Skeletal muscle atrophy represents a pathological condition characterized by impaired protein homeostasis that commonly occurs with aging, chronic inflammatory diseases, physical inactivity, and neuromuscular disorders. This condition significantly reduces patients' quality of life and increases mortality risk. Emerging research highlights the immune system, especially macrophages, as key regulators of this process. As core components of innate immunity, macrophages exhibit high plasticity and orchestrate muscle repair and the regulation of chronic inflammation through polarized pro-inflammatory (M1) and anti-inflammatory/reparative (M2) phenotypes. This review systematically examines the dual role of macrophages in muscle pathology. On one hand, they facilitate muscle regeneration by removing necrotic tissue and secreting growth factors like Insulin-like Growth Factor 1 (IGF-1) and Interleukin-10 (IL-10) to promote satellite cell activation. On the other hand, improper macrophage activation or polarization shifts toward sustained M1 dominance can release harmful cytokines such as Tumor Necrosis Factor-α (TNF-α) and Interleukin-6 (IL-6), activating Nuclear Factor-kappa B (NF-κB) and Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways that increase protein breakdown, inhibit muscle formation, and accelerate atrophy. Additionally, we evaluate macrophage-focused treatments including drug inhibitors, stem cell therapies, plant compounds that modify polarization, and genetic approaches to rebalance immune function and reduce muscle wasting. Collectively, these advances provide novel mechanistic insights into immune-mediated skeletal muscle pathology and lay the groundwork for a translational framework for targeted interventions.

Acute myeloid leukemia (AML) remains a therapeutic challenge with poor prognosis, particularly in high-risk genetic subtypes. Ubiquitin-specific protease 5 (USP5) plays a crucial role in the progression of various malignancies. However, its function in AML remains largely unknown. This study aims to investigate the biological role of USP5 in AML and elucidate its underlying molecular mechanisms. We observed that USP5 expression was significantly elevated in AML patients compared to healthy controls, and high USP5 levels correlated with poor prognosis. Functional studies demonstrated that USP5 knockdown markedly inhibited AML cell proliferation, colony formation, and cell cycle progression while promoting apoptosis. In vivo experiments revealed that USP5 depletion significantly suppressed leukemia cell proliferation and prolonged survival in AML mouse model. Mechanistically, co-immunoprecipitation coupled with mass spectrometry analysis identified that USP5 interacted with a protein complex containing C2 domain protein 5 (C2CD5), FGF1 intracellular binding protein (FIBP), and cyclin-dependent kinase 5 (CDK5). Notably, USP5 stabilizes C2CD5 through deubiquitination, thereby activating the phosphoinositide 3-kinase (PI3K)/ (protein kinase B) AKT/ mechanistic target of rapamycin (mTOR) signaling pathway and enhancing glycolytic flux via the HIF-1α transcription factor to drive AML progression. Importantly, USP5 knockdown enhanced the chemosensitivity of AML cells, and its small-molecule inhibitor potently curbed AML cell growth and proliferation. Generally, our findings establish the USP5-C2CD5 as a novel therapeutic target for AML treatment.

Depression is increasingly recognized as a comorbidity of dry eye disease (DED), yet its underlying mechanisms remain unclear. This study investigates the therapeutic effects of fluoxetine on depression-associated corneal injury and explores the molecular pathways involved. Chronic unpredictable mild stress (CUMS) mice received fluoxetine treatment. Behavioral tests, corneal wound healing, tear secretion, and 4D-DIA proteomics were performed. GRB2 expression was validated via immunohistochemistry, qRT-PCR, and western blot. Human corneal epithelial cells (hCECs) under hyperosmotic stress (450 mOsm) were transfected with GRB2 siRNA to assess oxidative stress, inflammation, and migration. Fluoxetine treatment significantly reduced depressive behaviors, accelerated corneal epithelial wound healing, and restored tear secretion. Proteomic analysis of corneal tissues revealed dysregulation of cytoskeletal and metabolic pathways in depressed mice, which fluoxetine partially reversed. GRB2 emerged as a critical protein, showing elevated expression in depressed mice and hyperosmolar-stressed hCECs. Silencing GRB2 in hCECs attenuated hyperosmolarity-induced oxidative stress, inflammation, and migration inhibition. Immunohistochemical and behavioral analyses confirmed GRB2's role in corneal epithelial thinning and depression-related DED pathology. These findings highlight GRB2 as a potential therapeutic target and underscore fluoxetine's dual efficacy in mitigating depressive symptoms and ocular surface damage. This study provides novel insights into the molecular interplay between depression and DED, advocating for integrated therapeutic strategies addressing both psychiatric and ophthalmic dimensions.

