Pharmacology & Therapeutics最新文献

O-linked β-N-acetylglucosamine (O-GlcNAc) represents a post-translational modification that occurs on serine or threonine residues on various proteins. This conserved modification interacts with vital cellular pathways. Although O-GlcNAc is widely distributed throughout the body, it is particularly enriched in the brain, where most proteins are O-GlcNAcylated. Recent studies have established a causal link between O-GlcNAc regulation in the brain and alterations in neurophysiological function. Alterations in O-GlcNAc levels in the brain are associated with the pathogenesis of several neurogenic diseases that can lead to cognitive impairment. Remarkably, manipulation of O-GlcNAc levels demonstrated a protective effect on cognitive function. Although the precise molecular mechanism of O-GlcNAc modification in the nervous system remains elusive, its regulation is fundamental to multiple neural and cognitive functions, fluctuating levels during normal and pathological cognitive processes. In this review, we highlight the significant functional importance of O-GlcNAc modification in pathological cognitive impairments and the potential application of O-GlcNAc as a promising target for the intervention or amelioration of cognitive impairments.

G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors in humans, playing a crucial role in regulating diverse cellular processes and serving as primary drug targets. Traditional drug design has primarily focused on ligands that uniformly activate or inhibit GPCRs. However, the concept of biased agonism-where ligands selectively stabilize distinct receptor conformations, leading to unique signaling outcomes-has introduced a paradigm shift in therapeutic development. Despite the promise of biased agonists to enhance drug efficacy and minimize side effects, a comprehensive understanding of the structural and biophysical mechanisms underlying biased signaling is essential. Recent advancements in GPCR structural biology have provided unprecedented insights into ligand binding, conformational dynamics, and the molecular basis of biased signaling. These insights, combined with improved techniques for characterizing ligand efficacy, have driven the development of biased ligands for several GPCRs, including opioid, angiotensin, and adrenergic receptors. This review synthesizes these developments, from mechanisms to drug discovery in biased signaling, emphasizing the role of structural insights in the rational design of next-generation biased agonists with superior therapeutic profiles. Ultimately, these advances hold the potential to revolutionize GPCR-targeted drug discovery, paving the way for more precise and effective treatments.

Multi-organ dysfunction is a major issue in critically ill patients, where a significant inflammatory response appears to be the primary factor driving the degree of organ impairment, which correlates with the extent of organ injury. The management of inflammation requires a multidisciplinary approach, including antibiotics for infection control, circulatory and respiratory support, and correction of coagulation abnormalities. However, the use of anti-inflammatory treatments is typically restricted to a selected group of medications, with their effectiveness remaining the subject of extensive debate. Xanthohumol (Xn), a natural compound extracted from hops, possesses strong anti-inflammatory and antioxidative properties, with a mild anti-coagulation effect. Its biological activity is related to the inhibition of different inflammatory pathways, reduction in cytokine production and secretion, and an increase in antioxidative enzyme activity. This review examined the potential use of Xn as an adjuvant in the treatment of various pathologies in critically ill patients.

Free-fatty acid receptor-4 (FFA4), previously known as GPR120, is a G protein-coupled receptor (GPCR) activated by medium-to-long chain free fatty acids (FFAs), including saturated, monounsaturated, and polyunsaturated fats, many of which (e.g., omega-3 fatty acids) are critical contributors to human health and disease. FFA4 is widely expressed across human tissues, and its activation supports a range of physiological functions, including the release of gastrointestinal incretin hormones like glucagon-like peptide-1 (GLP-1), regulation of pancreatic hormone secretion, peripheral glucose uptake, adipose regulation, and anti-inflammatory responses in macrophages. Due to its pivotal role in energy metabolism and inflammation, FFA4 has emerged as a major target in drug discovery. Historically, FFA4 signaling was linked to the Gαq/11 family of intracellular heterotrimeric G proteins, which mediate its GLP-1 releasing effects. However, emerging evidence indicates that FFA4 can signal through other Gα proteins in various cellular contexts. Notably, its anti-inflammatory effects are also dependent on interactions with β-arrestin proteins, further broadening the receptor's signaling versatility. This review explores the concept of biased agonism at FFA4, emphasizing how this receptor selectively signals through distinct transduction pathways, including Gα proteins and β-arrestins. We also examine the key structural elements of FFA4 that govern its interactions with different signaling partners, the elucidation of which has laid the groundwork for the development of biased agonists aimed at selectively modulating these FFA4-mediated pathways for therapeutic application.

