Biochemical pharmacology最新文献

Perception and processing of salient sensory input is vital for every animal. While sensory systems continuously receive a vast amount of information, animal brains are challenged to distinguish between relevant, i.e. salient, and neutral or unnecessary content. Stimulus salience can depend on intensity but also motivational and attentional states. Perception of salient information affects both immediate response behaviors and memory formation, which are both critical for survival. Conversely, aberrant salience processing may contribute to disorders such as schizophrenia or drug addiction. Research in recent decades has described several G protein-coupled receptor (GPCR) systems as important regulators of salience processing in the brain. They include receptors activated by monoamines, neuropeptides and lipid molecules. Although salience attribution is a critical brain function, a comprehensive survey of involved GPCRs and their endogenous transmitters has, to our knowledge, not been compiled. This review aims to close this gap by providing an overview of GPCRs involved in salience processing.

Pathogenic "non-cholera" Vibrio species of Vibrio parahaemolyticus (V. parahaemolyticus) and Vibrio vulnificus (V. vulnificus) frequently pose a serious threat to aquaculture security and public health by causing infectious diseases. In this study, we reported the discovery of a marine-sourced antimicrobial peptide (AMP) called Ajapocin, which identified through a sequence optimization strategy. Ajapocin exhibited potent activity against V. parahaemolyticus and V. vulnificus pathogens, with minimum inhibitory concentrations (MICs) of 6-12 μM-comparable to the clinical agent Polymyxin B (PMB). In vivo, a single administration of Ajapocin (1 mg/mL) displayed therapeutic efficacy in a zebrafish-Vibrio infection model. Multiple doses reduced bacterial burden and accelerated wound healing in a mouse model of V. vulnificus-infected skin wounds. Ajapocin showed no cytotoxicity in ZF4 cells and HaCaT cells at concentrations up to 32 μM. Notably, after intraperitoneal injection for 1 week, Ajapocin did not induce cumulative hepatic or renal toxicity, as confirmed by histopathology analysis and chemistry profiles. Mechanistically, membrane-interacting Ajapocin targeted negative cellular components, enhancing membrane permeation, inducing membrane depolarization, and ultimately causing membrane damage and bacterial dysfunction. Taken together, these results position Ajapocin as an appealing anti-Vibrio agent for combating vibriosis in both aquaculture and clinical settings.

The effects of three polyamines, spermine, spermidine, and putrescine, on thrombin-induced platelet activation and function were investigated. Our findings demonstrate that polyamines significantly influence platelet activity, with spermine exhibiting the most pronounced effects. Polyamines dose-dependently were able to inhibit platelet aggregation and CD62P exposure induced by thrombin, as well as the rise in intracellular calcium concentration, indicating the involvement of polyamines in platelet activation signaling pathways. Beyond their effects on platelet function, polyamines show potent antioxidant activity. In thrombin-stimulated platelets, polyamines, and spermine in particular, inhibit reactive oxygen species and superoxide anion production, as well as the consequent lipid peroxidation, demonstrating a protective effect against oxidative stress. Furthermore, polyamines restored mitochondrial function by improving oxidative phosphorylation efficiency. Polyamines can restore the oxygen consumption rate and ATP production, indicating a role in maintaining cellular energy homeostasis under pro-thrombotic conditions. These findings suggest that polyamines, particularly spermine, could have an interesting therapeutic role since they can modulate platelet activation, oxidative stress, and oxidative phosphorylation efficiency. The restoration of platelet function through treatment with polyamines could have a protective effect against a pro-thrombotic state, which is involved in venous and arterial thrombosis, which contributes to cardiovascular diseases.

Nephrotoxicity is a significant adverse effect of many cancer chemotherapies, often limiting treatment success and complicating clinical management. The kidneys are essential for removing antineoplastic drugs and their metabolites through glomerular filtration and tubular secretion. Unfortunately, both traditional cytotoxic agents and newer targeted therapies can harm various parts of the nephron, including the renal vasculature. This damage can present clinically as proteinuria, hypertension, electrolyte imbalances, glomerulopathies, acute and chronic interstitial nephritis, acute kidney injury (AKI), and often progression to chronic kidney disease (CKD). Among cytotoxic drugs, anthracyclines, potent natural antibiotics, are widely used to treat a broad range of cancers. Doxorubicin (DOX), the most common anthracycline, is particularly effective but also linked to notable nephrotoxic effects. Doxorubicin-induced kidney damage is multifactorial, involving oxidative stress, inflammation, and apoptosis, which collectively impair renal structure and function. This review discusses the mechanisms behind doxorubicin-induced nephrotoxicity and emphasizes the urgent need for nephroprotective strategies. It also reviews current therapies under investigation to reduce renal damage caused by DOX, including natural compounds and pharmacological agents that target oxidative and inflammatory pathways, aiming to preserve renal function and improve the safety of chemotherapy treatments.

