Sepsis is a systemic inflammatory response syndrome triggered by infection that frequently involves multiple organs, ultimately leading to multiple organ failure. Among affected organs, the lungs represent the most vulnerable target. Sepsis-associated lung injury (S-ALI) is a common critical illness that can progress to acute respiratory distress syndrome in severe cases, resulting in high morbidity and mortality. Currently, clinical management relies predominantly on mechanical ventilation and supportive care, as no specific pharmacological treatment exists for S-ALI. The pathogenesis of S-ALI is characterized by uncontrolled inflammation, microcirculatory dysfunction, immune dysregulation, mitochondrial impairment, and oxidative stress. Notably, mitochondrial dysfunction and oxidative stress are closely associated with tissue hypoxia and metabolic reprogramming. Hypoxia-inducible factor-1 (HIF-1) is a pivotal transcription factor that regulates gene expression under hypoxic conditions. It becomes activated during hypoxia and inflammatory responses, thereby coordinating cellular metabolic adaptation and inflammatory pathways. In S-ALI, both the expression and activity of HIF-1 are markedly upregulated, playing a critical role in modulating inflammation, immunity, and metabolic reprogramming. These findings suggest that targeted modulation of HIF-1-mediated metabolic reprogramming in S-ALI may improve patient outcomes by simultaneously addressing inflammatory, immune, and metabolic dysfunction. This review examines the pathogenesis of S-ALI, HIF-1-mediated metabolic reprogramming in S-ALI, the crosstalk between HIF-1 and multiple signaling pathways, and its impact on inflammatory responses and immune function. Our goal is to identify novel therapeutic targets for S-ALI treatment.

Ischemia-reperfusion injury, a critical pathophysiological phenomenon in multiple organ systems, remains a formidable therapeutic challenge in clinical practice. As the third endogenously produced gaseous signaling molecule, hydrogen sulfide (H2S) has emerged as a pivotal regulator of diverse physiological processes and pathological cascades. Accumulating evidence indicates that H2S exerts cytoprotective effects against cerebral, cardiac, hepatic, renal, and pulmonary ischemia-reperfusion injuries through multifaceted mechanisms involving mitigation of inflammatory responses, suppression of oxidative stress, modulation of autophagic processes, and inhibition of apoptotic pathways. This comprehensive review systematically examines the endogenous biosynthesis and metabolic regulation of H2S, while elucidating the molecular mechanisms underlying its organ protective effects during ischemia-reperfusion injury. Particular emphasis is placed on the therapeutic potential of H2S synthase isoforms and bioactive metabolites in ischemic pathophysiology. Notably, recent advances in H2S pharmacology have catalyzed the development of novel H2S donors and slow-releasing compounds, including HSDF-NH2, S-allyl cysteine, S-propargyl cysteine, and S-(4-fluorobenzyl)-N-(3,4,5-trimethoxybenzoyl)-L-cysteine. These pharmacological innovations demonstrate enhanced tissue specificity and controlled release kinetics, paving the way for clinical translation of H2S-based therapeutics in ischemia-reperfusion injury management. Future research directions should focus on optimizing drug delivery systems and elucidating the spatiotemporal dynamics of H2S signaling in organ-specific ischemia-reperfusion pathologies.

