Marasmius androsaceus mitigates depression-exacerbated intestinal radiation injuries through reprogramming hippocampal miRNA expression.

INTRODUCTION: Cancer patients commonly experience high levels of psychological stress, which poses significant risks to their well-being. Radiotherapy is a primary treatment modality for cancer; however, it often leads to intestinal injuries in these patients. Nevertheless, the impact of mental stress on radiotherapy-intertwined complications remains unclear. METHODS: To induce intestinal injury, we employed total abdominal irradiation in our experimental model. We conducted high-throughput sequencing to analyze the expression profile of miRNAs in the hippocampus. RESULTS: We observed that mice with depression exhibited more severe intestinal injuries following total abdominal irradiation. Remarkably, oral administration of Marasmius androsaceus not only alleviated the depressive phenotype but also mitigated radiation-induced intestinal toxicity. Notably, this radioprotective effect was not observed in mice without depression. Depression disrupted the hippocampal miRNA expression profile in mice subjected to local irradiation of the abdomen, leading to the accumulation of miR-139-5p and miR-184-3p in the hippocampus, serum, and small intestine tissues. However, treatment with Marasmius androsaceus reprogrammed the miRNA expression signature in mice with depression. Furthermore, intravenous injection of antagomirs targeting miR-139-5p and miR-184-3p ameliorated depression, up-regulated Spn expression, reduced radiation enteritis, and improved the integrity of the small intestine in irradiated mice. CONCLUSION: Our findings demonstrate the efficacy of Marasmius androsaceus, a small mushroom, in alleviating depression-aggravated intestinal toxicity following radiotherapy by reprogramming hippocampal miRNA expression.

Body weight, weight change and the risk of cardiovascular disease in patients with hypertension: a primary-care cohort study.

BACKGROUND/OBJECTIVES: Obesity and cardiovascular disease (CVD) often co-occur. However, the effects of excessive body weight and weight change on CVD in patients with hypertension are not clearly established. We examined the associations of BMI, weight change and the risk of CVD in patients with hypertension. SUBJECTS/METHODS: Our Data were drawn from the medical records of primary-care institutions in China. A total of 24,750 patients with valid weight measurements attending primary healthcare centers were included. Body weight were grouped in BMI categories of underweight ( < 18.5 kg/m2), healthy weight (18.5-22.9 kg/m2), overweight (23.0-24.9 kg/m2) and obesity ( ≥ 25.0 kg/m2). Weight change over 12 months was divided into: gain >4%, gain 1-4%, stable (-1 to 1%), loss 1-4%, and loss ≥4%. Cox regression analyses were used to estimate hazard ratio (HR) and 95% confidence interval (95% CI) between BMI, weight change and the risk of CVD. RESULTS: After multivariable adjustment, patients with obesity were related to higher risks of CVD (HR = 1.48, 95% CI: 1.19-1.85). Higher risks were seen in participants with loss ≥4% and gain >4% of body weight compared to stable weight (loss ≥4%: HR = 1.33, 95% CI: 1.04-1.70; gain >4%: HR = 1.36, 95% CI: 1.04-1.77). CONCLUSION: Obesity and weight change of loss ≥4% and gain >4% were related to higher risks of CVD. Close monitoring and appropriate interventions aimed at achieving an optimal weight are needed to prevent adverse cardiovascular outcomes for patients with hypertension.

Stable colonization of Akkermansia muciniphila educates host intestinal microecology and immunity to battle against inflammatory intestinal diseases.

Gut microbial preparations are widely used in treating intestinal diseases but show mixed success. In this study, we found that the therapeutic efficacy of A. muciniphila for dextran sodium sulfate (DSS)-induced colitis as well as intestinal radiation toxicity was ~50%, and mice experiencing a positive prognosis harbored a high frequency of A. muciniphila in the gastrointestinal (GI) tract. Stable GI colonization of A. muciniphila elicited more profound shifts in the gut microbial community structure of hosts. Coexisting with A. muciniphila facilitated proliferation and reprogrammed the gene expression profile of Lactobacillus murinus, a classic probiotic that overtly responded to A. muciniphila addition in a time-dependent manner. Then, a magnetic-drove, mannose-loaded nanophase material was designed and linked to the surface of A. muciniphila. The modified A. muciniphila exhibited enhancements in inflammation targeting and intestinal colonization under an external magnetic field, elevating the positive-response rate and therapeutic efficacy against intestinal diseases. However, the unlinked cocktail containing A. muciniphila and the delivery system only induced negligible improvement of therapeutic efficacy. Importantly, heat-inactivated A. muciniphila lost therapeutic effects on DSS-induced colitis and was even retained in the GI tract for a long time. Further investigations revealed that the modified A. muciniphila was able to drive M2 macrophage polarization by upregulating the protein level of IL-4 at inflammatory loci. Together, our findings demonstrate that stable colonization of live A. muciniphila at lesion sites is essential for its anti-inflammatory function.

