As the primary receptor of oxidized low-density lipoprotein (ox-LDL), LOX-1 is a putative therapeutic target for atherosclerotic disorders including ischemic stroke (IS), whereas the regulatory mechanism of LOX-1 remains largely unknown in IS. We employed computational algorithms to screen candidate miRNAs, followed by integrative analysis of differentially expressed miRNA profiles derived from blood cells of 25 acute IS cases and 25 controls matched with age and gender. MiR-187-3p-mediated regulation of LOX-1 was confirmed by a dual-luciferase reporter assay and Western Blot in THP-1 derived macrophages. Elevated blood levels of miR-187-3p were observed both in IS patients and the atherosclerotic mice. In a case-control study enrolling 279 IS cases and 279 controls, we found that miR-187-3p level was significantly associated with the occurrence of IS (adjusted OR = 1.204; 95% CI: 1.086-1.335; p < 0.001). Similar results were replicated in another coronary heart disease case-control population. In vivo, systemic delivery of agomiR-187-3p significantly reduced atherosclerotic plaque burden alongside decreased plasma lipids and suppressed inflammation. In vitro, miR-187-3p over-expression attenuated foam cell formation induced by ox-LDL and down-regulated pro-inflammatory mediators in macrophages. Conversely, miR-187-3p inhibition exacerbated these effects, which were partially rescued by LOX-1 inhibitor BI-0115. This study establishes miR-187-3p as a novel epigenetic regulator of LOX-1 and provides critical evidence supporting its therapeutic potential for modulating IS progression.

Persistent inflammation derived from neutrophil activation drives delayed healing of diabetic wounds. Herein, a dissolvable alginate methacryloyl-based microneedle patch functionalized with polypeptide CFLFLFK-NH2-coupled manganese/zinc ion metal-organic framework (MnZn-MOF) loading enalaprilat (Ena) (TMZE@A-MN) is developed. Ena promotes neutrophil repolarization from pro-inflammatory N1 to anti-inflammatory N2 state by inhibiting nuclear factor (NF)-κB axis and activating Smad3 pathway, attributed to Ena-induced level elevation of taurine and subsequently STING signaling cascade suppression, thus causing macrophage phenotype switching and endothelial cell ferroptosis repression. Due to identifiable property of CFLFLFK-NH2 on neutrophil membrane receptors, the delivery system endows Ena with targeting inhibitory roles in neutrophil activation. In addition, MnZn-MOFs possess free radical-eliminating performance and can effectively combat the growth of methicillin-resistant Staphylococcus aureus and Escherichia coli. In vivo evaluation on diabetic murine and porcine wounds also demonstrates that the TMZE@A-MN accelerates wound healing process. Consequently, the targeted microneedle delivery system holds great promise for diabetic wound treatment.

Osteoarthritis (OA) is a highly prevalent degenerative joint disease affecting over 500 million people globally, imposing substantial social and economic burdens. Current treatments, including platelet-rich plasma (PRP), are limited by...

Chronic diabetic wounds are characterized by persistent inflammation, impaired angiogenesis, and disrupted intercellular communication, including altered macrophage-endothelial interactions. In this study, we develop macrophage membrane-camouflaged, didymin (DM)-loaded metal-organic framework microneedles (Mac@DM-MOF MNs), a biomimetic nanozyme platform designed to selectively restore this intercellular communication and re-establish a pro-regenerative microenvironment. RNA-seq and mechanistic analyses identify activation of the SPP1-ApoE signaling axis, an unrecognized pathway linking M2 polarization to endothelial activation, as a central mechanism by which Mac@DM-MOF MNs synchronize inflammation resolution and angiogenesis. Nanozyme-mediated ROS scavenging relieves redox stress, while DM promotes macrophage polarizationtoward the reparative M2 state. M2-derived SPP1 subsequently interacts with endothelial ApoE, thereby promoting endothelial sprouting, and restoring vascular functionality. In diabetic mouse and Bama mini pig models, Mac@DM-MOF MNs attenuate inflammation, rescue angiogenic deficits, and markedly accelerate wound closure. Importantly, vascular restoration further reinforces M2 polarization, forming a self-sustaining pro-healing feedback loop. Our findings define macrophage-endothelial coupling as a pivotal regulatory mechanism in diabetic wound repair and introduce a synergistic nanomedicine-based strategy that concurrently resolves chronic inflammation and restores angiogenesis.

