Oluwatayo Israel Olasunkanmi, Luqi Zheng, Peng Zheng
Chinese Medical JournalVol.139,No.062026
DOI: 10.1097/CM9.0000000000003920
Abstract
The gut-brain axis is a complex, bidirectional network of communication systems that integrates neural, endocrine, and immune pathways, as well as metabolic processes, to regulate homeostasis and maintain physiological and cognitive equilibrium. Central to this axis is the gut microbiota, which exerts a profound influence on brain function through microbial metabolites, including short-chain fatty acids, tryptophan metabolites, and bile acids. Disruption of this microbial balance, known as dysbiosis, has been implicated in the onset and progression of major neuropsychiatric and neurodegenerative disorders, including depression, Alzheimer’s disease, and Parkinson’s disease. This review critically examines the mechanistic underpinnings of the gut-brain axis, emphasizing metabolic, immunological, and neuroendocrine signaling as key mediators. Furthermore, it explores how dietary components, particularly fiber, polyphenols, and fermented foods, modulate gut microbial composition and function to influence brain health. Emerging therapeutic strategies, such as probiotics, prebiotics, and fecal microbiota transplantation, are discussed, along with the potential of personalized targeted intervention. By integrating current findings, this review underscores the gut-brain axis as a dynamic interface that not only influences neurological and psychiatric outcomes but also represents a promising target for therapeutic intervention.
Yi Meng, Hua Wang, Dezhi Mu, Shuqin Zeng, Shaopu Wang
Chinese Medical JournalVol.139,No.062026
DOI: 10.1097/CM9.0000000000003959
Abstract
Pediatric health is the foundation for people’s lifelong health. The co-evolution of host genetics and the gut microbiome fosters a symbiotic relationship that is important for pediatric growth and the pathogenesis of various diseases. However, a comprehensive overview of the human genetics-gut microbiome axis in pediatric diseases remains unavailable. This review summarizes the human genetic variants that are associated with pediatric diseases, affecting the nervous, respiratory, and immune systems, as well as those linked to preterm birth (PTB), as identified by genome-wide association studies (GWAS). As the gut microbiome plays a crucial role in pediatric health, we have systematically discussed microbial biomarkers associated with the onset and progression of pediatric diseases, with an emphasis on their clinical impact across four key axes: the gut-brain, gut-lung, gut-skin, and gut-immune axes. The GWAS on the gut microbiome revealed numerous genetic variants that intricately regulate its composition. These variants predispose individuals to gut microbiome dysbiosis, potentially initiating or exacerbating pediatric disease manifestations. Moreover, the underrepresentation of populations from low- and middle-income countries in existing microbiome-related data, coupled with technical challenges, limits our understanding of the association between microbiome and health. Finally, we emphasize the promising potential of elucidating and modulating host gene-gut microbiome interactions to offer novel insights for advancing precision pediatric medicine and developing innovative therapeutic strategies.
Pancreatic ductal adenocarcinoma (PDAC), the deadliest epithelial malignancy, is increasingly prevalent and contributes significantly to cancer-related mortality. Research over the past decade has demonstrated that microbiota may play a pivotal role in both PDAC oncogenesis and its resistance to chemotherapy. Emerging preclinical and clinical data highlight the impact of microbiota on therapeutic outcomes in PDAC patients. This review systematically explores the role and underlying mechanisms of microbiota in PDAC, with a particular focus on their clinical implications and translational potential in disease progression and therapeutic responses. Finally, this review addresses the potential of microbiome-based therapies to enhance the efficacy of PDAC treatments.
Zan Wang, Chenhui Liu, Mengxing Wang, Shuning Cai, Ximing Nie, Liping Liu, Xiaochuan Huo, Yuesong Pan, Zhongrong Miao, Yilong Wang
Chinese Medical JournalVol.139,No.062026
DOI: 10.1097/CM9.0000000000003993
Abstract
Background:
Severe white matter lesions (WMLs) have been linked to poorer functional outcomes following endovascular therapy (EVT) in patients with acute ischemic stroke (AIS) due to large-vessel occlusion (LVO). However, the absence of a control group in previous studies has limited the ability to determine the benefit of EVT to patients with severe WMLs.