Selenium nanoparticles (SeNPs) have emerged as promising anticancer agents due to their selective cytotoxicity and ability to modulate oncogenic signaling pathways. In this study, we developed a novel L-cysteine-modified selenium nanoparticles (L-SeNPs) system and investigated its antitumor effects and underlying molecular mechanisms in ovarian cancer cells. Our results demonstrated that L-SeNPs significantly inhibited cell proliferation and clonogenic potential in a dose- and time-dependent manner in A2780 and SKOV3 ovarian cancer cells. Mechanistically, L-SeNPs induced intracellular reactive oxygen species (ROS) accumulation, which subsequently resulted in DNA damage, as indicated by the accumulation of γ-H2AX. Treatment with the ROS scavenger N-acetyl-L-cysteine (NAC) markedly attenuated L-SeNPs-induced DNA damage, indicating that ROS generation serves as an upstream event in this process. L-SeNPs further triggered mitochondrial apoptosis characterized by activation of Bax, Bak, and cleaved PARP-1, along with downregulation of Bcl-2. Transcriptomic profiling revealed significant enrichment of the FOXO signaling pathway following L-SeNPs treatment, with GADD45A identified as a key upregulated downstream effector. Further mechanistic studies demonstrated that ROS-mediated DNA damage promoted FOXO3a nuclear translocation, leading to transcriptional activation of GADD45A. Functional experiments confirmed that both FOXO3a and GADD45A are essential for L-SeNPs-induced apoptosis, and restoration of GADD45A partially rescued apoptotic activity in FOXO3a-silenced cells, indicating that GADD45A acts downstream of FOXO3a. In conclusion, L-SeNPs exert potent antitumor effects in ovarian cancer cells by inducing ROS-mediated DNA damage and activating the FOXO3a-GADD45A axis, thereby triggering mitochondrial apoptosis and suppressing tumor cell proliferation. These findings provide new mechanistic insights into selenium-based nanomaterials and suggest the FOXO3a-GADD45A pathway as a potential therapeutic target for ovarian cancer treatment.

Intestinal ischemia-reperfusion injury (IRI) is a significant clinical challenge with limited effective treatments. This study investigated the protective effects of ketogenic diet (KD) and β-hydroxybutyrate (BHB) against intestinal IRI using mouse models and intestinal organoids. Following two weeks of KD or BHB administration, mice were subjected to superior mesenteric artery occlusion (60 min) and reperfusion (4 h). Both interventions significantly elevated blood BHB levels and reduced fasting glucose. KD and BHB markedly attenuated intestinal villous damage, preserved epithelial barrier function (E-cadherin, Occludin, ZO-1), maintained mitochondrial integrity, reduced inflammatory cytokines (IL-6, IL-1β, TNF-α), and improved 72-h survival rates, with KD demonstrating superior efficacy. In intestinal organoid oxygen-glucose deprivation models, BHB exhibited differential protective effects at two tested concentrations (2 mM vs. 5 mM), with enhanced protection at the higher concentration on cellular viability, structural integrity, and inflammatory responses. These findings provide the first evidence that ketogenic interventions protect against intestinal IRI through multiple mechanisms including inflammatory suppression and barrier preservation, suggesting potential clinical applications in intestinal IRI prevention and management, though detailed mechanistic elucidation requires further investigation.

Intestinal ischemia reperfusion (II/R) injury is a common critical disease with high morbidity and mortality. The mechanism of II/R-induced acute lung injury (ALI) is not fully elucidated. Yes-associated protein (YAP), a downstream transcriptional coactivator of the Hippo signaling pathway, plays a central role in controlling organ development and cell proliferation. However, whether YAP is involved in regulating II/R-induced ALI remains to be further explored. This study aimed to investigate the regulatory role of YAP in ALI and ferroptosis caused by II/R, and to explore whether YAP exerts anti-ferroptosis and anti-inflammatory effects by promoting nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear entry and upregulating Nrf2 expression. In vivo models demonstrated that overexpression of YAP inhibited II/R-induced ALI and ferroptosis. This was evident through the upregulation of glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), and Nrf2 expression, as well as the mitigation of characteristic mitochondrial ferroptosis changes in lung type II epithelial cells. Additionally, YAP overexpression protected against II/R-induced ALI in mice, leading to notable improvements in lung pathology, reduced pulmonary edema, and decreased lung inflammation. Consistent conclusions were also reached in vitro models. It was observed that overexpression of YAP inhibited ferroptosis and oxidative stress by increasing Nrf2 expression and promoting its nuclear translocation. Additionally, it was discovered that knocking down Nrf2 resulted in the abolition of YAP-mediated ferroptosis alleviation in MLE-12 cells. Based on our findings, we can infer that YAP inhibits ferroptosis by upregulating Nrf2 expression and promoting its translocation into the nucleus, thereby ameliorating oxidative stress and lung injury along with the systemic inflammatory response following II/R. Furthermore, we propose that targeting YAP could be a promising approach for the treatment of ALI by suppressing ferroptosis.

