Current Medicinal Chemistry - Volume 27, Issue 37, 2020

Background: Chronic Liver Disorders (CLD), caused by the lifestyle patterns like alcoholism or by non-alcoholic fatty liver disease or because of virus-mediated hepatitis, affect a large population fraction across the world. CLD progresses into end-stage diseases with a high mortality rate. Liver transplant is the only approved treatment available for such end-stage disease patients. However, the number of liver transplants is limited due to the limited availability of suitable donors and the extremely high cost of performing the procedure. Under such circumstances, Stem Cell (SC) mediated liver regeneration has emerged as a potential therapeutic alternative approach. Objective: This review aims to critically analyze the current status and future prospects of stem cellbased interventions for end-stage liver diseases. The clinical studies undertaken, the mechanism underlying therapeutic effects and future directions have been examined. Method: The clinical trial databases were searched at https://clinicaltrials.gov.in and http://www.isrctn.com to identify randomized, non-randomized and controlled studies undertaken with keywords such as “liver disorder and Mesenchymal Stem Cells (MSCs)”, “liver cirrhosis and MSCs” and “liver disorder and SCs”. Furthermore, https://www.ncbi.nlm.nih.gov/pubmed/ database was also explored with similar keywords for finding the available reports and their critical analyses. Results: The search results yielded a significant number of studies that used bone marrow-derived stem cells, MSCs and hepatocytes. The studies clearly indicated that SCs play a key role in the hepatoprotection process by some mechanisms involving anti-inflammation, auto-immune-suppression, angiogenesis and anti-apoptosis. Further, studies indicated that SCs derived paracrine factors promote angiogenesis, reduce inflammation and inhibit hepatocyte apoptosis. Conclusion: The SC-based interventions provide a significant improvement in patients with CLD; however, there is a need for randomized, controlled studies with the analysis of a long-term follow-up.

Thymosin Beta-4 (Tβ4) is known as a major pleiotropic actin-sequestering protein that is involved in tumorigenesis. Tβ4 is a water-soluble protein that has different promising clinical applications in the remodeling and ulcerated tissues repair following myocardial infarction, stroke, plasticity and neurovascular remodeling of the Peripheral Nervous System (PNS) and the Central Nervous System (CNS). On the other hand, similar effects have been observed for Tβ4 in other kinds of tissues, including cardiac muscle tissue. In recent reports, as it activates resident epicardial progenitor cells and modulates inflammatory-caused injuries, Tβ4 has been suggested as a promoter of the survival of cardiomyocytes. Furthermore, Tβ4 may act in skeletal muscle and different organs in association/synergism with numerous other tissue repair stimulating factors, including melatonin and C-fiber-derived peptides. For these reasons, the present review highlights the promising role of Tβ4 in cardiac healing.

Background: Many pathways regarding healthy cells and/or linked to diseases onset and progression depend on large assemblies including multi-protein complexes. Protein-protein interactions may occur through a vast array of modules known as Protein Interaction Domains (PIDs). Objective: This review concerns with PIDs recognizing post-translationally modified peptide sequences and intends to provide the scientific community with state of art knowledge on their 3D structures, binding topologies and potential applications in the drug discovery field. Method: Several databases, such as the Pfam (Protein family), the SMART (Simple Modular Architecture Research Tool) and the PDB (Protein Data Bank), were searched to look for different domain families and gain structural information on protein complexes in which particular PIDs are involved. Recent literature on PIDs and related drug discovery campaigns were retrieved through Pubmed and analyzed. Results and Conclusion: PIDs are rather versatile as concerned with their binding preferences. Many of them recognize specifically only determined amino acid stretches with post-translational modifications, a few others are able to interact with several post-translationally modified sequences or with unmodified ones. Many PIDs can be linked to different diseases including cancer. The tremendous amount of available structural data led to the structure-based design of several molecules targeting protein-protein interactions mediated by PIDs, including peptides, peptidomimetics and small compounds. More studies are needed to fully role out, among different families, PIDs that can be considered reliable therapeutic targets, however, attacking PIDs rather than catalytic domains of a particular protein may represent a route to obtain selective inhibitors.

Osteoporosis is a skeletal pathology characterized by compromised bone strength leading to increased risk of fracture, mainly the spine and hip fractures. Osteoporosis affects more than 200 million people worldwide and because of the skeletal fractures it causes, represents a major cause of morbidity, disability and mortality in older people. Recently, the new discoveries of osteoimmunology have clarified many of the pathogenetic mechanisms of osteoporosis, helping to identify new immunological targets for its treatment opening the way for new and effective therapies with biological drugs. Currently, there are basically two monoclonal antibodies for osteoporosis therapy: denosumab and romosozumab. Here, we focus on the modern approach to the osteoporosis management and in particular, on current and developing biologic drugs targeted to new immunological checkpoints, in the landscape of osteoimmunology.