Sexual dimorphism in gut microbiota dictates therapeutic efficacy of intravenous immunoglobulin on radiotherapy complications.

INTRODUCTION: With the mounting number of cancer survivors, the complications following cancer treatment become novel conundrums and starve for countermeasures. Intravenous immunoglobulin (IVIg) is a purified preparation for immune-deficient and autoimmune conditions. OBJECTIVES: Here, we investigated whether IVIg could be employed to fight against radiation injuries and explored the underlying mechanism. METHODS: Hematopoietic or gastrointestinal (GI) tract toxicity was induced by total body or abdominal local irradiation. High-throughput sequencing was performed to analyze the gut microbiota configurations and gene expression profile of small intestine. The untargeted metabolomics of gut microbiome was assessed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) analyses. Hydrodynamic-based gene delivery was used to knockdown the target genes in vivo. RESULTS: Intravenous injection of IVIg protected against radiation-induced hematopoietic and GI tract toxicity in female mice but not in males. IVIg structured sex-characteristic gut microbiota configurations in abdominal irradiated mice. The irradiation enriched gut Lachnospiraceae in female mice but reduced those in males. IVIg injection combined with oral gavage of Lachnospiraceae or its metabolite hypoxanthine, alleviated radiation toxicity in male mice however, Lachnospiraceae or hypoxanthine alone failed to ameliorate the injuries. Abdominal local irradiation drove sex-distinct gene expression signatures in small intestine. Mechanistic investigation showed that replenishment of Lachnospiraceae or hypoxanthine offset abdominal radiation-reduced PLD1 expression in male mice. In females, irradiation elevated PLD1 expression. Deletion of PLD1 in GI tract of female mice erased the radioprotective effects of IVIg. CONCLUSION: IVIg battles against radiation injuries in a sex-specific, gut microbiome-dependent way through Lachnospiraceae/hypoxanthine/PLD1 axis. Our findings provide a sex-precise therapeutic avenue to improve the prognosis of cancer patients with radiotherapy in pre-clinical settings.

Social Hierarchy Dictates Intestinal Radiation Injury in a Gut Microbiota-Dependent Manner.

Social hierarchy governs the physiological and biochemical behaviors of animals. Intestinal radiation injuries are common complications connected with radiotherapy. However, it remains unclear whether social hierarchy impacts the development of radiation-induced intestinal toxicity. Dominant mice exhibited more serious intestinal toxicity following total abdominal irradiation compared with their subordinate counterparts, as judged by higher inflammatory status and lower epithelial integrity. Radiation-elicited changes in gut microbiota varied between dominant and subordinate mice, being more overt in mice of higher status. Deletion of gut microbes by using an antibiotic cocktail or restructuring of the gut microecology of dominant mice by using fecal microbiome from their subordinate companions erased the difference in radiogenic intestinal injuries. Lactobacillus murinus and Akkermansia muciniphila were both found to be potential probiotics for use against radiation toxicity in mouse models without social hierarchy. However, only Akkermansia muciniphila showed stable colonization in the digestive tracts of dominant mice, and significantly mitigated their intestinal radiation injuries. Our findings demonstrate that social hierarchy impacts the development of radiation-induced intestinal injuries, in a manner dependent on gut microbiota. The results also suggest that the gut microhabitats of hosts determine the colonization and efficacy of foreign probiotics. Thus, screening suitable microbial preparations based on the gut microecology of patients might be necessary in clinical application.

Visit-to-visit variability of blood pressure and risk of macrovascular and microvascular complications in patients with type 2 diabetes: A Chinese primary-care cohort study.