Ischemia-reperfusion injury (IRI) represents a pathophysiological phenomenon of profound clinical relevance that poses considerable threats to patient safety. IRI may manifest in a variety of clinical contexts including, but not limited to, sepsis, organ transplantation, shock, myocardial infarction, cerebral ischemia, and stroke. Critically, IRI exhibits complex interactions across different organs, with effects that surpass mere localized tissue damage. These impacts can amplify damage to both adjacent and remote organs through pathways such as the gut-brain axis and the gut-lung axis, facilitated by intricate signaling mechanisms. Noteworthy is the interaction between gut IRI and brain IRI, which involves sophisticated neuroendocrine, systemic, and immune mechanisms coordinated through the microbiome-gut-brain axis. This review seeks to delve into the intricate interactions between gut and brain IRI, viewed through the lens of the microbiota-gut-brain axis. It aims to assess its translational potential in clinical settings, provide a theoretical foundation for developing relevant therapeutic strategies, and pinpoint novel directions for research.

Hepatic encephalopathy (HE), a neuropsychiatric complication secondary to liver cirrhosis and hepatic failure, represents the leading cause of mortality in end-stage liver disease. While hyperammonemia remains the central pathogenic factor in HE progression, emerging evidence implicates oxidative stress, neuroinflammation, and neuronal apoptosis as critical synergistic contributors to HE pathogenesis. Hydrogen-rich water, known for its antioxidant, anti-inflammatory, and anti-apoptotic properties, has not been systematically investigated for therapeutic efficacy in HE management. In the current investigation, we successfully established a HE rat model by administering thioacetamide via intraperitoneal injection. By observing the general state and behavioral changes of the rats, detecting liver function and blood ammonia, and observing the pathological changes of liver and brain tissue, it was discussed whether hydrogen-rich water had a preventive and therapeutic effect on hepatic encephalopathy. Oxidative stress, inflammation and neuronal apoptosis were detected in plasma, prefrontal cortex and hippocampus to explore the possible mechanism of its protective effect. The results showed that hydrogen-rich water can improve the behavioral changes of the HE rats, reduce blood ammonia, reduce liver function damage, alleviate the pathological changes of liver and brain tissue, significantly inhibit the systemic and local oxidative stress and inflammation of the brain tissue of the HE rats, and reduce neuronal apoptosis. In summary, hydrogen-rich water might stabilize liver-brain disturbance in thioacetamide-induced HE rats by anti-inflammation, anti-oxidative stress and reducing neuronal apoptosis.

Intestinal ischemia-reperfusion injury (IIRI) represents a severe acute abdominal condition characterized by high mortality and multifaceted pathophysiological mechanisms. The principal features include tissue oxygen deficiency during ischemic phases followed by intensified oxidative stress during reperfusion, resulting in intestinal mucosal barrier dysfunction, inflammatory mediator release, and cellular death pathways activation. Recent advances have highlighted the significance of post-translational modifications (PTMs) in regulating protein functionality. This review explores various key PTMs (phosphorylation, acetylation, methylation, ubiquitination, and glycosylation) and their involvement in IIRI pathogenesis. We examine how these modifications orchestrate multiple signaling cascades, including JAK/STAT, PI3K/Akt, AMPK, and MAPK pathways, by altering protein activity, stability, and interaction networks, thereby influencing cellular survival, apoptotic mechanisms, and inflammatory processes. Looking forward, we anticipate further investigation into the complexity and temporal dynamics of additional PTM types, as well as the interplay between various modifications and their systemic regulatory functions, to better understand PTMs in IIRI pathophysiology and develop novel therapeutic interventions.