Serotonin (5-HT) plays a key role in shaping mammary tissue morphology and regulating growth, lactation and involution. Serotonin re-uptake inhibitors (SSRIs) retain 5-HT outside the cell membrane, but their impact on breast cancer risk through altered cell proliferation is unclear. Using transcriptomic and signaling profiles and a systematic screen of receptor-selective ligands we assessed the impact of 5-HT receptor activation on non-malignant breast cell growth. Paroxetine reduced 5-HT levels in immortalized primary breast epithelial (HME-hTert) cells, mitigated free oxygen radical formation and decreased cell migration and proliferation. Thus, pathways related to cell cycle and DNA damage repair were underrepresented in the transcriptomic profile of paroxetine-treated cells. However, enriched transcipts overrepresented genes affecting neural transmission and GPCR signaling, suggesting an increase in 5-HT receptor activation. As 5-HT induced the levels of both cAMP and inositol triphosphate (IP3), the contributions of individual receptors were deciphered using receptor-selective agonists and antagonists. 5-HT receptors coupled to every G protein subtype were expressed and functional. The activation of the G-coupled receptor 5-HT and the antagonists of G- and G-coupled 5-HT and 5-HT receptors generally suppressed proliferation. Paroxetine-dependent growth suppression was reversed by inhibitors of G-coupled 5-HT receptor, protein kinase A, adenylyl cyclase, and agonists of G and G-coupled receptors. This matrix of interactions suggest that the anti-proliferative responses to 5-HT in non-malignant breast cells align with the G protein preference of the receptors. The potential benefits of repurposing receptor subtype-selective agents and SSRIs, and their ideal combinations, represent a novel opportunity for cancer risk reduction.

Cinnamaldehyde (CA), a natural bioactive compound derived from Cinnamomum species, has demonstrated broad-spectrum antitumor activity. However, its therapeutic potential and precise mechanisms in ovarian cancer (OC) remain incompletely elucidated. In this study, we systematically investigated the inhibitory effects of CA on OC and the underlying molecular mechanisms through both in vitro and in vivo approaches. In vitro experiments demonstrated that CA significantly induces reactive oxygen species (ROS) accumulation in OC cells, activates mitochondria-mediated apoptosis, and induces mitochondrial autophagy via the AMPK/ULK1/Beclin1 signaling axis. These synergistic effects collectively lead to significant suppression of OC cell proliferation. In a murine xenograft model of OC, CA administration substantially inhibited the growth of heterotransplanted tumors. Further in vivo analyses revealed a significant increase in the number of apoptotic cells and upregulation of the expression of the autophagy markers LC3B, PINK1, and Parkin in tumor tissues. Concurrently, the expression of the autophagic substrate p62 and the mitochondrial membrane protein TOMM20 decreased. These findings consistently corroborated the cellular mechanisms observed in vitro. This study provides the first evidence that CA suppresses OC progression via ROS-mediated dual mechanisms: apoptosis induction and mitophagy activation. Our results underscore the translational potential of CA as a promising therapeutic candidate and provide a robust experimental foundation for its further development against OC.

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with limited therapeutic options. This study identifies nicotinamide riboside (NR), a natural NAD precursor, as a dual-function agent that enhances chemosensitivity and suppresses tumor progression by activating the mitochondrial deacetylase sirtuin 3 (SIRT3). Multi-level clinical analyses revealed progressive SIRT3 downregulation in PDAC pathogenesis, correlating with poor survival. Genetic ablation of SIRT3 accelerated premalignant lesions in spontaneous models, whereas NR administration restored SIRT3 expression and activated its mitochondrial regulatory network, comprising key metabolic enzymes and respiratory chain components, in a SIRT3-dependent manner. In spontaneous PDAC models, NR monotherapy delayed carcinogenesis by suppressing the progression of premalignant lesions. Moreover, NR significantly potentiated gemcitabine efficacy both in vitro and in subcutaneous PDAC models, demonstrating synergistic enhancement of chemotherapy-induced tumor cell death. These findings establish NR as a promising SIRT3-targeting adjuvant that both enhances the efficacy of standard chemotherapy and delays carcinogenesis, thereby overcoming therapeutic resistance in established PDAC and potentially impeding its development.