Methods:
This work is a secondary analysis of the Endovascular Therapy in Acute Anterior Circulation Large Vessel Occlusive Patients with a Large Infarct Core (ANGEL-ASPECT) trial, a multicenter, randomized controlled trial conducted at 46 comprehensive stroke centers across China, which enrolled 456 patients with AIS with anterior-circulation LVO and large ischemic cores between October 2020 and May 2022. WML severity was graded using the van Swieten Scale on pretreatment noncontrast computed tomography (CT). For supplementary analyses, WML severity was further assessed using T2 fluid-attenuated inversion recovery (T2-FLAIR) magnetic resonance imaging (MRI) and graded according to the Fazekas scale, with WMLs categorized into periventricular and deep subtypes. Treatment effect on the primary outcome (90-day modified Rankin Scale [mRS] score) was assessed using multivariable ordinal logistic regression, and a treatment-by-WML interaction term was tested to evaluate effect modification.
Results:
In patients with absent-to-moderate WMLs, EVT was associated with a favorable shift in the distribution of 90-day mRS scores (adjusted common odds ratio [cOR] 2.15, 95% confidence interval [CI, 1.48-3.13], P <0.001). However, this benefit was less pronounced in those with severe WMLs (adjusted cOR 2.25, 95% CI [0.95-5.30], P = 0.065). No significant interaction between WML severity and treatment effect was detected (Pinteraction = 0.888). Similarly, only among patients with absent-to-moderate WMLs, EVT significantly increased rates of mRS scores of 0-2 (adjusted OR 4.86, 95% CI [2.66-8.86], P <0.001), the rates of mRS scores of 0-3 (adjusted OR 2.23, 95% CI [1.39-3.57], P = 0.001), and the rates of early neurological improvement (adjusted OR 5.22, 95% CI [1.31-20.79], P = 0.019) compared to medical management alone. Supplementary analyses using T2-FLAIR MRI to stratify patients by WML burden yielded results consistent with those of the primary analyses.
Conclusions:
EVT significantly improved functional outcomes in patients with LVO-AIS with absent-to-moderate WMLs, while the benefit in those with severe WMLs appeared less pronounced. However, estimates within subgroups were underpowered. Future pooled analyses of randomized clinical trials with adequate statistical power are needed to clarify the impact of WML severity on EVT outcomes and to refine patient selection criteria.
Background:
Senescence significantly participates in shaping the pathobiological process underlying chronic obstructive pulmonary disease (COPD). Currently, the mechanisms underlying the anti-aging effects of hydrogen sulfide (H2S) in COPD are not fully illustrated.
Methods:
Immunohistochemistry (IHC) staining was performed on human lung tissue to detect the expression levels of sirtuin 3 (Sirt3), cyclin-dependent kinase 4 inhibitor (P16), and cystathionin gamma lyase (CTH). An animal COPD model including wild-type (WT) and Sirt3 knockout (KO) mice was established by exposing them to cigarette smoking (CS) for 24 weeks, with or without intraperitoneal injection of sodium hydrosulfide (NaHS, 50 µmol·L-1·kg-1) 30 min prior to CS exposure. Lung function was assessed. The expression levels of P16, cyclin-dependent kinase inhibitor 1A (P21), Sirt3, manganese superoxide dismutase (SOD2), manganese acetylated superoxide dismutase (ac-SOD2), interleukin-6 (IL-6), IL-8, malondialdehyde (MDA), and glutathione (GSH), as well as the activity of SOD2 and Sirt3, were evaluated. Human bronchial epithelial BEAS-2B cells were subjected to diverse cigarette smoking extract (CSE) concentrations for 48 h with or without sodium hydrosulfide (NaHS). Subsequently, the levels of total intracellular reactive oxygen species (T-ROS), mitochondrial reactive oxygen species (mitoROS), mitochondrial membrane potential (MMP), senescence-associated β-galactosidase (SA-β-gal) staining positive cells, and related marker proteins and cytokines were assessed. Furthermore, the Sirt3-specific inhibitor 3-TYP and small interfering RNAs (siRNAs) of Sirt3 were used to examine the mechanisms whereby H2S inhibits oxidative stress and senescence in COPD.