Sepsis is defined as a condition of immune dysregulation in response to an infection, and sepsis-associated encephalopathy (SAE) is often the initial symptom that manifests in patients with sepsis. This condition is characterized by its high mortality rates and the potential to cause significant disability among survivors. Despite its severity, the underlying pathophysiologic mechanisms that contribute to the development of SAE are not yet fully understood. Additionally, there are no established strict diagnostic criteria or potent treatment options available for this condition. However, an increasing body of evidence suggests that an imbalance in the gut microbiota is associated with SAE, potentially through the gut-brain axis (GBA). The GBA axis refers to the bidirectional communication between the gut microbiota and the central nervous system. In this review, we discuss the changes in the gut microbiota in SAE and the mechanisms of the GBA axis, involving neural, immune, endocrine, and neurotransmitter pathways. Finally, we conclude by evaluating the preclinical and clinical evidence for fecal microbiota transplantation and probiotics in SAE. Targeting the GBA axis will be an actionable target to ameliorate the development and progression of SAE.

BACKGROUND:Acute lung injury commonly arises as a secondary complication following intestinal ischemia/reperfusion (II/R) injury. Celastrol (CEL), recognized for its therapeutic effects on inflammation-related conditions such as acute lung injury. Its protective efficacy against II/R-induced acute lung injury remains insufficiently investigated. The Hippo-YAP signaling pathway regulates ferroptosis and plays a pivotal role in II/R injury. PURPOSE:To evaluate whether CEL can activate the Hippo-YAP signaling pathway, suppress ferroptosis, and mitigate II/R-induced acute lung injury. METHODS:Firstly, an II/R model in mice was established, Immunofluorescence staining and Western blot were used to evaluate the effects of CEL on the Hippo signaling pathway and ferroptosis regulation. Network pharmacology predicted the relevance of the Hippo-YAP signaling pathway in CEL's improvement of acute lung injury. Molecular docking experiment indicated that CEL binds effectively to yes-associated protein (YAP), and overexpression of YAP significantly alleviated both lung injury and ferroptosis. Furthermore, the oxygen-glucose deprivation/recovery (OGD/R) model of MLE-12 cells was developed to further confirm CEL's inhibition of ferroptosis via the Hippo-YAP signaling pathway. RESULTS:CEL ameliorated II/R-induced acute lung injury and inhibited inflammation. In vivo and in vitro studies further revealed that CEL significantly reduced ferroptosis and reactive oxygen species (ROS) accumulation in the lung epithelial cells. CONCLUSION:CEL effectively mitigated ferroptosis and II/R-induced acute lung injury through elevating YAP protein level, reducing lipid peroxidation, and decreasing intracellular iron accumulation. This study highlights CEL's therapeutic potential for inhibiting ferroptosis, provides mechanistic insights to support CEL's broader therapeutic utility.

MicroRNAs play crucial roles in regulating inflammatory responses and disease progression. Since its identification on chromosome 17q11.2 in 2005, miR-451 has emerged as a key regulator of multiple physiological and pathological processes. While its role in cancer has been extensively documented, accumulating evidence reveals miR-451’s broader significance in inflammatory conditions through the regulation of NF-κB, AMPK, and PI3K signaling pathways. This comprehensive review systematically analyzes miR-451’s multifaceted functions in inflammatory diseases, with particular focus on ischemia–reperfusion injury, arthritis, and acute organ injuries. We present compelling evidence for miR-451’s potential as a diagnostic biomarker, demonstrating its distinctive expression patterns across various biological specimens and disease states. Furthermore, we elucidate how miR-451 modulates inflammatory responses through the regulation of immune cell populations, including microglia activation, macrophage polarization, and neutrophil chemotaxis. By integrating current evidence and bioinformatic analyses, we establish a theoretical framework linking miR-451’s molecular mechanisms to its therapeutic applications. This review not only synthesizes the current understanding of miR-451 in inflammatory diseases but also provides critical insights for developing novel diagnostic tools and therapeutic strategies.

Ischemia-reperfusion injury (IRI) is a critical condition that poses a significant threat to patient safety. The production of lactate increases during the process of IRI, and lactate serves as a crucial indicator for assessing the severity of such injury. Lactylation, a newly discovered post-translational modification in 2019, is induced by lactic acid and predominantly occurs on lysine residues of histone or nonhistone proteins. Extensive studies have demonstrated the pivotal role of lactylation in the pathogenesis and progression of various diseases, including melanoma, myocardial infarction, hepatocellular carcinoma, Alzheimer’s disease, and nonalcoholic fatty liver disease. Additionally, a marked correlation between lactylation and inflammation has been observed. This article provides a comprehensive review of the mechanism underlying lactylation in IRI to establish a theoretical foundation for better understanding the interplay between lactylation and IRI.