Neutrophils play a central role in the initiation of inflammation. Dysregulated neutrophils produce excessive inflammatory mediators, contributing to the development and progression of autoimmune and inflammatory diseases. Formyl peptide receptor 1 (FPR1) is a G protein-coupled receptor that plays a key role in regulating neutrophil activation and is a promising target for therapeutic intervention. In this study, we used structure-based virtual screening to identify potential FPR1 inhibitors. We initially identified compound 333728 as a hit FPR1 inhibitor. Subsequent evaluation of its analogs led to the identification of compound 668429, which exhibited the most potent antagonistic activity with an IC value of 0.52 µM under our assay conditions. Structure-activity relationship analysis revealed crucial functional groups and interactions responsible for FPR1 inhibitory activity. In addition, compound 668429 demonstrated selectivity for FPR1 over FPR2. In vitro assays confirmed that 668429 effectively inhibited FPR1-mediated neutrophil functions, including reactive oxygen species production, degranulation, and integrin expression. Moreover, 668429 suppressed downstream FPR1 signaling pathways involving calcium mobilization, MAPK activation, and AKT phosphorylation. Together, these results suggest that compound 668429 is a selective FPR1 inhibitor and a promising starting point for the development of therapeutics targeting neutrophil-driven inflammatory disorders.

Ischemia/reperfusion (IR) injury during coronary artery bypass grafting surgery has detrimental impacts on endothelial integrity and function. Studies have suggested that canagliflozin (CANA) mitigates the risk of cardiovascular events, independently of diabetes. We hypothesized that the supplementation and/or administration of CANA protects vascular grafts in a bypass model in non-diabetic Lewis rats. The aortic arches of control rats (n = 9) were harvested, aortic rings were prepared, then mounted in organ baths. In the IR and IR + CANA groups (n = 8/group), aortic arches were preserved in either saline or CANA-supplemented saline (5 µM) for 1 h at 4 °C before transplantation. In the IR + CANA and IR + CANA groups (n = 9/group), aortic arches were preserved in cold saline or CANA for 1 h and recipients received CANA (10 µg/kg, intravenous) 5 min prior to reperfusion. After 1 h of in vivo blood reperfusion, ex vivo vascular function was assessed and immunohistochemistry was performed. The decreased maximum relaxation (R) to acetylcholine in the IR group compared to controls (20 ± 3 % vs 83 ± 2 %, p < 0.05) was improved in both the IR + CANA (36 ± 2 % vs. 20 ± 3 %, p < 0.05) and IR + CANA (45 ± 3 % vs. 20 ± 3 %, p < 0.05) groups. Additionally, the IR + CANA rings exhibited a further increased R to acetylcholine compared to both the IR + CANA (45 ± 3 % vs. 31 ± 2 %, p < 0.05) and IR + CANA (45 ± 3 % vs. 36 ± 2 %, p < 0.05) groups. Increased DNA strand breaks in the IR group compared to controls were decreased in all CANA groups. The reduced immunoreactivity of CD-31 was ameliorated in the IR + CANA and IR + CANA groups. CANA alleviates endothelial dysfunction induced by IR injury in a rodent model of revascularization.