Results:
IHC showed a significant reduction of CTH and Sirt3 protein levels in the lung tissue of COPD with smoking patients and smokers without COPD compared to non-smokers. Furthermore, the expression of the aging marker protein P16 was notably elevated in the COPD with smoking group compared to the smokers without COPD and non-smoker groups. Furthermore, our results demonstrated that exposure to CS resulted in imbalanced oxidative and cellular senescence, including elevated mitoROS, T-ROS, MDA, and ac-SOD2, along with increased proportions of SA-β-gal staining positive cells and the increased expression levels of IL-6, IL-8, P21, and P16, as well as decreased GSH levels, SOD2 and Sirt3 activities, and Sirt3 expression, which ultimately contribute to emphysema development and impaired lung function. However, pretreatment with NaHS effectively reversed these detrimental effects. Nevertheless, the protective effect of NaHS was alleviated in Sirt3 KO mice and in cellular models treated with Sirt3 siRNA and 3-TYP.
Conclusion:
Our study indicates that H2S inhibits oxidative stress and cellular senescence by modulating the Sirt3/SOD2 signaling pathway, therefore attenuating the emphysema and impaired lung function induced by CS.
Mingru Zhang, Min Liu, Tianlong Wang, Yingjie Du, Yimeng Chen, Yafan Bai, Yue Zhang, Dinghao Xue, Bingyang Ji, Guyan Wang
Chinese Medical JournalVol.139,No.062026
DOI: 10.1097/CM9.0000000000003552
Abstract
Background:
Cardiopulmonary bypass-associated acute kidney injury (CPB-AKI) is a serious and common complication following cardiopulmonary bypass (CPB), leading to worse outcomes and higher mortality. However, the underlying pathological mechanisms of CPB-AKI remain largely unknown. This study aimed to investigate the role of long non-coding RNA H19 (H19) in regulating CPB-AKI.
Methods:
We examined the expressions of H19 and mitophagy-related proteins in a CPB-AKI rat model and HK-2 cells following oxygen-glucose deprivation/reperfusion (OGD/R). In vivo, lentiviral-mediated overexpression of H19 was induced in the kidney through tail vein injection. We then evaluated renal functions, kidney pathological damage, levels of inflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-1β, IL-6, and IL-10), neutrophil infiltration, and the activation of PTEN-induced putative kinase 1 (Pink1)/Parkin-mediated mitophagy following CPB-AKI. In vitro, small interfering RNA (siRNA) was used to downregulate H19 expression in HK-2 cells. We also examined cell viability, apoptosis, inflammation, and Pink1/Parkin-mediated mitophagy after OGD/R.
Results:
We demonstrated an increase in H19 expression and activation of Pink1/Parkin-mediated mitophagy in the rat model of CPB-AKI and HK-2 cells following OGD/R. In the rat models of CPB-AKI, lentivirus-mediated overexpression of H19 significantly attenuated renal injury, characterized by better renal function, reduced tissue damage, decreased neutrophil infiltration, and lower inflammatory cytokine release (P <0.05). Notably, overexpression of H19 significantly activated Pink1/Parkin-mediated mitophagy. Furthermore, in vitro, downregulation of H19 by specific siRNA in HK-2 cells significantly decreased cell viability, worsened HK-2 injury after OGD/R, increased inflammatory cytokine release, and decreased Pink1/Parkin-mediated mitophagy activity, promoting cell apoptosis (P <0.05).