MicroRNAs (miRNAs) function to silence target gene expression by repressing transcription or inducing mRNA degradation, thereby suppressing protein translation. Bioinformatics databases predict that the low-density lipoprotein receptor-related protein 6 gene (LRP6) is a downstream target gene of human miRNA-346. LRP6 protein plays an important role in regulating low-density lipoprotein cholesterol (LDL-c) levels, and knockout of the LRP6 gene or reduced LRP6 protein activity is closely associated with hyperlipidemia and atherosclerosis. However, the relationship between circulating miR-346 and LRP6 protein levels in patients with coronary atherosclerotic heart disease (CAD) remains unclear. The present study aimed to investigate the expression levels of serum miR-346 and LRP6 protein in CAD patients and to evaluate the correlation between them. Patients who underwent coronary angiography for the first time at The First Affiliated Hospital of Chengdu Medical College between February 2023 and June 2023 were enrolled. Based on clinical presentation, they were divided into three groups: acute coronary syndrome (ACS, n = 52), stable angina pectoris (SAP, n = 58), and control (n = 40). Serum miRNA-346, LRP6 protein, and LDL-c levels were compared among the groups, and correlations between these parameters and disease status were analyzed. Serum miRNA-346 levels in the ACS group were significantly higher than those in the SAP and control groups (H = 8.885, df = 2, P < 0.05). A weak but statistically significant positive correlation was observed between miR-346 and LRP6 protein levels (r = 0.196, P < 0.05), which remained significant after multivariable adjustment for demographic and metabolic covariates. A moderate negative correlation was found between LRP6 protein and LDL-c levels (r = − 0.530, P < 0.001). Serum miRNA-346 is involved in the pathological process of coronary atherosclerotic heart disease. A weak correlation exists between miRNA-346 and LRP6 protein levels.

Changes in the blood-brain barrier (BBB) are key targets for mitigating cerebral ischemia/reperfusion injury. The rapid progression of reperfusion injury necessitates the development of carriers that target and regulate early BBB disruption, while supporting its structure and function during BBB recovery. This study proposes the use of brain microvascular endothelial cell (mECs)-based vascular bandages carrying siRNAs to simultaneously target, support, and regulate the damaged BBB. Specifically, mECs can target damaged cerebral blood vessels after intravenous injection by interacting with the highly expressed very late antigen - 4 (VLA-4) in the vessels. Furthermore, by covering the cerebral blood vessels and forming new junction proteins with the vascular endothelium, mECs support the permeability and structural integrity of the vasculature. Additionally, oxygen-glucose deprivation-treated mEC culture supernatants (OGD-SN) can promote connexin 43 (CX43) expression, facilitating the delivery of therapeutic p66Shc siRNA to the damaged endothelium for BBB regulation. Ultimately, vascular bandage treatment rescued BBB function, alleviated reperfusion injury, and reduced the infarct area. Our study offers a new therapeutic strategy and a novel brain-targeted delivery platform for treating cerebral ischemia/reperfusion injury.

The IL-33/ST2 pathway plays a crucial role in the development of essential hypertension (EH). This study aimed to investigate the relationship between EH and genetic variations in this pathway in the Chinese Han population. A total of 1,151 EH patients and 1,135 healthy controls were included in the study. Sixteen single nucleotide polymorphisms (SNPs) in the interleukin-33 (IL-33) and interleukin-1receptor associated protein (IL-1RAcP) genes were genotyped using the Sequenom MassArray and TaqMan assays. Genotype and allele frequencies were compared between the EH patients and controls using logistic regression analysis. The rs16865597 SNP in the IL-1RAcP gene was found to be associated with the risk of EH. Specifically, the presence of the C allele of rs16865597 was negatively correlated with EH susceptibility in both the additive model (P = 0.014, OR = 0.75, 95