Breast cancer as a multi-factorial disease has been widely concerned due to its high incidence. It is urgent to find new targets to treat breast cancers. Our previous research found silibinin induced apoptosis in both the hormone-sensitive breast cancer cells MCF-7 and the triple-negative breast cancer (TNBC) cells MDA-MB-231, through inhibiting the YAP pathway. Besides apoptosis, we here discover silibinin induces G2/M cell cycle arrest in both cells, which are also dependent on the inhibition of YAP. Interestingly, the F-actin assembly is markedly reduced by Silibinin. F-actin is found to be positively regulated by YAP, due to its transcriptional regulations of factors for polymerization. Meanwhile, disturbance of F-actin assembly by using Cytochalasin D contributes to cell cycle arrest, suggesting that F-actin disassembly is not just a consequence following YAP inhibition, but also plays a critical role in modulating cell cycle arrest. Further study on the interaction of silibinin and F-actin reveals that silibinin directly targets Capza1, which causes F-actin disassembly. Moreover, promoting F-actin assembly by si-Capza1 transfection restores YAP's activity, suggesting a positive interaction between YAP and F-actin. Of note, by simultaneous transfection of si-YAP/TAZ and si-Capza1, we find that although YAP has a regulatory effect on F-actin assembly, Capza1-mediated F-actin disassembly is decisive for silibinin-induced cell cycle arrest. Our results reveal the F-actin assembly is inhibited by silibinin, and this results in G2/M cell cycle arrest in human breast cancer cells, providing new ideas for anti-cancer therapies including TNBCs. Abbreviations: ABPs, actin binding proteins; ARP2, actin-related protein2; Capza1, capping actin protein of muscle Z-line subunit alpha 1; CDC2, Cell Division Cycle protein 2/CDK1, Cyclin-Dependent Kinase 1; CDKi, cyclin-dependent kinase inhibitors; CDKs, cyclin-dependent kinases; CETSA, cellular thermal shift assay; CFL1, cofilin 1; Cyto D, Cytochalasin D; DARTS, drug affinity responsive target stability; DIAPH3, diaphanous related formin 3; DMEM, Dulbecco's Modified Eagle medium; ER, estrogen receptor; F-actin, filamentous actin; FBS, fetal bovine serum; G-actin, globular actin; GSN, gelsolin; HER2, human epidermal growth factor receptor 2; LAMP1, lysosomal associated membrane protein 1; NLS, nuclear localization signal; PDB, protein data bank; PFN1, profilin 1; PR, progesterone receptor; qRT-PCR, quantitative real-time polymerase chain reaction; RT, room temperature; Sili, silibinin; si-RNAs, small interfering RNAs; TNBC, triple-negative breast cancer; VP, verteporfin; YAP, Yes-associated protein.

Pyroptosis, a lysogenic pro-inflammatory kind of regulatory cell death mediated by the family of gasdermins, has gained substantial attention over the past few years. In a novel approach to tumor treatment, modification of the immune system is used to regulate and eradicate tumor cells and restore the body's inherent defenses against cancer. However, tumor immunotherapy faces several significant challenges, including decreased T cell responsiveness, limited immunogenicity, and the emergence of tumor cell drug resistance. Pyroptosis and tumor immunity may be related, emphasizing that pyroptosis may elicit strong anti-tumor immunity as a viable tumor therapy option. The molecular process of pyroptosis, its possible connection with various tumor immunotherapies, and potential pathways for triggering immunity by inducing pyroptosis are thoroughly reviewed in this article, and we hope to promote the application of pyroptosis in tumor immunotherapy.

The classic Nachannel-inhibiting anticonvulsants, such as phenytoin (DPH), and the new-generation lacosamide (LCM) selectively bind to the fast and slow inactivated states of the channel, respectively. The effect of a combination of the two anticonvulsants acting on the same protein with differently modulated receptors by neuronal activities, a possible clinical scenario, is investigated in native mouse neurons and heterologously-expressed human Nachannels. A combination of DPH and LCM does not necessarily show stronger inhibition on different neuronal epileptiform burst discharges than that of a single drug. There is more likely a doubly occupied channel and thus a supra-additive effect of the two drugs at prolonged weak and strong depolarization which moves most channels to the fast and slow inactivated states, respectively. However, single occupancy or mutual exclusion and thusan infra-additive effect may prevail with prolonged modest or short strong depolarization which presumably moves the channel chiefly to the intermediate inactivated states. Although there could be gaps between in vitro and clinical settings, the results implicate thata combination ofDPH and LCMfor seizure therapy is in general warranted, especially if the seizure discharges are characterized by prolonged strong membrane depolarization or its equivalents (a condition also endowingLCMthe best effect). However, cases of no increment, or even a decrement, in efficacy shall be carefully monitored. On the other hand,the rare cardiac adverse events reported for LCM use is not expected to increase with the combination because of the little additive effect on intermediate inactivated states. Abbreviations: AUC, area-under-the-curve; ANOVA, analysis of variance; CA1, cornu ammonis area 1 of the hippocampus; CHO-K1, Chinese hamster ovary K1; CI, combination index; DPH, phenytoin; EEG, electroencephalography; FBS, fetal bovine serum; GFP, green fluorescent protein; I, fast inactivated states; I, intermediate inactivated states; I, slow inactivated states; LCM, lacosamide; Nav1.7, voltage-gated sodium channel subtype 1.7; SEM, standard error of the mean.