Conclusions:
These findings suggest that H19 overexpression may protect against CPB-AKI by activating Pink1/Parkin-mediated mitophagy and decreasing inflammatory responses and cellular apoptosis. Thus, H19 overexpression might be a promising therapeutic target for treating CPB-AKI.
Background:
Ulcerative colitis (UC), a chronic inflammatory bowel disease, is characterized by a multifactorial etiology and limited therapeutic options. Recent advancements in plant-derived exosome-like nanoparticles (PDENs) have demonstrated promising potential for UC treatment. This study explored the therapeutic efficacy of Andrographis paniculata-derived exosome-like nanoparticles (APELNs) in alleviating dextran sodium sulfate (DSS)-induced colitis.
Methods:
APELNs were isolated and purified using sucrose gradient centrifugation and subsequently characterized through visualization techniques. Their stability was assessed under simulated stomach-like and intestine-like conditions. The therapeutic potential of APELNs was evaluated through both in vivo and in vitro experiments. In addition, the biosafety of APELNs was comprehensively analyzed in these settings.
Results:
APELNs exhibited excellent stability and biosafety, with a targeted accumulation in inflamed colonic tissues under gastrointestinal conditions. The nanoparticles displayed a desirable size (about 180 nm) and a negative zeta potential (-40 mV). Treatment with APELNs significantly ameliorated colonic pathologies in vivo and suppressed the expression of pro-inflammatory cytokines in vitro. Mechanistically, APELNs enhanced gut microbiota richness and diversity, fostering the growth of the probiotic Lactobacillus murinus. Moreover, APELNs reduced intestinal permeability and preserved intestinal barrier integrity by upregulating tight junction proteins, including Claudin-1, zonula occludens-1, Mucin2, and anti-occludin. Importantly, oral administration of APELNs shifted macrophage polarization in the colon, inhibiting the pro-inflammatory M1 subset while promoting the anti-inflammatory M2 subset. This polarization was mediated through the activation of the phosphatidylinositol 3 kinase-protein kinase B (PI3K-AKT) and Janus tyrosine kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathways and the upregulation of interleukin-4 receptor expression.
Conclusion:
These findings highlighted the potential of APELNs as a novel therapeutic strategy for UC, offering a promising alternative for effective disease management.
Yafei Jiang, Dandan Wang, Ming Tao, Xiaona Cui, Jian Li, Tianjiao Wei, Jin Yang, Tianpei Hong, Rui Wei
Chinese Medical JournalVol.139,No.062026
DOI: 10.1097/CM9.0000000000003859
Abstract
Background:
Sodium-glucose cotransporter 2 inhibitor (SGLT2i) improves beta-cell function in animals and humans with diabetes. Herein, we aimed to investigate the effects of SGLT2i on beta-cell regeneration, trace the origin of regenerated beta cells, and reveal the potential mechanism.
Methods:
Type 2 and type 1 diabetic mice were treated with canagliflozin (10 mg/kg), dapagliflozin (1 mg/kg), or vehicle. Islet morphology was evaluated to investigate beta-cell regeneration. Inducible pancreatic neurogenin 3 (Ngn3)+ progenitor lineage-tracing mice and alpha-cell lineage-tracing mice were used to trace the origin of regenerated cells. Mouse and human islets, alpha cells, and beta cells were incubated with dapagliflozin (12.5 µmol/L) or vehicle. Insulin and glucagon-like peptide-1 (GLP-1) release, gene expression, and RNA sequencing analysis were performed to clarify the direct actions of SGLT2i and to screen potential targets. Alpha cells were transfected with peroxisome proliferator-activated receptor-γ coactivator 1α (Ppargc1α) plasmid or with Ppargc1α siRNA, followed by incubation with or without dapagliflozin to confirm the effects of Ppargc1α in alpha-cell phenotype conversion.
