Current Pharmaceutical Design - Volume 29, Issue 32, 2023

Physical inactivity and sedentary behaviors (SB) have promoted a dramatic increase in the incidence of a host of chronic disorders over the last century. The breaking up of sitting time (i.e., sitting to standing up transition) has been proposed as a promising solution in several epidemiological and clinical studies. In parallel to the large interest it initially created, there is a growing body of evidence indicating that breaking up prolonged sedentary time (i.e., > 7 h in sitting time) could reduce overall mortality risks by normalizing the inflammatory profile and cardiometabolic functions. Recent advances suggest that the latter health benefits, may be mediated through the immunomodulatory properties of extracellular vesicles. Primarily composed of miRNA, lipids, mRNA and proteins, these vesicles would influence metabolism and immune system functions by promoting M1 to M2 macrophage polarization (i.e., from a pro-inflammatory to anti-inflammatory phenotype) and improving endothelial function. The outcomes of interrupting prolonged sitting time may be attributed to molecular mechanisms induced by circulating angiogenic cells. Functionally, circulating angiogenic cells contribute to repair and remodel the vasculature. This effect is proposed to be mediated through the secretion of paracrine factors. The present review article intends to clarify the beneficial contributions of breaking up sitting time on extracellular vesicles formation and macrophage polarization (M1 and M2 phenotypes). Hence, it will highlight key mechanistic information regarding how breaking up sitting time protocols improves endothelial health by promoting antioxidant and anti-inflammatory responses in human organs and tissues.

Multiple sclerosis (MS) is a central nervous system (CNS) immune-mediated disease that mainly strikes young adults and leaves them disabled. MS is an autoimmune illness that causes the immune system to attack the brain and spinal cord. The myelin sheaths, which insulate the nerve fibers, are harmed by our own immune cells, and this interferes with brain signal transmission. Numbness, tingling, mood swings, memory problems, exhaustion, agony, vision problems, and/or paralysis are just a few of the symptoms. Despite technological advancements and significant research efforts in recent years, diagnosing MS can still be difficult. Each patient's MS is distinct due to a heterogeneous and complex pathophysiology with diverse types of disease courses. There is a pressing need to identify markers that will allow for more rapid and accurate diagnosis and prognosis assessments to choose the best course of treatment for each MS patient. The cerebrospinal fluid (CSF) is an excellent source of particular indicators associated with MS pathology. CSF contains molecules that represent pathological processes such as inflammation, cellular damage, and loss of blood-brain barrier integrity. Oligoclonal bands, neurofilaments, MS-specific miRNA, lncRNA, IgG-index, and anti-aquaporin 4 antibodies are all clinically utilised indicators for CSF in MS diagnosis. In recent years, a slew of new possible biomarkers have been presented. In this review, we look at what we know about CSF molecular markers and how they can aid in the diagnosis and differentiation of different MS forms and treatment options, and monitoring and predicting disease progression, therapy response, and consequences during such opportunistic infections.

Worldwide, adrenaline is considered the first choice therapy in the international guidelines for the management of anaphylaxis. However, the heart and cardiovascular apparatus are strongly involved in anaphylaxis; for that reason, there are some cardiac conditions and certain anaphylaxis patterns that make epinephrine use problematic without adequate heart monitoring. The onset of Kounis syndrome, takotsubo cardiopathy, or the paradoxical anaphylaxis require great attention in the management of anaphylaxis and adrenaline administration by clinicians, who should be aware of the undervalued evolution of anaphylaxis and the potential cardiologic complications of epinephrine administration. Numerous case reports and studies describe the unexpected onset of cardiac diseases following epinephrine treatment, despite the latter being the recommended therapy for anaphylaxis. Our review suggests that future anaphylaxis guidelines should incorporate cardiovascular specialists since the treatment of Kounis syndrome or takotsubo cardiopathy requires cardiologist skills.

