Mini Reviews in Medicinal Chemistry - Volume 22, Issue 18, 2022

Background: Recently, the beneficial effects of nicotinamide adenine dinucleotide (NAD⁺) as an antiaging and antioxidant molecule have become a focus of research. However, the mechanisms by which NAD⁺ supplementation affects the associated metabolites under physiological conditions remain unclear. Specifically, although NAD⁺ is involved in several processes that are dysregulated in cardiovascular diseases, some effects of NAD⁺ precursors and NAD⁺ on cardiac diseases have started to gain recognition only recently. Objective: To discuss the influence of NAD⁺ supplementation on adverse cardiac remodeling and aging. Results: Supplementation with NAD⁺ precursors or nicotinamide riboside, which enhances or supplements the NAD⁺metabolome, might have a protective effect on the heart. NAD⁺ can alleviate chronic heart failure via mitochondrial oxidation-reduction (redox) state mechanism. Furthermore, NAD⁺ replenishment can improve the life span of mice. Conclusion: NAD⁺ exerts considerable antiaging and antioxidant effects with promising therapeutic effects. However, its effect on humans and its use as a dietary supplement need to be studied further.

Membrane lipids are generally viewed as inert physical barriers, but many vital cellular processes greatly rely on the interaction with these structures, as expressed by the membrane hypothesis that explain the genesis of schizophrenia, Alzheimer's and autoimmune diseases, chronic fatigue or cancer. The concept that the cell membrane displays transient membrane microdomains with distinct lipid composition providing the basis for the development of selective lipid-targeted therapies, the membrane-lipid therapies (MLTs). In this concern, medicinal chemists may design therapeutically valuable compounds 1) with a higher affinity for the lipids in these microdomains to restore the normal physiological conditions, 2) that can directly or 3) indirectly (via enzyme inhibition/activation) replace damaged lipids or restore the regular lipid levels in the whole membrane or microdomain, 4) that alter the expression of genes related to lipid genesis/metabolism or 5) that modulate the pathways related to the membrane binding affinity of lipid-anchored proteins. In this context, this mini-review aims to explore the structural diversity and clinical applications of some of the main membrane and microdomain-targeted lipid drugs.

MicroRNAs (miRNAs) are a class of non-coding RNAs that regulate gene expression. miRNAs have tissue-specific expression and are also present in various extracellular body fluids, including blood, tears, semen, vaginal fluid, and urine. Additionally, the expression of miRNAs in body fluids is linked to various pathological diseases, including cancer and neurodegenerative diseases. Examination of body fluids is important in forensic medicine as they serve as a valuable form of evidence. Due to its stability, miRNA offers an advantage for body fluid identification, which can be detected even after several months or from compromised samples. Identification of unique miRNA profiles for different body fluids enables the identification of the body fluids. Furthermore, miRNAs profiling can be used to estimate post-mortem interval. Various biochemical and molecular methods used for the identification of miRNAs have shown promising results. We discuss different miRNAs as specific biomarkers and their clinical importance in different pathological conditions, as well as their medicolegal importance.

COVID-19 has entered our lives as an infection with high mortality rates. Although the vaccination process has provided benefits, the death toll remains frightening worldwide. Therefore, drugs and combined therapies that can be used against COVID-19 infection are still being investigated. Most of these antiviral medications are investigational drug candidates that are still in clinical trials. In this context, holistic and different approaches for the treatment of COVID-19, including prophylactic use of natural medicines, are under investigation and may offer potential treatment options due to the fact that this is still an unmet medical need of the world. Thus, inhibiting the increased glycolysis in COVID-19 infection with glycolysis inhibitors may be beneficial for patient survival. This short review highlights the potential benefits of glycolysis inhibition as well as controlling the elevated glucose levels in patients with COVID-19.

The ancient composite formulae Angong Niuhuang pill and Pien Tze Huang, which were used a few hundred years ago to treat febrile disease and inflammation, respectively, are found to exert effects benefiting other neurological diseases and conditions. This short review introduces the main constituents of the two formulae, looking into both the cumulative synergetic and possible individual effects of each herb or animal apcoien. In essence, the main effects of Angong Niuhuang pill include anti-inflammation, antioxidation, anti-cell death, anticonvulsion, antiedema, antipyretic, antithrombotic, antimicrobial (bacteria, viruses, fungi), neuroprotective effects, and cardiovascular protection. The main effects of Pien Tze Huang include anti-inflammation, antioxidation, anti-cell death, antithrombotic, antimicrobial, neuroprotective effects, and cardiovascular protection. Comparing both composites, similarities in the effects and part of the components are found, showing some pharmacological evidence. This review casts light on research on the effects of neuroprotective and cardiovascular protective mechanisms as well as treatment mechanisms for cerebral accidents from the integrative medicine perspective.

B cells are the only player of humoral immune responses by the production of various types of antibodies. However, B cells are also involved in the pathogenesis of several immune-mediated diseases. Moreover, different types of B cell lymphoma have also been characterized. Selective depletion of B cells by anti-CD20 and other B cell-depleting agents in the clinic can improve a wide range of immune-mediated diseases. B cells' capacity to act as cytokine-producing cells explains how they can control immune cells' activity and contribute to disease pathogenesis. Thus, researchers investigated a safe, low-cost, and effective treatment modality for targeting B cells. In this respect, curcumin, the biologically active ingredient of turmeric, has a wide range of pharmacological activities. Evidence showed that curcumin could affect various immune cells, such as monocytes and macrophages, dendritic cells, and T lymphocytes. However, there are few pieces of evidence about the effects of curcumin on B cells. This study aims to review the available evidence about curcumin's modulatory effects on B cells' proliferation, differentiation, and function in different states. Apart from normal B cells, the modulatory effects of curcumin on B cell lymphoma will also be discussed.