To investigate whether Liraglutide had a neuroprotective after cardiac arrest and return of spontaneous circulation (CA/ROSC) and explore its potential mechanisms. Adopting an 8-min asphyxial cardiac arrest model. Evaluate the neurological deficit score (NDS), observe pathological changes in hippocampal tissue with HE staining, and measure the expression level of proteins in hippocampal tissue with Western blot. Detection of hippocampal cell apoptosis using TUNEL (TdT-mediated dUTP Nick-End Labeling) method. Immunofluorescence staining was used to detect the expression of LC-3 in the hippocampus, and enzyme linked immunosorbent assay (ELISA) was used to detect the inflammatory factor TNF-α and IL-1β in serum and hippocampus. Autophagy and apoptosis were activated and the expressions of proteins reached significance at 24 h after CA/ROSC. Moreover, rapamycin enhanced apoptosis, ferroptosis and aggravated neuro-pathological damage while 3-methyladenine reduced that. Furthermore, liraglutide treatment improved the 7-day survival rate and NDS, reduced histological signs of injury and inhibited apoptosis, ferroptosis and inflammatory cytokines released after cardiac arrest, and these effects were offset by autophagy agonist. Liraglutide could exert a protective role against post-cardiac arrest brain injury, which could be partially mediated by inhibiting autophagy and ferroptosis. Results clearly indicate that liraglutide may attenuate post-cardiac arrest brain injury (PCABI) by anti-apoptotic and anti-inflammatory via inhibiting autophagy and ferroptosis.

Background:Irisin, a novel myokine, has garnered significant attention for its roles in metabolic regulation and anti-inflammatory responses. Sepsis disrupts the intestinal microenvironment, exacerbating its progression and highlighting the need for novel therapeutic approaches. This study aims to investigate whether irisin exerts protective effects against lipopolysaccharide (LPS)-induced intestinal injury in septic conditions and to explore the underlying mechanisms involving the gut microbiota. Methods:To induce sepsis, C57BL/6 mice were injected intraperitoneally with LPS at a dose of 10 mg/kg, and then administered with 1 µg/kg of irisin. The Activity levels and 7-day survival rate were recorded. The intestinal expression of irisin/FNDC5 was assessed using Western blotting and immunofluorescence staining. Inflammatory factors were measured using enzyme-linked immunosorbent assay (ELISA). Peripheral blood bacteria were cultured on blood agar plates. Intestinal histomorphology was analyzed via hematoxylin and eosin (H&E) staining. The expression of occludin and apoptotic-related proteins was determined by Western blot, and apoptotic cells were detected using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method. The intestinal microbiota was analyzed through 16S rRNA amplicon sequencing. Results:Irisin improved the survival state and rate of LPS-induced septic mice. It restored endogenous irisin/FNDC5 levels in intestinal tissues, mitigated intestinal barrier injury, and alleviated bacteremia following sepsis treatment. Furthermore, irisin exhibited anti-inflammatory properties by increasing the levels of IL-22 while decreasing those of TNF-α and IL-6, as well as anti-apoptotic effects by increasing levels of pro-caspase-3 and Bcl-2 while decreasing cleaved caspase-3, Bax, and the positive density of apoptotic cells. Additionally, it regulated intestinal microbiota dysfunction. Conclusion:Irisin effectively treats septic acute intestinal injury by reducing apoptosis and inflammation, with the intestinal microbiota likely playing a crucial role. This finding offers a novel approach to clinical management of sepsis.

