Differentiation of Adipose Tissue-Derived Stem Cells into Cardiomyocytes: An Overview

Cardiovascular diseases, including congenital and acquired cardiovascular diseases, impose a severe burden on healthcare systems worldwide. Although bone marrow-derived stem cells (BMSCs) therapy can be an effective therapeutic strategy for the heart disease, relatively low abundance, difficult accessibility, and small tissue volume hinder the clinical usefulness. Adipose tissue-derived stem cells (ADSCs) show similar potential with BMSCs to differentiate into lineages and tissues, such as smooth muscle cells, endothelial cells, and adipocytes, with attractiveness of obtaining adipose tissue easily and repeatedly, and a simple separation procedure. We briefly summarize the current understanding of the cardiomyocytes differentiated from ADSCs

Omicron favors neuropilin1 binding over ACE2: Increased infectivity and available drugs

COVID-19 pandemic is continue with thousands of new cases every day around the world, even then different vaccines have been developed and proven efficacious against SARS-CoV-2. Several know antivirals drugs have been repurposed or tested against SARS-CoV-2 but we still don’t have an effective therapeutic strategy to control this viral infection. Moreover, in the race of finding out an efficient antiviral, excess uses of antiviral drugs developed a selective pressure on the virus that results in the high frequency of mutations and the possible emergence of antiviral drug resistance against SARS-CoV-2. Omicron is a recently emerged, highly mutated variant of SARS-CoV-2, reported for high infectivity. In the present study, we performed molecular docking analysis between available potential antiviral drugs (remdesivir, nirmatrelvir, molnupiravir, EIDD-1931, GS-441524, and favipiravir) and omicron S protein including S protein/ACE2 complex. Our results suggest high infectivity of omicron, however, the known antiviral drugs were found efficacious against omicron variant. Further, to investigate the high infectivity of omicron, we performed a docking experiment between omicron S protein and neuropilin1 (NRP1). Surprisingly, results suggest high affinities with NRP1 than ACE2. Overall, results suggest that omicron favors NRP1 binding over ACE2, the possible reason behind improved infectivity of omicron variant.

Upregulation of CD36, a Fatty Acid Translocase, Promotes Colorectal Cancer Metastasis by Increasing MMP28 and Decreasing E-Cadherin Expression

Altered fatty acid metabolism continues to be an attractive target for therapeutic intervention in cancer. We previously found that colorectal cancer (CRC) cells with a higher metastatic potential express a higher level of fatty acid translocase (CD36). However, the role of CD36 in CRC metastasis has not been studied. Here, we demonstrate that high expression of CD36 promotes invasion of CRC cells. Consistently, CD36 promoted lung metastasis in the tail vein model and GI metastasis in the cecum injection model. RNA-Seq analysis of CRC cells with altered expression of CD36 revealed an association between high expression of CD36 and upregulation of MMP28, a novel member of the metallopeptidase family of proteins. Using shRNA-mediated knockdown and overexpression of CD36, we confirmed that CD36 regulates MMP28 expression in CRC cells. siRNA-mediated knockdown of MMP28 decreases invasion of CRC cells, suggesting that MMP28 regulates the metastatic properties of cells downstream of CD36. Importantly, high expression of MMP28 leads to a significant decrease in active E-cadherin and an increase in the products of E-cadherin cleavage, CTF1 and CTF2. In summary, upregulation of CD36 expression promotes the metastatic properties of CRC via upregulation of MMP28 and an increase in E-cadherin cleavage, suggesting that targeting the CD36–MMP28 axis may be an effective therapeutic strategy for CRC metastasis.