Hydrogen sulfide (H₂S) is an environmental hazard well known for its neurotoxicity. In mammalian cells, H₂S is predominantly generated by transsulfuration pathway enzymes. In addition, H₂S produced by gut microbiome significantly contributes to the total sulfide burden in the body. Although low levels of H₂S is believed to exert various physiological functions such as neurotransmission and vasomotor control, elevated levels of H₂S inhibit the activity of cytochrome c oxidase (i.e., mitochondrial complex IV), thereby impairing oxidative phosphorylation. To protect the electron transport chain from respiratory poisoning by H₂S, the compound is actively oxidized to form persulfides and polysulfides by a mitochondrial resident sulfide oxidation pathway. The reaction, catalyzed by sulfide:quinone oxidoreductase (SQOR), is the initial and critical step in sulfide oxidation. The persulfide species are subsequently oxidized to sulfite, thiosulfate, and sulfate by persulfide dioxygenase (ETHE1 or SDO), thiosulfate sulfurtransferase (TST), and sulfite oxidase (SUOX). While SQOR is abundantly expressed in the colon, liver, lung, and skeletal muscle, its expression is notably low in the brains of most mammals. Consequently, the brain's limited capacity to oxidize H₂S renders it particularly sensitive to the deleterious effects of H₂S accumulation. Impaired sulfide oxidation can lead to fatal encephalopathy, and the overproduction of H₂S has been implicated in the developmental delays observed in Down syndrome. Our recent findings indicate that the brain's limited capacity to oxidize sulfide exacerbates its sensitivity to oxygen deprivation. The beneficial effects of sulfide oxidation are likely to be mediated not only by the detoxification of H₂S but also by the formation of persulfide, which exerts cytoprotective effects through multiple mechanisms. Therefore, pharmacological agents designed to scavenge H₂S and/or enhance persulfide levels may offer therapeutic potential against neurological disorders characterized by impaired or insufficient sulfide oxidation or excessive H₂S production.

High grade gliomas (HGG) are a group of CNS tumors refractory to currently existing therapies, which routinely leads to early recurrence and a dismal prognosis. Recent advancements in nucleic acid-based therapy using a wide variety of different molecular targets and non-viral nanocarrier systems suggest that this approach holds significant potential to meet the urgent demand for improved therapeutic options for the treatment of these tumors. This review provides a comprehensive and up-to-date overview on the current landscape and progress of preclinical and clinical developments in this rapidly evolving and exciting field of research, including optimized nanocarrier delivery systems, promising therapeutic targets and tailor-made therapeutic strategies for individualized HGG patient treatment.