Chronic kidney disease (CKD) overactivates the renin-angiotensin system (RAS), causing vascular dysfunction and hypertension. Additionally, hydrogen sulfide (HS) is a gasotransmitter that modulates the cardiovascular system by attenuating the RAS. Therefore, this study aimed to investigate the effects of chronic administration of sodium hydrosulfide (NaHS, an exogenous HS donor) on RAS-mediated vascular responses, oxidative stress, and progression of hypertension in rats with CKD. Thirty-two normotensive male Wistar rats were divided into four groups (n = 8): 1) sham + vehicle (1 mL/kg/d, 100 mM of phosphate buffer, PBS), 2) sham + NaHS (5.6 mg/kg/d), 3) CKD induced by 5/6 nephrectomy + vehicle, and 4) CKD + NaHS. One week after surgery, pharmacological treatments began and were administered intraperitoneally daily for six weeks. Hemodynamic variables, renal function, and HS serum levels were assessed. Additionally, HS formation, oxidative stress, and the expression of AT, AT, Mas receptors, and HS-synthesizing enzymes, along with vascular responses to angiotensin (1-7), angiotensin II and HS were assessed in the thoracic aorta. CKS impairs: 1) RAS-mediated vascular responses; 2) downregulates Mas receptor expression; 3) upregulates AT and AT receptor expression; 4) increases HS-mediated vascular response, 5) decreases HS levels, tissue production of HS and the expression of the producing enzymes; and 6) induces oxidative stress. Interestingly, NaHS treatment prevented CKD-induced impairments. In conclusion, NaHS administration protects against RAS-mediated vascular dysfunction and progression of hypertension by preventing alterations in AT, AT Mas receptors, HS-synthesizing enzymes, and oxidative stress.

Colorectal cancer (CRC), one of the primary causes of gastrointestinal malignancy-related mortality worldwide, encounters significant therapeutic challenges due to multidrug resistance. Multidrug resistance-associated protein 2 (MRP2), encoded by ABCC2, plays a crucial role in the development of drug resistance during clinical CRC treatment. This study elucidates a novel mechanism by which formononetin (FMNT), a bioactive isoflavone commonly found in food and medicinal-related plants, suppresses CRC via microRNA-490-3p (miR-490-3p)-mediated regulation of ABCC2 and synergizes with 5-fluorouracil (5-FU). HCT116 and SW480 cell lines as well as AOM/DSS-induced CRC models in wild-type and Mrp2 mice were employed. The results demonstrated that FMNT markedly suppresses CRC proliferation in vitro and tumorigenesis in vivo. Transcriptomic profiling identified ABCC2 as the top target associated with FMNT's efficacy. This finding was validated in clinical specimens, which revealed significant upregulation of MRP2 in human CRC tissues. FMNT markedly downregulated the MRP2 expression. Genetic ablation experiments further confirmed enhanced FMNT sensitivity in Mrp2 mice and MRP2 silencing CRC cells. Mechanistically, FMNT upregulated tumor-suppressive miR-490-3p, which directly targets the ABCC2 3'UTR, thereby establishing a regulatory axis corroborated by gain/loss-of-function experiments. Notably, overexpression of miR-490-3p augmented FMNT's antitumor effects, whereas inhibition of miR-490-3p diminished its efficacy. Therapeutic combination index analysis indicated robust synergy between FMNT and 5-FU, with combination therapy achieving superior tumor growth inhibition compared to monotherapies. Collectively, our findings uncover a novel miR-490-3p/ABCC2 regulatory mechanism underlying FMNT's antitumor activity and highlight its potential for chemosensitization through ABCC2 inhibition, providing a strong rationale for flavonoid-based adjuvant therapy in CRC management.