Our study aimed to analyze the reported cardiovascular AEs (CVAEs) associated with approved bispecific T-cell engagers (BiTEs) for multiple myeloma (MM), providing insights that could guide safer clinical use of BiTEs. Data were obtained from the FDA Adverse Event Reporting System (FAERS) database for the period from the fourth quarter of 2022 to the first quarter of 2024. A total of 1336 adverse events were reported, of which 112 were CVAEs, accounting for 8.4%. Reporting odds ratio (ROR) and information components (ICs) were extracted from the disproportionality analysis. At standardized MedDRA querie (SMQ) level, arrhythmias (n = 41, ROR025 = 1.49), noninfectious myocarditis/pericarditis (n = 184, ROR025 = 3.11), cardiomyopathy (n = 33, ROR025 = 1.52), shock (n = 23, ROR025 = 4.13) and cardiac failure (n = 16, ROR025 = 1.17) exhibited the positive signal strengths in ROR. And logistic regression analysis reveals that critical risk factors for BiTE-associated CVAEs include older age, male sex, weight loss, cytokine release syndrome, and respiratory failure. In the time-to-onset analysis, majority of CVAEs occurred within the first month (60.9%) and had early-failure type characteristics. It also should be emphasized that CVAEs were commonly associated with serious outcomes, with the most frequently reported being death (34%) Findings above suggest BiTE therapy in MM patients is significantly associated with an increased risk of CVAEs in clinic, and those who develop CVAEs have poorer prognosis. The study may provide important evidence for the precise management and mitigation of cardiovascular risks during BiTE therapy in MM patients, ensuring better clinical outcomes.

With the rapid development of neuroscience, many probes have been developed for detecting various neurotransmitters. However, in complex biological environments, single-reaction based probes may have false positives due to their poor anti-interference capability. Herein, we presented the development of sequential activated 'AND' logic-gate based fluorescent probes for monitoring ROS and tyrosine hydroxylase (TH) activity in complex nervous systems with high selectivity and accuracy. In hypertension (HTN) disease, stress can trigger sympathetic overactivation. Based on the synergistic elevation of H2O2 and TH activities in the nucleus of the nucleus tractus solitarius (NTS) in HTN model, 3-hydroxybenzyl was masked that responds to TH with arylboronate ester and arylboronic acid, thereby constructing the H2O2-TH sequential activated 'AND' logic gate-based ratiometric fluorescent probes. The cellular and in vivo imaging further validated the reliability of our design strategy for the H2O2-TH sequential response. Overall, the 'AND' logic gate-based ratiometric fluorescent probe PTH-2 can serve as an effective tool to detect ROS-activated sympathetic nerve activity in complex biological systems.

We aimed to evaluate the association between BMI and OS in patients with cancer by a combination of available evidence. Articles published from January 1st 2019 to June 1st 2024 were identified from PubMed, EMBASE, China National Knowledge Infrastructure (CNKI), and Wan Fang Library. Cohort studies including adult patients (≥ 18 years), who were confirmed with cancer and followed for 12 months or more, and whose BMI measurements and OS were available, were included. We used both fixed and random-effects models to estimate overall hazard ratios (HRs) for OS. The primary outcome was OS. The exposure was BMI, which was further classified into four groups based on both WHO and Chinese criteria. The current meta-analysis included 36 studies, involving 123,913 cancer patients (56,951 men and 66,962 women, medium follow-up 41.3 months). Compared with cancer patients with normal weight, the estimated HRs of OS for underweight was 1.43 (95