Sleep Treatments in Disorders of Consciousness: A Systematic Review

Sleep disorders are among the main comorbidities in patients with a Disorder of Consciousness (DOC). Given the key role of sleep in neural and cognitive functioning, detecting and treating sleep disorders in DOCs might be an effective therapeutic strategy to boost consciousness recovery and levels of awareness. To date, no systematic reviews have been conducted that explore the effect of sleep treatments in DOCs; thus, we systematically reviewed the existing studies on both pharmacological and non-pharmacological treatments for sleep disorders in DOCs. Among 2267 assessed articles, only 7 were included in the systematic review. The studies focused on two sleep disorder categories (sleep-related breathing disorders and circadian rhythm dysregulation) treated with both pharmacological (Modafinil and Intrathecal Baclofen) and non-pharmacological (positive airway pressure, bright light stimulation, and central thalamic deep brain stimulation) interventions. Although the limited number of studies and their heterogeneity do not allow generalized conclusions, all the studies highlighted the effectiveness of treatments on both sleep disorders and levels of awareness. For this reason, clinical and diagnostic evaluations able to detect sleep disorders in DOC patients should be adopted in the clinical routine for the purpose of intervening promptly with the most appropriate treatment.

Essential Oils: An Effective Therapeutic Strategy against SARS-CoV-2

Thousands of individuals have perished as a result of Covid-19 and it has turned into a global problem. The novel coronavirus 2019 (nCoV-2019), also known as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has spread rapidly following its discovery in Wuhan patients with acute pneumonia in China. No medication or vaccine are available to treat human coronavirus infection successfully. The alternative therapies and cures are not are effective or authorised to treat Corona virus. Treatments are primarily supportive because no particular pandemic cure has been licenced. New interventions will most likely take months to years to mature. Using antiviral medicinal herbs as an auxiliary or supportive therapy seems to be a viable alternative. The essential oils of medicinal plants have antiviral and immunomodulatory effects. Being rich in antioxidants, essential oils can be used to develop new antiviral remedies. Such beneficial essential oils are being evaluated and exploited for its potent therapeutic use against many viruses. These natural compounds bestow antiviral actions by disrupting the viral life cycle during viral entry, assembly, replication, discharge and virus-specific host targets. This study highlights the essential oils derived from medicinal and aromatic plants with in vitro and in vivo antiviral effects. Essential oils having known pharmacokinetic and pharmacodynamic properties can be repurposed as a strategy against deadly SARS-CoV-2 infection. These essential oils of herbal plants can be an effective therapeutic strategy against SARS-CoV-2 when used along with conventional antiviral medicines.

Ischemia/Reperfusion Injury of Fatty Liver Is Protected by A2AR and Exacerbated by A1R Stimulation through Opposite Effects on ASK1 Activation

Hepatic ischemia/reperfusion injury (IRI) is aggravated by steatosis and is a main risk factor in fatty liver transplantation. Adenosine receptors (ARs) are emerging as therapeutic targets in liver diseases. By using cellular and in vivo systems of hepatic steatosis and IRI, here we evaluated the effects of pharmacological A2AR and A1R activation. The A2AR agonist CGS21680 protected the primary steatotic murine hepatocyte from IR damage and the activation of ASK1 and JNK. Such an effect was attributed to a phosphatidylinositol-3-kinase (PI3K)/Akt-dependent inhibition of ASK1. By contrast, the A1R agonist CCPA enhanced IR damage, intracellular steatosis and oxidative species (OS) production, thereby further increasing the lipid/OS-dependent ASK1-JNK stimulation. The CGS2680 and CCPA effects were nullified by a genetic ASK1 downregulation in steatotic hepatoma C1C7 cells. In steatotic mice livers, CGS21680 protected against hepatic IRI and ASK1/JNK activation whereas CCPA aggravated hepatic steatosis and IRI, and enhanced ASK1 and JNK stimulation. These results evidence a novel mechanism of CGS21680-mediated hepatoprotection, i.e., the PI3K/AKT-dependent inhibition of ASK1, and they show that CGS21680 and CCPA reduces and enhances the IRI of fatty liver, respectively, by preventing or increasing the activation of the cytotoxic ASK1/JNK axis. They also indicate the selective employment of A2AR agonists as an effective therapeutic strategy to prevent IRI in human fatty liver surgery.