Chimeric antigen receptor (CAR) T-cell therapy has achieved potent antitumor efficacy in hematological malignancies; however, because of limitations in CAR T-cell recruitment, infiltration, activation, and functional persistence in the tumor, its efficacy in solid tumors has been suboptimal. To overcome these challenges, combinational strategies that include chemotherapy, radiation therapy, or immune checkpoint inhibitor agent therapy with CAR T-cell therapy are being investigated. The established functional characteristics of the abovementioned therapies provide a rationale for the use of a combinational approach with CAR T cells. Chemotherapy reshapes the peritumoral stroma, decreases the immunosuppressive cell population, and promotes a proinflammatory milieu, all of which allow for increased recruitment, infiltration, and accumulation of CAR T cells. Radiation therapy promotes a chemokine gradient, which augments tumor infiltration by CAR T cells and further increases expression of tumor-associated antigens, allowing for increased activation of CAR T cells. Immune checkpoint inhibitor agent therapy inactivates T-cell exhaustion pathways-most notably, the PD1/PDL1 pathway-thereby improving the functional persistence of CAR T cells and promoting endogenous immunity. In this review, we discuss the requisites and rationales for combinational therapy, and we review 25 ongoing phase I and II clinical trials, of which 4 use chemotherapy, 3 use radiation therapy, 11 use immunotherapy, and 7 use another agent. While safety, efficacy, and improved outcomes are the primary goals of these ongoing studies, the knowledge gained from them will help pave the way for subsequent studies focused on optimizing combinational regimens and identifying predictive biomarkers.

The importance of non-vesicular extracellular RNA in the mammalian system is becoming increasingly apparent. Non-vesicular extracellular RNA is defined as RNA molecules not included in a lipid bilayer such as exosomes. Because non-vesicular extracellular RNA is not protected from RNases and is therefore rapidly degraded, they were not easily captured by conventional biofluid analyses. Recent publications showed that some non-vesicular extracellular RNAs are relatively stable in biofluids or tissue culture media, and they have unique biological functions. Major RNAs (rRNA, mRNA, and tRNA) and other non-cording RNAs play important roles in transcription or translation in the cell. In contrast, non-vesicular extracellular RNA has functions related to intercellular communication rather than protein synthesis. This review discusses the basics of non-vesicular extracellular RNA, including its definition, purification, receptors, and future prospects as a drug target.

Ewing sarcoma, the second most prevalent malignant bone tumor with potential occurrence in soft tissues, exhibits a high level of aggressiveness, primarily afflicting children and adolescents. It is characterized by fusion proteins arising from chromosomal translocations. The fusion proteins induce aberrations in multiple signaling pathways and molecules, constituting a key event in oncogenic transformation. While diagnostic and therapeutic modalities have advanced in recent decades and multimodal treatments, including surgery, radiotherapy, and chemotherapy, have significantly improved survival of patients with localized tumors, patients with metastatic tumors continue to face poor prognoses. There persists a pressing need for novel alternative treatments, yet the translation of our understanding of Ewing sarcoma pathogenesis into improved clinical outcomes remains a critical challenge. Here, we provide a comprehensive review of Ewing sarcoma, including fusion proteins, various signaling pathways, pivotal pathogenetic molecules implicated in its development, and associated targeted therapies and immunotherapies. We summarize past endeavors, current advancements, and deliberate on limitations and future research directions. It is envisaged that this review will furnish novel insights into prospective treatment avenues for Ewing sarcoma.

Polycystic Ovarian Syndrome is one of the major prevalent causes of infertility reported worldwide nearly 6-26 %, especially in girls hitting puberty and women at their childbearing age. The main clinical manifestations include irregular menstrual cycle, small cysts on one or both ovaries, chronic oligo-anovulation, and hirsutism. The etiological criteria are very complex and related to many factors like obesity, insulin sensitivity, inflammation, hyperandrogenism, diabetes mellitus type II, cardiovascular diseases, and dysbiosis of gut microbiota. The given review focuses on managing PCOS through probiotics by analyzing the effects on the symptoms of the disease. The probiotics effective in treating PCOS belong to Bifidobacterium, Lactobacilli, Clostridium, Enterococcus, and other Lactic acid bacteria. Its significance in PCOS is mainly due to the antagonizing of the growth of pathogenic microorganisms, increasing intestinal mucus layer production, reducing intestinal permeability, and modulating the gastrointestinal immune system. Also, their interaction with certain hormones such as insulin, androgen, and estrogen through short-chain fatty acids influences fertility. More research is necessary to validate these results. Probiotic supplements could be a viable option for treating PCOS in adults.