Atherosclerosis (AS) is a significant pathological contributor to cardiovascular disease, marked by high rates of death and illness globally. Yiqi Huoxue Huatan formula (YHH), a Chinese traditional decoction, has been clinically validated as effective for patients with AS; however, its underlying mechanisms remain partially unexplained. The goal of this research is to understand the protective effects of YHH against AS and the mechanisms involved. In vivo, YHH was administered orally at 14.24 and 28.47 g/kg/day (raw medicinal herbs) to ApoE-/- mice on a high-fat diet (HFD) to model AS. In vitro, RAW264.7 macrophages were exposed to oxidized low-density lipoprotein (ox-LDL) and YHH-conducting serum. The therapeutic effects of YHH were assessed using biochemical assays, histopathological observations, and enzyme-linked immunosorbent assays. Mass spectrometry, network pharmacology analyses, molecular docking, and western blotting were used to identify the primary components and anti-AS mechanisms of YHH. YHH significantly reduced AS development, as evidenced by decreased aortic plaque and lower blood lipid levels in HFD-induced AS mice. Meanwhile, YHH significantly decreased the increase in inflammatory cytokines in the supernatant of macrophages induced by ox-LDL. Mechanistic studies revealed that YHH significantly downregulated protein levels of TLR4, p-NF-κB, and HIF-1α. Moreover, molecular docking showed that key active compounds in YHH, including Gardenin A, isosinensetin, alisol B, 3',4',5',5,7-pentamethoxyflavanone, and scutellarein, exhibited strong binding activity to the core targets. YHH emerges as a promising agent in ameliorating AS by reducing inflammatory responses, achieved via the downregulation of TLR4/NF-κB/HIF-1α signaling pathways.

Introduction:Diabetic foot ulcer (DFU) is one of the most common complications of diabetes, with substantial morbidity and mortality. Narirutin (Nar), a bioactive phytochemical derived from citrus peel, has been suggested to possess anti-inflammatory abilities. However, the involvement of Nar in DFU development remains poorly understood. Methods:The polarization traits of bone marrow derived macrophages (BMDMs) with indicated treatments were determined by flow cytometry, immunofluorescence staining, western blot and qRT-PCR. Levels of lactate and α-ketoglutarate were measured for investigating the metabolic profiles. The cutaneous wounds of diabetic mice were established for evaluating the promotive roles of Nar in wound healing in vivo. Results:We found that high glucose treatment significant elevated the contents of TNF-α and IL-1β and lactate and reduced the levels of TGF-β1 and IL-4 and α-ketoglutarate in BMDMs. Then, Nar intervention effectively induced BMDMs repolarization from M1 to M2 state and the molecular mechanism was ascribed to drug-elicited activation of AMPK, which in turn increased the expression of downstream Mfn2, thereby enhancing the activity of oxidative phosphorylation and GATA3 cascade activation and disrupting the progress of glycolysis and NF-κB axis activation. Subsequently, we discovered that Nar injection effectively enhanced the healing rate of skin wounds in diabetic mice. Histological analysis showed that Nar dose-dependently induced dermis growth and collagen deposition in the wound area. Via activating AMPK/Mfn2 axis, Nar inhibited the activity of glycolysis and enhanced the extent of oxidative phosphorylation, accompanied by inflammation repression and angiogenesis promotion in the damaged tissue. Discussion:Our study discovered that macrophages repolarization to M2 phenotype was required for Nar-induced promotive effects on diabetic wound repair by regulating reprogramming of glucose metabolism via mediating AMPK/Mfn2 pathway, providing a promising strategy for DFU management.

Circadian rhythms are intrinsic 24-h biological cycles that govern various physiological processes. In addition to the hypothalamic suprachiasmatic nucleus, the circadian system is organized in multiple peripheral tissues, such as the brain, heart, bone, liver, and lung. Emerging evidence suggests that disruptions in these rhythms, which are regulated by a network of clock genes, play pivotal roles in human health. A deeper understanding of the interplay between circadian rhythms and tissue homeostasis holds significant potential for the development of targeted therapies aimed at improving human health. This review explores the link between circadian rhythms and tissue homeostasis, delving into their biological functions, including influences on metabolic homeostasis, neuroendocrine signaling, immune and oxidative stress responses, tissue repair, and autophagy activity. It also summarizes the connections between circadian disruptions and circadian disruption-related diseases, including degenerative diseases, cardiometabolic disorders, and cancers. Furthermore, this review offers valuable perspectives on the treatment of circadian disruption-related diseases. By revealing the regulatory influence of circadian rhythms on human health and disease, this work aims to inspire the development of novel strategies for the prevention, diagnosis, and treatment of circadian disruption-related diseases.

