Current Molecular Medicine - Volume 24, Issue 4, 2024

Alzheimer's disease (AD) is a specific brain disease that gradually worsens due to dementia over a long period. AD accounts for almost 60% to 80% of cases of dementia. Any damage to neurons affects their ability to communicate, leading to alteration in thinking, behaviour and feelings. Besides mental, motor abilities of an individual may also be affected due to AD. Therefore, it is cardinal to understand the key mechanisms by which either AD progression can be ceased or, after the onset of the disease it could be reverted. Both of these steps need the identification of a particular receptor or a molecular marker through which a drug can enter the neurons. Cholinergic transporters are such potential targets of AD, which regulate the movement of acetylcholine and thus regulate the nerve impulse conduction in the brain. The current article entails information regarding a variety of cholinergic transporters, which will provide a research gap to the global scientific community.

Natural killer (NK) cells are among the most important cells in innate immune defense. In contrast to T cells, the effector function of NK cells does not require prior stimulation and is not MHC restricted. Therefore, chimeric antigen receptor (CAR)-NK cells are superior to CAR-T cells. The complexity of the tumor microenvironment (TME) makes it necessary to explore various pathways involved in NK cell negative regulation. CAR-NK cell effector function can be improved by inhibiting the negative regulatory mechanisms. In this respect, the E3 ubiquitin ligase tripartite motif containing 29 (TRIM29) is known to be involved in reducing NK cell cytotoxicity and cytokine production. Also, targeting TRIM29 may enhance the antitumor efficacy of CAR-NK cells. The present study discusses the negative effects of TRIM29 on NK cell activity and proposes genomic deletion or suppression of the expression of TRIM29 as a novel approach to optimize CAR-NK cell-based immunotherapy.

Cancer is a rapidly rising health problem among the global population, and this burden causes a significant challenge for public health. Current chemotherapeutic agents have different limitations, including drug resistance and severe side effects, and it demands a robust approach to accessing promising anti-cancer therapeutics. The natural compounds have been extensively studied to identify improved therapeutic agents for cancer therapy. Withaferin A (WA) is a steroidal lactone found in Withania somnifera and possesses anti-inflammatory, antioxidant, anti-angiogenesis, and anticancer properties. Multiple studies have shown that WA treatment attenuated various cancer hallmarks by inducing apoptosis and reducing angiogenesis and metastasis with reduced side effects. WA is a promising agent for the treatment of various cancer, and it targets various signaling pathways. With recent updates, the current review highlights the therapeutic implications of WA and its molecular targets in different cancer.

Neurodegenerative disorders are among the most common life-threatening disorders among the elderly worldwide and are marked by neuronal death in the brain and spinal cord. Several studies have demonstrated the beneficial role of dietary fatty acids in different brain disorders. This is due to their neurotrophic, antioxidant, and anti-inflammatory properties. Furthermore, extensive evidence shows that an unbalanced intake of certain dietary fatty acids increases the risk of neuropsychiatric diseases. Several research has been done on erucic acid, an ingestible omega-9 fatty acid that is found in Lorenzo's oil. Erucic acid was previously thought to be a natural toxin because of its negative effects on heart muscle function and hepatic steatosis, but it has been discovered that erucic acid is regularly consumed in Asian countries through the consumption of cruciferous vegetables like mustard and rapeseed oil with no evidence of cardiac harm. Erucic acid can also be transformed into nervonic acid, a crucial element of myelin. Therefore, erucic acid may have remyelinating effects, which may be crucial for treating different demyelinating conditions. Also, erucic acid exerts antioxidant and anti-inflammatory effects, suggesting its possible therapeutic role in different neurodegenerative disorders. Considering the fruitful effects of this compound, this article reviews the probable role of erucic acid as a pharmacological agent for treating and managing different neurodegenerative disorders.

The coronavirus disease 2019 (Covid-19) pandemic has been considered a major threat to human health. Effective therapeutic approaches are urgently required. Spike protein and the Angiotensin-converting enzyme 2 (ACE2) receptors have critical roles in SARS-CoV-2 infection. As a result, these two proteins are considered potential targets for the development of a wide variety of biotherapeutics and vaccines for controlling Covid-19. The fusion proteins have desirable medicinal properties, including high serum half-life, stability, and solubility in the body. Moreover, other Fc-fusion proteins used to treat other diseases have no known side effects. These Fc-fusion proteins are valuable biopharmaceuticals and have been proposed as therapeutic candidates for the treatment and prevention of Covid-19 owing to their potential therapeutic benefits.