Breast cancer is the most common neoplasm, comprising 16% of all women's cancers worldwide. Research of Copper (Cu) concentrations in various body specimens have suggested an association between Cu levels and breast cancer risks. This systematic review and meta-analysis summarize the results of published studies and examine this association. We searched the databases PubMed, Scopus, Web of Science, and Google Scholar and the reference lists of relevant publications. The Standardized Mean Differences (SMDs) between Cu levels in cancer cases and controls and corresponding Confidence Intervals (CIs), as well as I2 statistics, were calculated to examine heterogeneity. Following the specimens used in the original studies, the Cu concentrations were examined in three subgroups: serum or plasma, breast tissue, and scalp hair. We identified 1711 relevant studies published from 1984 to 2017. There was no statistically significant difference between breast cancer cases and controls for Cu levels assayed in any studied specimen; the SMD (95% CI) was -0.01 (-1.06 - 1.03; P = 0.98) for blood or serum, 0.51 (-0.70 - 1.73; P = 0.41) for breast tissue, and -0.88 (-3.42 - 1.65; P = 0.50) for hair samples. However, the heterogeneity between studies was very high (P < 0.001) in all subgroups. We did not find evidence for publication bias (P = 0.91). The results of this meta-analysis do not support an association between Cu levels and breast cancer. However, due to high heterogeneity in the results of original studies, this conclusion needs to be confirmed by well-designed prospective studies.

NG2-glia, also called Oligodendrocyte Precursor Cells (OPCs), account for approximately 5%-10% of the cells in the developing and adult brain and constitute the fifth major cell population in the central nervous system. NG2-glia express receptors and ion channels involved in rapid modulation of neuronal activities and signaling with neuronal synapses, which have functional significance in both physiological and pathological states. NG2-glia participate in quick signaling with peripheral neurons via direct synaptic touches in the developing and mature central nervous system. These distinctive glia perform the unique function of proliferating and differentiating into oligodendrocytes in the early developing brain, which is critical for axon myelin formation. In response to injury, NG2-glia can proliferate, migrate to the lesions, and differentiate into oligodendrocytes to form new myelin sheaths, which wrap around damaged axons and result in functional recovery. The capacity of NG2-glia to regulate their behavior and dynamics in response to neuronal activity and disease indicate their critical role in myelin preservation and remodeling in the physiological state and in repair in the pathological state. In this review, we provide a detailed summary of the characteristics of NG2-glia, including their heterogeneity, the regulators of their proliferation, and the modulators of their differentiation into oligodendrocytes.

Many serious inflammatory disorders and nutrient deficiencies induce chronic pain, and anti-inflammatory diets have been applied successfully to modify the inflammatory symptoms causing chronic pain. Numerous scientific data and clinical investigations have demonstrated that long-term inflammation could lead to an inappropriate or exaggerated sensibility to pain. In addition, some Non-steroidal Anti-inflammatory Drugs (NSAID), which directly act on the many enzymes involved in pain and inflammation, including cyclooxygenases, are used to dampen the algesic signal to the central nervous system, reducing the responses of soft C-fibers to pain stimuli. On the other hand, there are a few reports from both health authorities and physicians, reporting that decreased transmission of pain signals can be achieved and improved, depending on the patient’s dietary habit. Many nutrients, as well as a suitable level of exercise (resistance training), are the best methods for improving the total mitochondrial capacity in muscle cells, which can lead to a reduction in sensitivity to pain, particularly by lowering the inflammatory signaling to C-fibers. According to the current literature, it could be proposed that chronic pain results from the changed ratio of neuropeptides, hormones, and poor nutritional status, often related to an underlying inflammatory disorder. The current review also evaluates the effective role of nutrition-related interventions on the severity of chronic pain. This review pointed out that nutritional interventions can have a positive effect on pain experience through the indirect inhibitory effect on prostaglandin E2 and attenuation of mitochondrial dysfunction caused by ischemia/reperfusion in skeletal muscle, improving the intracellular antioxidant defense system. These data highlight the need for more nutrition studies where chronic pain is the primary outcome, using accurate interventions. To date, no nutritional recommendation for chronic pain has been officially proposed. Therefore, the goal of this article is to explore pain management and pain modulation, searching for a mode of nutrition efficient in reducing pain.

Background: N-acetyl-cysteine (NAC) has shown widespread utility in different psychiatric disorders, including a beneficial role in schizophrenic patients. Although the replenishment of glutathione and the antioxidant activity of NAC have been suggested as the mechanisms that improve such a wide range of disorders, none seems to be sufficiently specific to explain these intriguing effects. A sensitive cysteine proteome is emerging as a functional and structural network of interconnected Sensitive Cysteine-containing Proteins (SCCPs) that together with reactive species and the cysteine/ glutathione cycles can regulate the bioenergetic metabolism, the redox homeostasis and the cellular growth, differentiation and survival, acting through different pathways that are regulated by the same thiol radical in cysteine residues. Objective: Since this sensitive cysteine network has been implicated in the pathogenesis of Parkinson’s and Alzheimer's diseases, I have reviewed if the proteins that play a role in schizophrenia can be classified as SCCPs. Results: The results show that the principal proteins playing a role in schizophrenia can be classified as SCCPs, suggesting that the sensitive cysteine proteome (cysteinet) is defective in this type of psychosis. Conclusion: The present review proposes that there is a deregulation of the sensitive cysteine proteome in schizophrenia as the consequence of a functional imbalance among different SCCPs, which play different functions in neurons and glial cells. In this context, the role of NAC to restore and prevent schizophrenic disorders is discussed.