The death rate from cancer is declining as a result of earlier identification and more advanced treatments. Nevertheless, a number of unfavourable adverse effects, including prolonged, long-lasting inflammation and reduced immune function, usually coexist with anti-cancer therapies and lead to a general decline in quality of life. Improvements in standardized comprehensive therapy and early identification of a variety of aggressive tumors remain the main objectives of cancer research. Tumor markers in those with cancer are tumor- associated proteins that are clinically significant. Even while several tumor markers are routinely used, they don't always provide reliable diagnostic information. Serum cytokines are promising markers of tumor stage, prognosis, and responsiveness to therapy. In fact, several cytokines are currently proposed as potential biomarkers in a variety of cancers. It has actually been proposed that the study of circulatory cytokines together with biomarkers that are particular to cancer can enhance and accelerate cancer diagnosis and prediction, particularly via blood samples that require minimal to the absence of invasion. The purpose of this review was to critically examine relevant primary research literature in order to elucidate the role and importance of a few identified serum cytokines as prospective therapeutic targets in oncological diseases.

Hypertension, a prevalent chronic ailment, has the potential to impair kidney function, and thereby resulting in hypertensive nephropathy. The escalating incidence of hypertensive nephropathy attributed to the aging population in urban areas, has emerged as a prominent cause of end-stage renal disease. Nevertheless, the intricate pathogenesis of hypertensive nephropathy poses considerable obstacles in terms of precise clinical diagnosis and treatment. This paper aims to consolidate the research findings on the pathogenesis of hypertensive nephropathy by focusing on the perspective of molecular biology.

Background: Rosuvastatin contributes to the improvement of vascular complications in diabetes, but the protective mechanisms remain unclear. The aim of the present study was to investigate the effect and mechanism of rosuvastatin on endothelial dysfunction induced by diabetes.Methods: Calpain-1 knockout (Capn1 EK684-/-) and C57BL/6 mice were intraperitoneally injected with STZ to induce type 1 diabetes. Human umbilical vein endothelial cells (HUVECs) were incubated with high glucose in this study. The function of isolated vascular rings, apoptosis, and endoplasmic reticulum stress (ERS) indicators were measured in this experiment.Results: The results showed that rosuvastatin (5 mg/kg/d) and calpain-1 knockout improved impaired vasodilation in an endothelial-dependent manner, and this effect was abolished by an ERS inducer. Rosuvastatin administration inhibited calpain-1 activation and ERS induced by high glucose, as well as apoptosis and oxidative stress both in vivo and in vitro. In addition, an ERS inducer (tunicamycin) offset the beneficial effect of rosuvastatin on endothelial dysfunction and ERS, which was accompanied by increased calpain-1 expression. The ERS inhibitor showed a similar improvement in endothelial dysfunction with rosuvastatin but could not increase the improvement in endothelial function of rosuvastatin.Conclusion: These results suggested that rosuvastatin improves endothelial dysfunction by suppressing calpain- 1 and normalizing ERS, subsequently decreasing apoptosis and oxidative stress.

Background: Osimertinib (Osm) is the preferred treatment for non-small cell lung cancer (NSCLC) patients with the epidermal growth factor receptor (EGFR) T790M mutation. Nevertheless, the resistance of NSCLC cells to Osm will eventually develop, which remains the biggest obstacle to treating such diseases. Raddeanin A (RA) exhibits a potent anti-tumor effect on various types of cancer cells. In this study, we aimed to investigate whether RA suppresses NSCLC growth and increases the therapeutic effect of Osm.Methods: The effects of RA on inhibiting NSCLC cell viability and proliferation were tested using cell counting kit 8 (CCK-8) and EdU assay. The roles of RA in improving the anti-tumor effect of Osm were tested with CCK-8 and colony formation assays. The roles of RA in regulating reactive oxygen species (ROS)/NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3)-mediated pyroptosis were assessed using quantitative real- time PCR (qRT-PCR) and western blotting analysis.Results: RA treatment decreased A549 and H1975 cell viability in a dose- and time-dependent way. RA inhibited NSCLC cell proliferation and tumor growth in vivo. Mechanistically, RA induced ROS overgeneration and resulted in subsequent NLRP3-mediated pyroptosis. In particular, combination treatment with Osm and RA reduced cell viability and clonogenic growth capacity more efficiently than Osm mono treatment in A549 and H1975 cells. Combination treatment also promoted NLRP3-mediated pyroptosis more efficiently than Osm mono treatment.Conclusion: RA inhibited the NSCLC growth and increased the anti-tumor role of Osm in NSCLC by facilitating ROS/NLRP3-mediated pyroptosis. These results suggested that combination therapy with RA and Osm might be an effective strategy to treat Osm-resistant NSCLC.