In the present scenario, the SARS-CoV-2 virus has imposed enormous damage on human survival and the global financial system. It has been estimated that around 111 million people all around the world have been infected, and about 2.47 million people died due to this pandemic. The major symptoms were sneezing, coughing, cold, difficulty breathing, pneumonia, and multi-organ failure associated 1with SARS-CoV-2. Currently, two key problems, namely insufficient attempts to develop drugs against SARSCoV-2 and the lack of any biological regulating process, are mostly responsible for the havoc caused by this virus. Henceforth, developing a few novel drugs is urgently required to cure this pandemic. It has been noticed that the pathogenesis of COVID-19 is caused by two main events: infection and immune deficiency, that occur during the pathological process. Antiviral medication can treat both the virus and the host cells. Therefore, in the present review, the major approaches for the treatment have been divided into "target virus" and "target host" groups. These two mechanisms primarily rely on drug repositioning, novel approaches, and possible targets. Initially, we discussed the traditional drugs per the physicians' recommendations. Moreover, such therapeutics have no potential to fight against COVID-19. After that, detailed investigation and analysis were conducted to find some novel vaccines and monoclonal antibodies and conduct a few clinical trials to check their effectiveness against SARSCoV- 2 and mutant strains. Additionally, this study presents the most successful methods for its treatment, including combinatorial therapy. Nanotechnology was studied to build efficient nanocarriers to overcome the traditional constraints of antiviral and biological therapies.

Melatonin is a neuroendocrine hormone secreted by the pineal gland. The secretion of melatonin follows a circadian rhythm controlled by the suprachiasmatic nucleus, and its secretion is synchronized with the changes in light and dark periods in nature, with the highest secretion level at night. Melatonin is a critical hormone that coordinates external light stimulation and cellular responses of the body. It transmits information about the environmental light cycle, including the circadian and seasonal rhythms, to the relevant tissues and organs in the body, which, along with changes in its secretion level, ensures that its regulated functional activities are adapted in response to changes in the outside environment. Melatonin takes beneficial actions mainly through the interaction with specific membrane-bound receptors, termed MT1 and MT2. Melatonin also acts as a scavenger of free radicals via non-receptor-mediated mechanism. For more than half of acentury melatonin has been associated with vertebrate reproduction, especially in the context of seasonal breeding. Though modern humans show little remaining reproductive seasonality, the relationships between melatonin and human reproduction continue to attract extensive attention. Melatonin plays important roles in improving mitochondrial function, reducing the damage of free radicals, inducing oocyte maturation, increasing fertilization rate and promoting embryonic development, which improves the outcomes of in vitro fertilization and embryo transfer. The present article reviews the progress that has been made in our evolving understanding of the physiological role of melatonin in reproduction and its potential clinical applications in reproductive medicine.

In the last years, with the increase in the average life expectancy, the world’s population is progressively aging, which entails social, health and economic problems. In this sense, the need to better understand the physiology of the aging process becomes an urgent need. Since the study of aging in humans is challenging, cellular and animal models are widely used as alternatives. Omics, namely metabolomics, have emerged in the study of aging, with the aim of biomarker discovering, which may help to uncomplicate this complex process. This paper aims to summarize different models used for aging studies with their advantages and limitations. Also, this review gathers the published articles referring to biomarkers of aging already discovered using metabolomics approaches, comparing the results obtained in the different studies. Finally, the most frequently used senescence biomarkers are described, along with their importance in understanding aging.

mTOR is a serine/threonine kinase that plays various roles in cell growth, proliferation, and metabolism. mTOR signaling in cancer becomes irregular. Therefore, drugs targeting mTOR have been developed. Although mTOR inhibitors rapamycin and rapamycin rapalogs (everolimus, rapamycin, temsirolimus, deforolimus, etc.) and new generation mTOR inhibitors (Rapalink, Dual PI3K/mTOR inhibitors, etc.) are used in cancer treatments, mTOR resistance mechanisms may inhibit the efficacy of these drugs. Therefore, new inhibition approaches are developed. Although these new inhibition approaches have not been widely investigated in cancer treatment, the use of nanoparticles has been evaluated as a new treatment option in a few types of cancer. This review outlines the functions of mTOR in the cancer process, its resistance mechanisms, and the efficiency of mTOR inhibitors in cancer treatment. Furthermore, it discusses the next-generation mTOR inhibitors and inhibition strategies created using nanoparticles. Since mTOR resistance mechanisms prevent the effects of mTOR inhibitors used in cancer treatments, new inhibition strategies should be developed. Inhibition approaches are created using nanoparticles, and one of them offers a promising treatment option with evidence supporting its effectiveness.