Long-term or high-dose glucocorticoids (GCs) exposure leads to rapid bone loss and microarchitectural deterioration, ultimately resulting in glucocorticoid-induced osteoporosis (GIOP). Although the progression of GIOP is closely associated with impaired type H blood vessel function, the underlying mechanisms remain insufficiently defined. Using a dexamethasone (DEX)-induced GIOP mouse model, we observed a simultaneous reduction in type H blood vessels and Ephrin type-B receptor 4 (EphB4) expression. Co-culture of bone marrow mesenchymal stem cells (BMSCs) with endothelial cells (ECs) overexpressing EphB4 confirmed that endothelial EphB4 is a critical regulator of angiogenesis-dependent osteogenesis, a process disrupted by DEX-mediated EphB4 downregulation. Specifically, DEX-induced EphB4 downregulation induced cellular senescence in ECs, and the resulting senescence-associated secretory phenotype (SASP) may further impair BMSC osteogenic differentiation. We additionally observed that diminished EphB4-EphrinB2 crosstalk between ECs and BMSCs may further exacerbate osteogenesis. The Wnt/β-catenin pathway was identified as a critical mediator through which DEX inhibits EphB4 expression in ECs. Collectively, these findings reveal a previously unrecognized EphB4-mediated mechanism contributing to GIOP pathogenesis and provide mechanistic insight into potential therapeutic strategies targeting angiogenesis-osteogenesis coupling.

Diabetic kidney disease (DKD), a leading contributor of kidney failure, arises from glomerular damage, podocyte depletion, and fibrosis due to high blood glucose, worsened by inflammation and oxidative stress. Current therapies targeting late-stage symptoms (e.g., proteinuria, declining glomerular filtration rate) show limited efficacy and side effects.Extracellular vesicles (EVs), enriched in urine and kidney tissues, carry disease-associated cargoes, such as miRNAs and pro-fibrotic proteins, which interfere with intercellular communication and enhance pathological remodeling when absorbed by renal cells. Urinary and blood EV profiles are emerging as non-invasive biomarkers applicable to early diagnosis and surveillance with DKD advancement. Preclinical studies demonstrate engineered EVs deliveringanti-fibrotic agentsorpodocyte-protective moleculesas promising therapies, mitigating renal damage. This review describes the dual functions of EVs in DKD progression, highlighting their promise for diagnostic tools and targeted drug delivery systems, and discusses strategies to utilize EVs for precise kidney protection.

The present work investigates the in vitro hepatic metabolism of six commonly used sunscreen UV filters: oxybenzone, avobenzone, octocrylene, octinoxate, octisalate, and homosalate, using human liver microsomes. In vitro-in vivo extrapolation was performed to predict key metabolic parameters, including hepatic clearance (CL) and hepatic extraction ratio (E), providing valuable insights into the potential systemic persistence of these compounds after dermal or oral absorption. Additionally, reaction phenotyping was conducted for the first time to characterize the human liver enzymes involved in the metabolism of these sunscreen UV filters, with carboxylesterases (CES) playing a key role in the biotransformation of ester-containing compounds such as octocrylene and octinoxate. Furthermore, oxybenzone is predominantly metabolized by CYP2C19 and CYP1A2, while avobenzone is primarily metabolized by CYP2C19, CYP2C9, and CYP1A2. The results showed significant variability in metabolic stability and systemic clearance, with compounds like octocrylene exhibiting relatively higher half-lives, suggesting potential for bioaccumulation. The findings highlight the importance of understanding the kinetic profiles of sunscreen UV filters for more accurate risk assessments, particularly in the context of prolonged human exposure.

Cannabinoids and their G protein-coupled receptors (GPCRs) within the endocannabinoidome are pivotal regulators of neuromodulation, inflammation, and metabolic homeostasis. Dysregulation of this system has been associated with a wide spectrum of pathological conditions, including neuropsychiatric disorders, chronic pain, and immune dysfunction. In this review, we summarize recent structural advances in cannabinoid receptors that have deepened our understanding of receptor activation, allosteric modulation, transducer coupling selectivity, and dynamic conformational mechanisms. These structural insights will facilitate cannabinoid receptor-targeted drug discovery, enabling the development of therapeutics with improved subtype selectivity, enhanced signaling precision, and reduced off-target effects.