Glutamine metabolism is a key driver of tumor progression, yet the molecular basis and prognostic relevance of glutamine metabolism-related genes in breast cancer (BC) remain incompletely defined. In this study, integrated analysis of public datasets identified Actin-like protein 8 (ACTL8) as a key prognostic gene significantly upregulated in BC tissue and associated with poor patient survival. In vitro, shRNA knockdown of ACTL8 reduced MYC expression and its downstream targets SLC1A5 and GLS1, suppressing cell proliferation, migration and invasion. This disruption led to impaired redox homeostasis as evidenced by reduced GSH/GSSG and NADPH/NADP⁺ ratios. Mechanistically, MYC overexpression restored metabolic enzymes and phenotypes but failed to rescue p-AKT levels, confirming ACTL8 acts upstream of the PI3K/AKT/mTOR axis. Virtual screening identified Momordin Ic as a small molecule that directly interacts with ACTL8. Surface plasmon resonance (SPR) and Thermal shift assay (TSA) confirmed this high-affinity binding, which destabilized ACTL8 and promoted its ubiquitin-proteasome degradation. Moreover, ACTL8 knockdown significantly attenuated the sensitivity of BC cells to Momordin Ic treatment, confirming ACTL8 as the specific therapeutic target. In vivo, suppression of ACTL8 markedly reduced tumor growth. Together, these findings establish ACTL8 as a key oncogenic driver of BC progression. Targeting ACTL8 offers a novel strategy to disrupt glutamine-dependent metabolic reprogramming, and Momordin Ic represents a promising lead agent to combat ACTL8-driven BC.

Nicotinamide N-methyltransferase (NNMT) plays a critical role in the pathogenesis, progression, and treatment resistance of breast cancer (BC). This enzyme facilitates tumor progression through multiple mechanisms: it regulates NAD⁺ metabolism, thereby influencing the activity of key enzymes such as sirtuins (SIRTs) and Poly(ADP-ribose) polymerase (PARP), which drives metabolic reprogramming and enhances chemoresistance; it consumes the methyl donor S-adenosylmethionine (SAM), leading to histone hypomethylation and promoting the expression of genes associated with epithelial-mesenchymal transition (EMT) and metastasis; and its metabolite, 1-methylnicotinamide (MNA), acts as a signaling molecule within the tumor microenvironment (TME) to accelerate tumor development by facilitating cell cycle progression and suppressing protective autophagy. NNMT is frequently overexpressed in BC tissues and is correlated with poor prognosis, highlighting its potential as a diagnostic biomarker and therapeutic target. Studies have demonstrated that targeting NNMT effectively inhibits tumor growth and metastasis and may augment the efficacy of immunotherapy. Future research should prioritize the development of potent NNMT inhibitors and further elucidate the role of NNMT in modulating the TME and mediating drug resistance. As a pivotal molecule linking metabolism, epigenetics, and the TME, NNMT offers promising new avenues for BC treatment.

Hepatic ischemia-reperfusion injury (HIRI) represents a frequent and unavoidable complication following liver resection or liver transplantation, which can profoundly impair hepatic function and even cause irreversible tissue damage, precipitating multiple organ dysfunction and ultimately adversely influencing both the prognosis and overall patient survival. Inflammation demonstrates a robust association with HIRI and serves a crucial function across the entire pathological course of HIRI. In this context, pyroptosis constitutes a controlled inflammatory cell death mechanism that contributes substantially to the pathological progression of HIRI. Throughout HIRI development, gasdermin D (GSDMD) functions as the primary effector following caspase 1 activation. This review provides a concise summary and emphasizes the intricate cellular and molecular mechanisms underlying GSDMD-mediated pyroptosis, particularly focusing on its involvement in HIRI. Meanwhile, the potential therapeutic effect of the natural products that act on GSDMD was predicted, which would broaden the treatment options available for HIRI. However, existing research remains confined to laboratory-based investigations and lacks clinical studies to advance a comprehensive understanding of GSDMD-induced pyroptosis in the occurrence and progression of HIRI. Therefore, enhanced comprehension of GSDMD mechanisms and the development of GSDMD-targeting inhibitors may offer promising clinical application prospects for managing HIRI.

Current pharmacological treatments for alopecia mainly aim to prevent further hair loss. However, efforts to identify therapeutic agents capable of reactivating the hair cycle have limited success. Herein, we identify that TBG096, a novel natural product-derived molecule with anti-aging properties promotes hair growth. In particular, we investigated hair regeneration effects of topical and oral TBG096 treatments across various models, including female and male rats, naturally aged and dihydrotestosterone (DHT)-induced alopecia model mice. TBG096 facilitated the transition of hair follicles from the telogen to the anagen phase, enhancing hair growth rate in a dose-dependent manner. Mechanistically, TBG096 directly binds and activates insulin-like growth factor 1 receptor (IGF-1R) that in turn activates downstream phosphatidylinositol 3-kinase /protein Kinase B (PI3K/AKT) signaling pathway. IGF-1R/PI3K/AKT activation increased angiogenesis in the dermal papilla to promote hair follicle proliferation and differentiation. Conversely, inhibition of IGF-1R impaired TBG096 mediated angiogenesis and hair regrowth. In addition, TBG096 also reduced DHT levels, increased keratin 15 (k15) expression and regulated growth factors like IGF-1 and epidermal growth factor (EGF), suggesting a restoration of normal follicular function. This is the first study to comprehensively demonstrate that TBG096 effectively promotes hair regeneration independent of age, gender, or application method, making it a promising candidate for treating androgenic alopecia and age-related hair loss.