Background: It has been observed previously that chronic methamphetamine (METH) administration could upregulate neuropeptide Y (NPY) expression and promote atherosclerotic formation in apolipoprotein E knockout (ApoE-/-) mice fed with a normal cholesterol or high diet and NPY might be involved in the pathogenesis of METHinduced atherogenic effects through NPY Y1 receptor pathway. Vulnerable coronary atherosclerotic plaque (VP) is a critical pathological finding responsible for the acute coronary syndrome (ACS). In this study, we explored whether METH abuse could aggravate the formation of VP in ApoE-/- mice fed with high cholesterol diet. Objective: The purpose of this study was to observe if chronic METH administration could aggravate vulnerable plaque (VP) formation in ApoE-/- mice fed with a highcholesterol diet. Methods: Male ApoE-/- mice fed with a high-cholesterol diet were intraperitoneally injected with normal saline (NS) or 8 mg/kg/day METH (M8) for 24 weeks. Body weight was monitored from baseline to 24 weeks at 2 weeks intervals. After 24 weeks of treatment, plasma lipid variables were measured. Movat's staining and immunohistochemical staining were performed on frozen sections of the aortic roots to calculate VP percentage and intraplaque hemorrhage (IPH) percentage and detect expression of NPY, vascular endothelial growth factor (VEGF), and CD31. In vitro, the expressions of Y2R, VEGF, and CD31 were detected by immunofluorescence staining in aortic endothelial cells incubated with PBS, 100μM METH, 10nmol NPY, or 100μM METH plus 10nmol NPY for 12 hours. Results: The CD31 positive area, percentage of IPH, VP, and the expressions of NPY and VEGF were significantly increased in the M8 group than in the NS group. In vitro, the expressions of Y2R, VEGF, and CD31 were significantly increased in the METH+NPY group than in the PBS, METH, and NPY groups and these effects could be blunted by treatment with a Y2R antagonist or DPPIV inhibitor. Conclusion: Chronic METH administration could aggravate VP in ApoE-/- mice fed with a high-cholesterol diet, possibly through upregulating vascular NPY and VEGF expression and promoting angiogenesis and vessel rupture in atherosclerotic plaques. Our findings indicated that increased VP formation might contribute to the development of acute coronary syndrome post-chronic METH abuse by activating DPPIV/NPY/Y2R pathway.

Background: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammatory fibrosis usually involving the whole biliary tree. However, there are very limited treatment options to treat this disease. Our previous study found a lipid-protein rCsHscB from a liver fluke - Clonorchis sinensis, which had full capacities of immune regulation. Therefore, we investigated the role of rCsHscB in a mouse model of sclerosing cholangitis induced by xenobiotic 3,5- diethoxycarbonyl-1,4-dihydrocollidine (DDC) to explore whether this protein had potential therapeutic value for PSC. Methods: Mice were fed 0.1% DDC for 4 weeks and treated with CsHscB (30 μg/mouse, intraperitoneal injection, once every 3 days); the control group was given an equal amount of PBS or CsHscB under normal diet conditions. All the mice were sacrificed at 4 weeks for the evaluation of biliary proliferation, fibrosis, and inflammation. Results: rCsHscB treatment attenuated DDC-induced liver congestion and enlargement and significantly decreased the upregulation of serum AST and ALT levels. The administration of rCsHscB to DDC-fed mice significantly decreased cholangiocyte proliferation and pro-inflammatory cytokine production compared to mice fed with DDC alone. Also, rCsHscB treatment showed a decreased expression of α-SMA in the liver and other markers of liver fibrosis (Masson staining, Hydroxyproline content, and collagen deposit). More interestingly, DDC-fed mice treated with rCsHscB showed a significant up-regulation of PPAR-γ expression, which was similar to control mice, indicating the involvement of PPAR-γ signaling in the protective action of rCsHscB. Conclusion: Overall, our data show that rCsHscB attenuates the progression of cholestatic fibrosis induced by DDC and supports the potential for manipulating the parasite-derived molecule to treat certain immune-mediated disorders.

Background: Intrauterine adhesion (IUA) caused by endometrial mechanical injury has been found as a substantial risk factor for female infertility (e.g., induced abortion). Estrogen is a classic drug for the repair of endometrial injury, but its action mechanism in the clinical application of endometrial fibrosis is still unclear. Objective: To explore the specific action mechanism of estrogen treatment on IUA. Methods: The IUA model in vivo and the isolated endometrial stromal cells (ESCs) model in vitro were built. Then CCK8 assay, Real-Time PCR, Western Blot and Dual- Luciferase Reporter Gene assay were applied to determine the targeting action of estrogen on ESCs. Results: It was found that 17β-estradiol inhibited fibrosis of ESCs by down-regulating miR-21-5p level and activating PPARα signaling. Mechanistically, miR-21-5p significantly reduced the inhibitory effect of 17β-estradiol on fibrotic ESCs (ESCs-F) and its maker protein (e.g., α-SMA, collagen I, and fibronectin), where targeting to PPARα 3’- UTR and blocked its activation and transcription, thus lowering expressions of fatty acid oxidation (FAO) associated key enzyme, provoking fatty accumulation and reactive oxygen species (ROS) production, resulting in endometrial fibrosis. Nevertheless, the PPARα agonist caffeic acid counteracted the facilitation action of miR-21-5p on ESCs-F, which is consistent with the efficacy of estrogen intervention. Conclusion: In brief, the above findings revealed that the miR-21-5p/PPARα signal axis played an important role in the fibrosis of endometrial mechanical injury and suggested that estrogen might be a promising agent for its progression.