Tissue regeneration is essential for repairing and restoring damaged tissues, which has significant implications for clinical outcomes. Understanding the cellular mechanisms and the role of the immune system in this process provides a basis for improved regenerative techniques. The emergence of nanomedicine has advanced this field by introducing nanoscale technology that offer precise control over therapeutic delivery and cellular interactions. By modulating immune responses, various immunotherapeutic approaches, including cytokine therapy and immune checkpoint inhibitors, can establish an optimal environment for tissue repair. This review summarizes recent findings and applications of nanomedicine-based immunotherapy in tissue regeneration. It highlights the properties and advantages of nanomedicine in immunotherapy, discusses recent progress in using nanocomposite biomaterials for tissue engineering, and addresses the challenges and future directions in this evolving field. This review aims to emphasize the promising potential of nanomedicine-based immunotherapy in tissue engineering, thereby contributing to the functional design and strategic development of next-generation nanomedicine for regenerative medicine.

Continuously bacterial infection, undue oxidative stress, and inflammatory responses in the skin tissue microenvironment determine the delayed healing outcome of diabetic wounds, which remain a tough clinical challenge and need multifaceted therapeutic strategies. In this work, HA-ADH/HA-QA-ALD-based hydrogel microneedle (HAQA-MN) with antimicrobial and antioxidative activities incorporating kinsenoside (KD) coated with macrophage membrane (M-KD) targeting inflammation relief is developed to improve the cutaneous micro-niche. KD is observed to trigger trimethylamine N-oxide-irritated proinflammatory macrophages repolarization from M1 state to anti-inflammatory M2 phenotype, and the underlying mechanism is due to drug-induced IRE1α/XBP1/HIF-1α pathway suppression, accompanied by diminution of glycolysis and enhancement of oxidative phosphorylation, resulting in proinflammatory cascade inhibition and anti-inflammatory signaling enhancement. The hydrazone cross-linked HAQA-MN possesses favorable biocompatibility, self-healing, controlled release of M-KD and excellent mechanical properties. Moreover, the MN patch remarkedly restrains the survival of E. coli and S. aureus and eliminates hydrogen peroxide to preserve cellular viability. Notably, M-KD@HAQA-MN array effectively ameliorates cutaneous inflammation and oxidative stress and facilitate angiogenesis and collagen deposition, thereby accelerating tissue regeneration of diabetic mice with a full-thickness skin defect model. Collectively, this study highlights a multifunctional MN platform as a promising candidate in clinical application for the treatment of diabetic wounds.

Metal–organic frameworks (MOFs) exhibit exceptional characteristics, including high porosity and adjustable properties, rendering them highly suitable for biomedical applications. Recently, researchers have directed their attention toward the integration of MOFs into composites for bone tissue regeneration (BTE), presenting distinct advantages over conventional substitutes. In this comprehensive review, the authors delve into the latest advancements concerning MOF‐integrated composites for BTE. This exploration encompasses an examination of the properties of MOFs and the various synthesis techniques employed to fabricate these materials. Furthermore, the diverse applications of MOF‐integrated composites in BTE are investigated, encompassing areas such as antibacterial properties, osteogenic differentiation, angiogenesis, and immunomodulation. By providing a comprehensive overview of the ongoing research on MOF‐integrated composites for BTE, this study holds the promise of yielding innovative solutions within the realm of orthopedics.