Results:
SGLT2i increased islet and beta-cell areas in type 2 diabetic mice and showed a similar trend in type 1 diabetic mice. SGLT2i induced alpha-cell dedifferentiation into Ngn3+ progenitors and promoted progenitor differentiation toward beta cells. In cultured diabetic mouse and human islets and in stressed alpha cells, SGLT2i increased supernatant insulin and active GLP-1 levels, downregulated alpha-cell-specific marker expression, and upregulated the expression of endocrine progenitor- and beta-cell-specific markers, including prohormone convertase 1/3. Although dapagliflozin did not affect beta cells directly, it affected alpha cells (457 upregulated and 235 downregulated genes). Ppargc1α, a coactivator participating in oxidative phosphorylation, was identified as a potential target. By using overexpression and knockdown, we confirmed that Ppargc1α participated in SGLT2i-induced regulation of alpha-cell phenotype conversion.
Conclusion:
Alpha-cell regression to progenitors and progenitor differentiation toward beta cells represent a novel pathway for beta-cell neogenesis induced by SGLT2i in diabetes, with Ppargc1α playing a role in this process.
Mingxin Ao, Ruilan Dai, Xiaoming Shi, Yunan Zhou, Mingxuan Gao, Yingfang Ao
Chinese Medical JournalVol.139,No.062026
DOI: 10.1097/CM9.0000000000004040
Abstract
Background:
Visual input supports locomotion through sensorimotor integration. However, the neural mechanisms underlying how the brain adapts to degraded vision are not well understood. This study investigated the effects of visual occlusion on interactions between regions within the sensorimotor network.
Methods:
Twelve healthy young adults (8 males, 4 females; mean age 24.0 ± 2.1 years) were recruited from the Department of Ophthalmology at Peking University Third Hospital between December 2024 and September 2025. Pattern-reversal visual evoked potentials were recorded under both normal vision and visual occlusion condition (Snellen 20/60 acuity). We acquired resting-state functional magnetic resonance imaging (rs-fMRI) data to calculate the amplitude of low-frequency fluctuations (ALFF) and seed-based functional connectivity (FC) focused on visuomotor integration regions. A one-way repeated-measures analysis of variance was conducted with three within-subject conditions: seated rest, level walking with normal vision, and level walking with visual occlusion.
Results:
Stimuli consisted of checkerboard patterns with large (1°) and small (15′) checks. Under 1° visual stimulation, visual occlusion prolonged binocular P100 latency (117.00 ± 8.55 ms vs. 111.81 ± 5.12 ms; 116.78 ± 9.79 ms vs. 110.96 ± 4.28 ms; all P <0.05) and reduced N75-P100 amplitude (5.798 ± 2.372 µV vs. 8.613 ± 3.949 µV; 6.230 ± 2.459 µV vs. 7.453 ± 2.692 µV, all P <0.05). For 15′ stimulation, occlusion decreased both binocular N75-P100 (5.935 ± 3.500 µV vs. 10.794 ± 5.249 µV; 3.991 ± 1.585 µV vs. 10.361 ± 3.143 µV, all P <0.001) and P100-N135 amplitudes (6.218 ± 3.516 µV vs. 12.499 ± 4.236 µV; 4.427 ± 2.218 µV vs. 10.767 ± 4.904 µV, all P <0.001). Rs-fMRI analysis showed reduced ALFF in the right paracentral lobule after walking (peak Montreal Neurological Institute [MNI] coordinates: 3, -39, 66; P <0.001, F = 14.009). Walking activated multiple visuomotor pathways (all P <0.001), including the bilateral calcarine and middle temporal gyri, the right calcarine and middle frontal gyri, the bilateral supplementary motor area and right cuneus, and the bilateral precentral gyrus and right cerebellar lobule VI. The visual occlusion strengthened FC between the right precentral and the right middle frontal gyri (peak MNI: 27, 57, 27; F = 16.456, P <0.001).
Conclusions:
Basic visuomotor pathways demonstrate consistent activation to maintain locomotion. Increased functional connectivity between the right precentral and middle frontal gyri serves as a compensatory mechanism for reduced visual input.