Opioid Analgesia and Opioid-Induced Adverse Effects: A Review

Opioids are widely used as therapeutic agents against moderate to severe acute and chronic pain. Still, these classes of analgesic drugs have many potential limitations as they induce analgesic tolerance, addiction and numerous behavioural adverse effects that often result in patient non-compliance. As opium and opioids have been traditionally used as painkillers, the exact mechanisms of their adverse reactions over repeated use are multifactorial and not fully understood. Older adults suffer from cancer and non-cancer chronic pain more than younger adults, due to the physiological changes related to ageing and their reduced metabolic capabilities and thus show an increased number of adverse reactions to opioid drugs. All clinically used opioids are μ-opioid receptor agonists, and the major adverse effects are directly or potentially connected to this receptor. Multifunctional opioid ligands or peripherally restricted opioids may elicit fewer adverse effects, as shown in preclinical studies, but these results need reproducibility from further extensive clinical trials. The current review aims to overview various mechanisms involved in the adverse effects induced by opioids, to provide a better understanding of the underlying pathophysiology and, ultimately, to help develop an effective therapeutic strategy to better manage pain.

Neutropenia and Large Granular Lymphocyte Leukemia: From Pathogenesis to Therapeutic Options

Large granular lymphocyte leukemia (LGLL) is a rare lymphoproliferative disorder characterized by the clonal expansion of cytotoxic T-LGL or NK cells. Chronic isolated neutropenia represents the clinical hallmark of the disease, being present in up to 80% of cases. New advances were made in the biological characterization of neutropenia in these patients, in particular STAT3 mutations and a discrete immunophenotype are now recognized as relevant features. Nevertheless, the etiology of LGLL-related neutropenia is not completely elucidated and several mechanisms, including humoral abnormalities, bone marrow infiltration/substitution and cell-mediated cytotoxicity might cooperate to its pathogenesis. As a consequence of the multifactorial nature of LGLL-related neutropenia, a targeted therapeutic approach for neutropenic patients has not been developed yet; moreover, specific guidelines based on prospective trials are still lacking, thus making the treatment of this disorder a complex and challenging task. Immunosuppressive therapy represents the current, although poorly effective, therapeutic strategy. The recent identification of a STAT3-mediated miR-146b down-regulation in neutropenic T-LGLL patients emphasized the pathogenetic role of STAT3 activation in neutropenia development. Accordingly, JAK/STAT3 axis inhibition and miR-146b restoration might represent tempting strategies and should be prospectively evaluated for the treatment of neutropenic LGLL patients.

The Role of Microglia in the Development of Neurodegenerative Diseases

Microglia play an important role in the maintenance and neuroprotection of the central nervous system (CNS) by removing pathogens, damaged neurons, and plaques. Recent observations emphasize that the promotion and development of neurodegenerative diseases (NDs) are closely related to microglial activation. In this review, we summarize the contribution of microglial activation and its associated mechanisms in NDs, such as epilepsy, Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD), based on recent observations. This review also briefly introduces experimental animal models of epilepsy, AD, PD, and HD. Thus, this review provides a better understanding of microglial functions in the development of NDs, suggesting that microglial targeting could be an effective therapeutic strategy for these diseases.

The Effect of Trehalose in Inhibiting Liver Damage via The Il-6 Pathway in Old Mice

Trehalose is a non-reducing disaccharide consisting of two glucose molecules linked by a 1–1 glycosidic bond. Trehalose can play a role in organ detoxification, antioxidant enzyme activity, reducing lipid peroxidation and reducing the secretion of inflammatory factors TNF-, IL-1β, Il-6, thereby inhibiting liver damage. Because of its role, this study aims to determine the effect of trehalose administration on liver damage through the IL-6 expression pathway with experimental post-test design with control group design. This research was conducted using samples of old rats, namely Wistar rats (Rattus novergicus). The old rats used were 21 male species which were then divided into 3 groups, namely the old control group, the old rat group that was given sucrose, and the old rat group that was given trehalose. Then observed for 8 weeks, namely in March - May 2021 at the Faculty of Medicine, Hasanuddin University Makassar. The results obtained from the 3 groups showed a significant value that the administration of trehalose sugar in elderly mice had an effect on reducing the inflammatory factor IL-6 because it activated autophagy in macrophages thereby reducing cytokine production and vascular inflammation so as to be able to restore all aging mice to a level like observed in young mice. It is also known that aged rat liver, which is characterized by ER UPR activation and inflammatory signaling, decreases nicotinamide and UDP-N-acetyl-hexosamines, and reduces proteasome activity. Therefore, trehalose can be an effective therapeutic strategy against age-related disorders of proteostasis in the liver.