Heart disease, the leading cause of death worldwide, refers to various illnesses that affect heart structure and function. Specific abnormalities affecting cardiac muscle contractility and remodeling and common factors including oxidative stress, inflammation, and apoptosis underlie the pathogenesis of heart diseases. Epidemiology studies have associated green tea consumption with lower morbidity and mortality from cardiovascular diseases, including heart and blood vessel dysfunction. Among the various compounds found in green tea, catechins are believed to play a significant role in producing benefits to cardiovascular health. Comprehensive literature reviews have been published to summarize the tea catechins' antioxidative, anti-inflammatory, and anti-apoptosis effects in various diseases, such as cardiovascular diseases, cancers, and metabolic diseases. However, recent studies on tea catechins, especially the most abundant (−)-Epigallocatechin-3-Gallate (EGCG), revealed their capabilities in regulating cardiac muscle contraction by directly altering myofilament Ca²⁺ sensitivity on force development and Ca²⁺ ion handling in cardiomyocytes under both physiological and pathological conditions. In vitro and in vivo data also demonstrated that green tea extract or EGCG protected or rescued cardiac function, independent of their well-known effects against oxidative stress and inflammation. This mini-review will focus on the specific effects of tea catechins on heart muscle contractility at the molecular and cellular level, revisit their effects on oxidative stress and inflammation in various heart diseases, and discuss EGCG's potential as one of the lead compounds for new drug discovery for heart diseases.

Adrenoceptors are the receptors for catecholamines, adrenaline, and noradrenaline. They are divided in α (α1 and α2) and β (β1, β2 and β3). α1-adrenoceptors are subdivided in α1A, α1B and α1D. Most tissues express mixtures of α1-adrenoceptors subtypes, which appear to coexist in different densities and ratios, and in most cases, their responses are probably due to the activation of more than one type. The three subtypes of α1-adrenoceptors are G-protein-coupled receptors (GPCR), specifically coupled to Gq/11. Additionally, the activation of these receptors may activate other signaling pathways or different components of these pathways, which leads to a great variety of possible cellular effects. The first clinically used α1 antagonist was Prazosin for Systemic Arterial Hypertension (SAH). It was followed by its congeners, Terazosin and Doxazosin. Nowadays, there are many classes of α-adrenergic antagonists with different selectivity profiles. In addition to SAH, the α1-adrenoceptors are used to treat Benign Prostatic Hyperplasia (BPH) and urolithiasis. This antagonism may be part of the mechanism of action of tricyclic antidepressants. Moreover, the activation of these receptors may lead to adverse effects such as orthostatic hypotension, similar to what happens with antidepressants and with some antipsychotics. Structure-activity relationships can explain, in part, how antagonists work and how selective they can be for each one of the subtypes. However, it is necessary to develop new molecules which antagonize the α1- adrenoceptors or make chemical modifications in these molecules to improve the selectivity and pharmacokinetic profile and/or reduce the adverse effects of known drugs.

Gut Microbiota (GM) are microorganisms that live in the host gastrointestinal tract, and their abundance varies throughout the host’s life. With the development of sequencing technology, the role of GM in various diseases has been increasingly elucidated. Unlike earlier studies on orthopedic diseases, this review elucidates the correlation between GM health and bone health and discusses the potential mechanism of GM effects on host metabolism, inflammation, and ability to induce or aggravate some common orthopedic diseases, such as osteoarthritis, osteoporosis, rheumatoid arthritis, etc. Finally, the prospective methods of GM manipulation and evaluation of potential GM-targeting strategies in the diagnosis and treatment of orthopedic diseases are reviewed.

Interleukin-6 (IL-6) influences both inflammatory response and anti-inflammatory processes. This cytokine can be released by exercising skeletal muscle, which characterizes it as a myokine. Unlike what is observed in inflammation, IL-6 produced by skeletal muscle is not preceded by the release of other pro-inflammatory cytokines, but it seems to be dependent on the lactate produced during exercise, thus causing different effects from those seen in inflammatory state. After binding to its receptor, myokine IL-6 activates the PI3K-Akt pathway. One consequence of this upregulation is the potentiation of insulin signaling, which enhances insulin sensitivity. IL-6 increases GLUT-4 vesicle mobilization to the muscle cell periphery, increasing the glucose transport into the cell, and also glycogen synthesis. Muscle glycogen provides energy for ATP resynthesis, and regulates Ca2+ release by the sarcoplasmic reticulum, influencing muscle contraction, and, hence, muscle function by multiple pathways. Another implication for the upregulation of the PI3K-Akt pathway is the activation of mTORC1, which regulates mRNA translational efficiency by regulating translation machinery, and translational capacity by inducing ribosomal biogenesis. Thus, IL-6 may contribute to skeletal muscle hypertrophy and function by increasing contractile protein synthesis.