Intestinal ischemia/reperfusion (II/R) is a common and grave clinical event, with high morbidity and mortality which can cause cerebral dysfunctions. There are no ideal prevention and treatment measures yet. The present study aimed to determine whether muscle-derived factors can alleviate gut-associated cerebral dysfunctions (GACD) following II/R. We measured the tibialis anterior muscle thickness and irisin levels in patients with and without cognitive dysfunction following cardiopulmonary bypass surgery, calculating the correlation between irisin and cognitive impairment. We found that this protective effect is related to muscle-derived irisin. To elucidate the role of irisin in improving GACD, we knocked out FNDC5 to deplete endogenous irisin and supplemented exogenous irisin. Mechanistic insights into irisin's effects on GACD were investigated using in vivo and in vitro models, incorporating techniques such as transmission electron microscopy, protein docking analysis, gene overexpression, and western blotting. FNDC5/irisin deficiency aggravated cognitive impairments, the pro-inflammation microglia activation, oxidative injury, inflammatory response, neuronal apoptosis and ferroptosis, while recombinant FNDC5/irisin reversed the above changes leading to neurostructural and cognition recovery. Mechanistically, thioredoxin-interacting protein (TXNIP) was activated in the II/R-related neuropathology and was deteriorated in FNDC5/irisin knockout mice. Our results highlight the potential of FNDC5/irisin to slow GACD, providing new insights and potential therapeutic strategies for the prevention and treatment of GACD.

Bladder cancer (BLCA), particularly due to the high recurrence and progression rates of non-muscle-invasive bladder cancer (NMIBC), is a significant global health challenge. Current treatments, such as Bacillus Calmette-Guérin (BCG) immunotherapy and intravesical chemotherapy, often cause substantial side effects and exhibit limited efficacy, highlighting the urgent need for novel therapeutic strategies. Single-cell spatial transcriptomic advancements have identified cuproptosis as a critical pathway in BLCA, presenting a promising target for treatment. In this study, these insights were leveraged to design Cu-VT nanoparticles (NPs), an innovative composite material that combines the unique properties of copper ions and the natural flavonoid vitexin, to induce cuproptosis. Cu-VT NPs could effectively induce apoptosis and oxidative stress in BLCA cells concurrently modulating the immune response within the tumor microenvironment. Comprehensive in vitro and in vivo experiments demonstrated that Cu-VT NPs significantly inhibited tumor growth and reduced lung metastasis through cuproptosis induction. This dual-function composite material enhances therapeutic efficacy and minimizes side effects, showcasing its potential as a revolutionary treatment for BLCA. Our findings highlight the transformative potential of Cu-VT NPs in the context of BLCA treatment, establishing a new paradigm in the use of composite materials for the treatment of advanced cancer.

In the study, the protective effects of wheat gluten hydrolysates (WGH) on the ethanol-induced injury in yeast cells were investigated, and the peptides that enhanced the resistance to 10% (v/v) ethanol-stress were identified. Results showed that the growth and viability of yeast under ethanol-stress were significantly enhanced by WGH, and it indicated that there were high activity fractions in WGH. Interestingly, eight wheat gluten peptides (WGP) were obtained and identified as EP, LL, LW, LPL, LML, LLL, LLW, and EFPL, respectively, and five (LL, LLL, LW, LML and EP) of them worked best. Furthermore, WGP could enhance the yeast resistance to ethanol-stress, and the WGP apparently maintained the morphology and structure (especially the cell walls and membranes) of yeast under ethanol-stress. Further studied found that WGP (especially LL and LW) contributed to increasing cell wall integrity and cell membrane fluidity while also reducing cell membrane permeability. TEM analysis found that due to the existence of LL and LW, both the thickness of cell wall and the integrity of cell membrane were enhanced, on the contrary, the cell membrane degradation and cytoplasmic efflux were reduced. These results revealed that WGP could be considered as an effective protector of yeast against ethanol-stress damage.