Osteoporosis, characterized by a reduction in bone mineral density, represents a prevalent skeletal disorder with substantial global health implications. Conventional therapeutic strategies, exemplified by bisphosphonates and hormone replacement regimens, though effective, encounter inherent limitations and challenges. Recent years have witnessed the surge of cell-membrane-coated nanoparticles (CMNPs) as a promising intervention for osteoporosis, leveraging their distinct attributes including refined biocompatibility, heightened pharmaceutical payload capacity, as well as targeted drug release kinetics. However, a comprehensive review consolidating the application of CMNPs-based therapy for osteoporosis remains absent within the existing literature. In this review, we provide a concise overview of the distinctive pathogenesis associated with osteoporosis, alongside an in-depth exploration of the physicochemical attributes intrinsic to CMNPs derived from varied cellular sources. Subsequently, we explore the potential utility of CMNPs, elucidating emerging trends in their deployment for osteoporosis treatment through multifaceted therapeutic approaches. By linking the notable attributes of CMNPs with their roles in mitigating osteoporosis, this review serves as a catalyst for further advances in the design of advanced CMNPs tailored for osteoporosis management. Ultimately, such progress is promising for enhancing outcomes in anti-bone loss interventions, paving the way for clinical translation in the near future.

Diabetes-associated chronic skin wounds present a formidable challenge due to inadequate angiogenesis and nerve regeneration during the healing process. In the present study, we introduce a groundbreaking approach in the form of a novel cocktail therapy utilizing a multifunctional supramolecular hydrogel. Formulated through the photo-crosslinking of gelatinized aromatic residues and β-cyclodextrin (β-CD), this injectable hydrogel fosters weak host-guest interactions, offering a promising solution. The therapeutic efficacy of the hydrogel is realized through its integration with adipose-derived stem cells (ADSCs) and lipid nanoparticles encapsulating ginsenoside RG1 and Stromal cell-derived factor-1 (SDF-1). This strategic combination directs ADSCs to the injury site, guiding them toward neurogenic specialization while establishing an advantageous immunomodulatory environment through macrophage reprogramming. The synergistic effects of the newly differentiated nerve cells and the regenerative cytokines secreted by ADSCs contribute significantly to enhanced angiogenesis, ultimately expediting the diabetic wound healing process. To summarize, this innovative hydrogel-based therapeutic system represents a novel perspective for the management of diabetic wounds by concurrently targeting immune response, angiogenesis, and nerve regeneration—a pivotal advancement in the quest for effective solutions in diabetic wound care.

Introduction & Objective: HR17031 is a once-daily, novel combination of basal insulin analogue (INS068) and GLP-1 receptor agonist (SHR20004). This trial assessed efficacy and safety of HR17031 vs INS068 and SHR20004 in pts with T2D. Methods: In this randomized phase 2 trial, 455 Chinese adults with T2D (HbA1c 7.5%-11.0%; previous metformin±another OAD) were randomized (2:2:1) to daily injections of HR17031 (n = 183), INS068 (n = 182) or SHR20004 (0.12 mg/d; n = 90). Primary outcome was HbA1c change at 26 weeks. Results: After 26 weeks, greater reduction in HbA1c from baseline was achieved with HR17031 compared with INS068 and SHR20004 (-2.4% vs -1.5% and -1.7%; Fig 1), indicating superiority for HR17031 vs both INS068 (difference [D] = -0.9%) and SHR20004 (D = -0.7%). More pts reached HbA1c target <7% and <6.5% with HR17031 (<7%, 81.4%; <6.5%, 74.3%) than INS068 (47.8%; 26.4%) and SHR20004 (55.6%; 41.1%). HR17031 led to weight loss in contrast to INS068 (-0.1 vs 2.0 kg). Insulin dose of HR17031 was lower than INS068 (30.3 vs 38.1 U/d). All the above results were statistically significant (all P <0.001). Documented <3.0 mmol/L hypoglycemia was similar with HR17031 (5.5%) and INS068 (4.4%). No unexpected safety issues occurred. Conclusion: HR17031 is effective and well-tolerated in pts with T2D uncontrolled on OAD(s). Disclosure L. Ji: None. D. Huang: None. X. Lin: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. X. Dong: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. L. Li: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Q. Sun: None. X. Sun: None. L. Mao: None. S. Zhao: None. Q. Wang: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Z. Ye: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Funding Jiangsu Hengrui Pharmaceuticals Co., Ltd (sponsor)