Arterial remodeling is strongly linked to cardiovascular morbidity and mortality. Adventitial inflammation is a key driver in the pathological process of arterial remodeling. However, the underlying molecular mechanism remains largely unknown. This study was conducted to elucidate the role and mechanism of peroxisome proliferator-activated receptor alpha (PPARα) in arterial remodeling. Here, by using the transverse aortic constriction (TAC) model to mimic overload pressure-induced arterial remodeling, we observed significantly decreased expression of PPARα in macrophages that infiltrated into the remodeled arterial adventitia, whereas the administration of PPARα agonist Wy14643 efficiently ameliorated such arterial changes, especially in adventitia. PPARα activation strengthened its interaction with yes-associated protein (YAP) in the cytoplasm thus decreasing the translocation of YAP into nucleus to trigger macrophage infiltration and polarization toward the classical activation phenotype. Finally, blockade of YAP signaling could also suppress pathological arterial alternations in the TAC model. Our study thus identifies PPARα as a promising therapeutic target for treating arterial remodeling.

Drug delivery using nanoparticles (NPs) represents a promising strategy to overcome the intrinsic skin barriers, particularly the stratum corneum, thereby enhancing the efficacy of anti-inflammatory therapies. A wide range of nanocarriers has been developed for transdermal and topical drug delivery; however, most studies to date have concentrated on drug stabilization within nanoparticles and system characterization, with limited emphasis on evaluating their therapeutic potential in animal models. In this review, we summarize research from the past decade that investigated in vivo models of inflammation (rats or mice), focusing on studies where drugs were encapsulated in NPs and administered via topical or transdermal routes. We concluded that although both organic and inorganic nanoparticles are utilized, most researchers favor organic nanoparticles due to their greater compatibility with the skin's structure. Across all studies, nanocarriers were shown to enhance the therapeutic potential of drugs. The data suggest the potential of nanoparticles in optimizing drug delivery systems and improving the efficacy of topical and transdermal anti-inflammatory therapies.

Environmental chemical exposure is associated with T2D incidence and may underly some of the large observed variation in therapeutic responses. Clinical and applicable preclinical studies could help reveal whether environmental chemicals interact with the action of drugs used for glucose management. We systematically searched for studies testing the interaction between environmental contaminants and T2D drug action on glucose regulation outcomes. We found no clinical studies that examined chemical exposure interaction with T2D drug action. Nine of 458 papers were eligible, all of which were preclinical. Four contained in vivo studies, four contained in vitro work and one contained both approaches. Bisphenols were the main focus (n = 4). Inhaled particulates (PM), polychlorinated biphenyls (PCBs), cadmium, arsenic, and per-and-poly-fluorinated-alkalated substances (PFAS) were each examined once. Metformin and rosiglitazone were the most frequently examined drugs (n = 4). Exendin-4 was investigated twice and glibenclamide once. Lack of study design comparability precluded meta-analysis. Instead, we calculated effect sizes and differences in outcome values (mean ± 95 % CI) for synthesis without meta-analysis (SWiM). Five studies reported impairment of drug action. Our analysis shows support for this conclusion was only present in two papers. Small sample sizes, short duration exposures, unrealistic chemical levels, lack of full factorial analysis and absence of testing in suitable T2D models restrict the applicability of the current, limited preclinical evidence for translation to clinical practice. The potential for chemical exposure to impact T2D medication effects on glucose control needs to be addressed with dedicated clinical studies in patients with T2D.

Hydrogen sulfide (HS), an endogenously produced gaseous signaling molecule, plays a pivotal role in cardiovascular physiology and pathology. In the cardiovascular system, HS is extensively involved in regulating a wide range of key cellular processes critical for maintaining cardiovascular health. Maintaining HS homeostasis is essential for cardiovascular health, and disruptions in its biosynthesis or signaling are implicated in the onset and progression of cardiovascular diseases (CVDs) such as atherosclerosis, heart failure, myocardial infarction, ischemia/reperfusion injury, stroke, cardiac hypertrophy, and fibrosis. Restoring HS balance, either by stimulating endogenous production or through the administration of exogenous HS donors, has shown considerable therapeutic potential in CVD management. In this review, we comprehensively summarize the essential functions of HS, examine HS-mediated cellular and pathophysiological processes within the cardiovascular system, including oxidative stress, mitochondrial function, inflammation, cellular senescence, cell death, proliferation, autophagy, calcium channels, calcium homeostasis, and glucose/lipid metabolism, and elucidate the underlying molecular mechanisms contributing to various CVDs. Additionally, we discuss recent progress in HS-based therapeutic strategies and their associated challenges, aiming to provide a thorough understanding of HS as a novel therapeutic target in CVDs.