patients develop cardiac, digestive, or neurological alterations. There are only two drugs currently used for treatment, benznidazole and nifurtimox. However, both therapeutic regimens present several limitations, such as toxicity, mutagenicity and low efficiency during the chronic phase. Some reports in the literature point to the occurrence of parasite resistance. To overcome these limitations, the bioprospection of novel molecules as alternatives is one of the major goals to improve therapeutic success in this chronic disease. Bioprospecting active metabolites from natural resources might bring new hopes for disease control and parasite elimination. Here we summarize the most recent advances to identify and test Algae, Bacteria and Fungi-derived bioactive compounds with trypanocidal activity using experimental models, in vitro testing and in silico approaches.

Gene therapy is one of the most important developments for modern medicine. As such methods for the compaction and delivery of nucleic acids bearing therapeutic sequences is essential. The quest for non-viral carriers of nucleic acids has produced a number of possible candidates with dendrimer being among the most promising. Their hyper-branched structure and well-defined size together with low cytotoxicity has found success in both ex-vivo and in-vivo studies. The compaction of DNA with dendrimer has produced a rich array of different structures depending on the physiochemical conditions. Mechanisms that drive the compaction have been shown to be a number of physical interactions that reduce the large polymeric entity from 100s of nanometers to some tens of nanometers to fit into the cell nucleus. The mechanisms driving the compaction of DNA will be discussed in detail while the focus will be directed to tuning the structural properties of the complexes and their structural characterization using small-angle scattering techniques.

Human African and American trypanosomiasis are the vector-borne parasitic diseases that have killed millions of people early, and many people are yet suffering from these neglected diseases. The causative agents of these infections are parasitic protozoans of the genus Trypanosoma. Current treatment regimens against these endemic diseases have several limitations in terms of safety, efficacy, route of administration, and some of them have lost efficacy due to the emergence of resistance in their respective parasites. In this review, the most promising compounds identified by different strategies of drug development against these neglected diseases including target-based approach, the phenotypic high-throughput screening, the drug repurposing approach and combination therapy are emphasized. The potent heterocyclic compounds currently undergoing pre-clinical or clinical studies have also been assessed to ascertain an effective class of organic compounds having significant therapeutic potential against these tropical diseases. The molecular hybridization of outlined motifs may result in more active compounds and circumvent the development of resistance by specific targets in future.

Background: Studies on the prognostic value of homocysteine level have yielded controversial results in patients with acute ischemic stroke (AIS). The aim of this meta-analysis was to evaluate the prognostic utility of homocysteine among patients with AIS in terms of recurrent stroke, poor functional outcome or all-cause mortality. Methods: Two independent authors searched the articles published in PubMed and Embase databases prior to March 31, 2020. Original studies that investigated the value of homocysteine level in predicting recurrent stroke, poor functional outcome (modified Rankin Scale ≥ 3) or all-cause mortality in AIS patients were eligible. Results: Eleven articles (10 studies) that enrolled 19,435 patients with AIS were included. Meta-analysis indicated that the patients with the highest homocysteine level had an increased risk of all-cause mortality (risk ratio [RR] 1.40; 95% confidence interval [CI] 1.26-1.55). However, elevated homocysteine level was not significantly associated with recurrent stroke (RR 1.28; 95% CI 0.99-1.65) or poor functional outcome (RR 1.71; 95% CI 0.77-3.83). Conclusion: Elevated homocysteine level is independently associated with a higher risk of all-cause mortality but not recurrent stroke or poor functional outcome in patients with AIS. However, additional well-designed studies are required to confirm the findings of this meta-analysis.