BACKGROUND: We evaluated the effects of visit-to-visit variability of systolic blood pressure (SBP) and diastolic blood pressure (DBP) on macrovascular and microvascular complications among patients with type 2 diabetes. METHODS: A total of 11 043 patients with type 2 diabetes from primary healthcare institutions between January 2010 and June 2020 were included. The visit-to-visit blood pressure variability was calculated using three metrics: SD, coefficient of variation (CV), and average real variability (ARV), obtained over a 12-month measurement period. The associations of visit-to-visit blood pressure variability with macrovascular and microvascular complications were evaluated using multivariate-adjusted Cox proportional hazards models, and hazard ratio (HR) with 95% confidence interval (CI) were reported. RESULTS: There were 330 macrovascular events and 542 microvascular events. Compared to those for participants with the lowest quartile of SD of SBP and DBP, increased risks were observed in patients with the highest quartile of SD of SBP and DBP for macrovascular complications (SD-SBP: HR = 1.78, 95% CI: 1.24-2.57; SD-DBP: HR = 2.20, 95% CI: 1.50-3.25) and microvascular complications (SD-SBP: HR = 1.85, 95% CI: 1.39-2.46; SD-DBP: HR = 1.82, 95% CI: 1.36-2.44). CV and ARV of SBP and DBP also had statistically significant associations with macrovascular and microvascular complications. The optimal variability of blood pressure target was SD of SBP <6.45 mm Hg and SD of DBP <4.81 mm Hg. CONCLUSIONS: Visit-to-visit blood pressure variability may be a potential predictor for macrovascular and microvascular complications in patients with type 2 diabetes.

The Risks of Cardiovascular Disease Following Weight Change in Adults with Diabetes: A Cohort Study and Meta-analysis.

CONTEXT: Weight management is recognized as critical in reducing cardio-metabolic risk factors for adults with diabetes, but the effects of weight change on cardiovascular disease in patients with diabetes are unknown. OBJECTIVE: To evaluate 18-month weight change and subsequent risk of macrovascular and microvascular complications in established individuals with type 2 diabetes. DESIGN AND SETTING: This study consisted of a cohort study and a meta-analysis. In the cohort study, weight change over 18 months was divided into: gain ≥5%, gain 1%-5%, stable (-1%-1%), loss 1%-5%, and loss ≥5%. Cox regression analyses were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). We then used random-effect models to pool the results combing our study with other relevant studies. RESULTS: In the cohort study, 8920 participants with valid weight measurements were included. Compared with patients with stable weight, higher risks were seen in those with weight change for total vascular complications (gain ≥5%: HR=1.43, 95% CI: 1.10-1.85; gain 1-5%: HR=1.44, 95% CI: 1.02-2.03; loss ≥5%: HR=1.58, 95% CI: 1.20-2.08), macrovascular complications (gain ≥5%: HR=1.84, 95% CI: 1.16-2.91; loss 1-5%: HR=1.91, 95% CI: 1.06-3.43; loss ≥5%: HR=2.18, 95% CI: 1.36-3.49) and microvascular complications (loss ≥5%: HR=1.48, 95% CI: 1.06-2.06). Meta-analysis also showed similar results. CONCLUSIONS: Weight gain and loss over 18 months among patients with type 2 diabetes, especially weight change ≥5%, may be a warning sign of adverse cardiovascular outcomes.

The Risks of Cardiovascular Disease Following Weight Change in Adults with Diabetes: A Cohort Study and Meta-analysis (jc.2022-01089).

CONTEXT: Weight management is recognized as critical in reducing cardio-metabolic risk factors for adults with diabetes, but the effects of weight change on cardiovascular disease in patients with diabetes are unknown. OBJECTIVE: To evaluate 18-month weight change and subsequent risk of macrovascular and microvascular complications in established individuals with type 2 diabetes. DESIGN AND SETTING: This study consisted of a cohort study and a meta-analysis. In the cohort study, weight change over 18 months was divided into: gain ≥5%, gain 1%-5%, stable (-1%-1%), loss 1%-5%, and loss ≥5%. Cox regression analyses were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). We then used random-effect models to pool the results combing our study with other relevant studies. RESULTS: In the cohort study, 8920 participants with valid weight measurements were included. Compared with patients with stable weight, higher risks were seen in those with weight change for total vascular complications (gain ≥5%: HR=1.43, 95% CI: 1.10-1.85; gain 1-5%: HR=1.44, 95% CI: 1.02-2.03; loss ≥5%: HR=1.58, 95% CI: 1.20-2.08), macrovascular complications (gain ≥5%: HR=1.84, 95% CI: 1.16-2.91; loss 1-5%: HR=1.91, 95% CI: 1.06-3.43; loss ≥5%: HR=2.18, 95% CI: 1.36-3.49) and microvascular complications (loss ≥5%: HR=1.48, 95% CI: 1.06-2.06). Meta-analysis also showed similar results. CONCLUSIONS: Weight gain and loss over 18 months among patients with type 2 diabetes, especially weight change ≥5%, may be a warning sign of adverse cardiovascular outcomes.

Gut Microbiota-Derived l-Histidine/Imidazole Propionate Axis Fights against the Radiation-Induced Cardiopulmonary Injury.