The gut microbial metabolite trimethylamine N-oxide (TMAO) is regarded as a novel risk factor for hypertension. Berberine (BBR) exerts cardiovascular protective effects by regulating the gut microbiota-metabolite production pathway. However, whether and how BBR alleviates TMAO-induced vascular dysfunction in hypertension remains unclear. In the present study, we observed that plasma TMAO and related bacterial abundance were significantly elevated and negatively correlated with vascular function in 86 hypertensive patients compared with 46 normotensive controls. TMAO activated endoplasmic reticulum stress (ERS) signaling pathway to promote endothelial cell dysfunction and apoptosis in vitro. BBR (100, 200 mg · kg-1 ·d-1) for 4 weeks ameliorates TMAO-induced vascular dysfunction and ERS activation in a choline-angiotensin II hypertensive mouse model. We found that plasma TMAO levels in 15 hypertensive patients treated with BBR (0.4 g, tid) were reduced by 8.8 % and 16.7 % at months 1 and 3, respectively, compared with pretreatment baseline. The oral BBR treatment also improved vascular function and lowered blood pressure. Faecal 16 S rDNA showed that BBR altered the gut bacterial composition and reduced the abundance of CutC/D bacteria in hypertensive mice and patients. In vitro bacterial cultures and enzyme reaction systems indicated that BBR inhibited the biosynthesis of TMAO precursor in the gut microbiota by binding to and inhibiting the activity of CutC/D enzyme. Our results indicate that BBR improve vascular dysfunction at least partially by decreasing TMAO via regulation of the gut microbiota in hypertension.

Introduction: Metastatic castration-resistant prostate cancer (mCRPC) patients face challenges due to limited treatment options. About 50% of patients with mCRPC have a functional loss of phosphatase and tensin homology deleted on chromosome 10 (PTEN), leading to tumor progression, metastasis, and immune suppression. Moreover, elevated IL-23 produced by myeloid-derived suppressor cells (MDSCs) is found in CRPC patients, driving tumor progression. Therefore, a combination strategy based on PTEN restoration and IL-23 inhibition may block CRPC progression and metastasis.Methods: The antitumor effect of restoring PTEN expression combined with the IL-23 inhibitor Apilimod was studied in a mouse model of bone metastasis CRPC and mouse prostate cancer RM-1 cells. To verify the targeting ability of PTEN DNA coated with lipid nanoparticles (LNP@PTEN) in vitro and in vivo. In addition, RT-qPCR and flow cytometry were used to investigate the related mechanisms of the antitumor effect of LNP@PTEN combined with Apilimod.Results: LNPs exhibited significant tumor-targeting and tumor accumulation capabilities both in vitro and in vivo, enhancing PTEN expression and therapeutic efficacy. Additionally, the combination of LNP@PTEN with the IL-23 inhibitor Apilimod demonstrated enhanced inhibition of tumor growth, invasion, and metastasis (particularly secondary organ metastasis) compared to other groups, and extended the survival of mice to 41 days, providing a degree of bone protection. These effects may be attributed to the PTEN function restoration combined with IL-23 inhibition, which help reverse immune suppression in the tumor microenvironment by reducing MDSCs recruitment and increasing the CD8+/CD4+ T cell ratio.Discussion: In summary, these findings highlight the potential of LNPs for delivering gene therapeutic agents. And the combination of LNP@PTEN with Apilimod could achieve anti-tumor effects and improve tumor microenvironment. This combinational strategy opens new avenues for the treatment of mCRPC.

Diabetic cardiomyopathy (DCM) triggers a detrimental shift in mitochondrial dynamics, characterized by increased fission and decreased fusion, contributing to cardiomyocyte apoptosis and cardiac dysfunction. This study investigated the impact of modulating mitochondrial dynamics on DCM outcomes and underlying mechanisms in a mouse model. DCM induction led to upregulation of fission genes (Drp1, Mff, Fis1) and downregulation of fusion genes (Mfn1, Mfn2, Opa1). Inhibiting fission with Mdivi-1 or promoting fusion with Ginsenoside Rg1 preserved cardiac function, as evidenced by improved left ventricular ejection fraction (LVEF), fractional shortening (FS), and E/A ratio. Both treatments also reduced infarct size and attenuated cardiomyocyte apoptosis, indicated by decreased caspase-3 activity. Mechanistically, Mdivi-1 enhanced mitochondrial function by improving mitochondrial membrane potential, reducing reactive oxygen species (ROS) production, and increasing ATP generation. Ginsenoside Rg1 also preserved mitochondrial integrity and function under hypoxic conditions in HL-1 cardiomyocytes. These findings suggest that restoring the balance of mitochondrial dynamics through pharmacological interventions targeting either fission or fusion may offer a promising therapeutic strategy for mitigating MI-induced cardiac injury and improving patient outcomes.