Radiation-induced cardiopulmonary injuries are the most common and intractable side effects that are entwined with radiotherapy for thorax cancers. However, the therapeutic options for such complications have yielded disappointing results in clinical applications. Here, we reported that gut microbiota-derived l-Histidine and its secondary metabolite imidazole propionate (ImP) fought against radiation-induced cardiopulmonary injury in an entiric flora-dependent manner in mouse models. Local chest irradiation decreased the level of l-Histidine in fecal pellets, which was increased following fecal microbiota transplantation. l-Histidine replenishment via an oral route retarded the pathological process of lung and heart tissues and improved lung respiratory and heart systolic function following radiation exposure. l-Histidine preserved the gut bacterial taxonomic proportions shifted by total chest irradiation but failed to perform radioprotection in gut microbiota-deleted mice. ImP, the downstream metabolite of l-Histidine, accumulated in peripheral blood and lung tissues following l-Histidine replenishment and protected against radiation-induced lung and heart toxicity. Orally gavaged ImP could not enter into the circulatory system in mice through an antibiotic cocktail treatment. Importantly, ImP inhibited pyroptosis to nudge lung cell proliferation after radiation challenge. Together, our findings pave a novel method of protection against cardiopulmonary complications intertwined with radiotherapy in pre-clinical settings and underpin the idea that gut microbiota-produced l-Histidine and ImP are promising radioprotective agents.

Prevalence and risk factors of physical inactivity among middle-aged and older Chinese in Shenzhen: a cross-sectional study.

OBJECTIVE: Investigations on physical inactivity are common around the world; however, little is known about the status of physical inactivity in mainland China. The aim of this study was to examine the prevalence and risk factors associated with physical inactivity in Shenzhen in Southern China. DESIGN: A community-based, cross-sectional study. SETTING: A multistage-stratified, random cluster survey was conducted in Xixiang Street, Bao'an District of Shenzhen in Southeast China. PARTICIPANTS: 3920 adults aged 40 years or more were recruited to the study and completed the International Physical Activity Questionnaire Short Form between 1 March 2015 and 30 July 2016. MAIN OUTCOME MEASURES: Physical inactivity was defined as engaging in physical activity levels insufficient to reach the current guidelines. Bivariate and multivariate analyses were undertaken to assess the prevalence and risk factors associated with physical inactivity. RESULTS: The prevalence of physical inactivity was 63.1% for all participants, 63.9% for women and 61.9% for men, respectively. Participants who were older (OR=1.31, 95% CI 1.11 to 1.54), who were female (OR=1.22, 95% CI 1.04 to 1.43), who had higher education experience (OR=1.38, 95% CI 1.19 to 1.61), who are under economic pressure (OR=2.17, 95% CI 1.48 to 3.17), who ever smoked a cigarette (OR=1.44, 95% CI 1.13 to 1.82) and drank alcohol (OR=1.42, 95% CI 1.14 to 1.77), and participants in the lowest body mass index category (OR=1.40, 95% CI 1.03 to 1.89), were more likely to report physical inactivity. CONCLUSIONS: These findings indicate that physical inactivity is prevalent in Southern China. Interventions and programmes aimed at increasing physical activity among middle-aged and older Chinese adults may also be tailored to participants under economic pressure and those with unhealthy behaviours such as smoking and drinking.

Author Correction: Prevalence and risk factors associated with stroke in middle-aged and older Chinese: A community-based cross-sectional study.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Prevalence and risk factors associated with stroke in middle-aged and older Chinese: A community-based cross-sectional study.

Although the prevalence of stroke and its risk factors has been widely reported in some Western countries, information on essential stroke parameters is lacking in China, the most populous nation. A community-based cross-sectional study with 8,018 Chinese adults aged ≥40 years was used to determine the prevalence of stroke and associated risk factors. Within the screened population, the prevalence of stroke was 2.21% for both sexes, 1.60% for females, and 3.18% for males. Prevalence increased with age in both sexes (P < 0.0001). In a multivariable model, factors significantly associated with stroke were increasing age (odds ratio [OR] = 1.87, 95% CI: 1.58-2.24), male gender (OR = 2.03, 95% CI: 1.42-2.90), family history of stroke (OR = 4.33, 95% CI: 2.89-6.49), history of hyperlipidemia (OR = 1.87, 95% CI 1.31-2.68), history of hypertension (OR = 1.47, 95% CI 1.02-2.12), and physical inactivity (OR = 1.74, 95% CI: 1.16-2.59). The findings indicate that stroke prevalence in middle-aged and older Chinese adults is higher in males than in females, and increases with age in both sexes. Population-based public health intervention programs and policies targeting hyperlipidemia and hypertension control and encouragement of physical activity should be highly prioritized for middle-aged and older adults in Shenzhen, China.