BackgroundDietary polyphenols, polypeptides, and oligosaccharides modulate inflammation and immunity by altering the composition of gut microbiota. The polyphenols and polypeptides in Chinese rice wine have protective effects against cardiovascular disease. In this study, we hypothesized that the polyphenols, polypeptides, and oligosaccharides in Chinese rice wine can ameliorate diabetic cardiomyopathy (DCM) by altering gut microbiota and metabolites.MethodsMice with DCM and high glucose cells were treated with rice wine polyphenols (RWPH), rice wine polypeptides (RWPE), and rice wine oligosaccharides. Cardiac function was evaluated by echocardiography and detection of myocardial injury markers. We observed the pathological structures using hematoxylin and eosin staining, Masson's trichrome staining, and transmission electron microscopy. The expression levels of autophagy-related proteins and stubRFP-sensGFP-LC3 fluorescence were measured to evaluate autophagy. We performed TUNEL staining and measured the levels of Bax, Bcl-2, and p53 to assess apoptosis. To analyze the effects of the rice wine functional components on the gut microbiota and metabolites of DCM mice, we performed fecal 16S-rDNA gene sequencing and serum untargeted metabolomics.ResultsOur results showed an increase in cardiac and mitochondrial function, promotion of autophagy, and inhibition of cardiomyocyte apoptosis, which indicates that RWPH and RWPE can ameliorate DCM. The abundance of Akkermansia and Desulfovibrio were reduced by the presence of RWPH and RWPE. The growth of the Lachnospiraceae_NK4A136_group and Clostridiales-unclassified were promoted by the presence of RWPH. Tryptophan metabolism-associated metabolites were increased and phenylalanine levels were reduced by the presence of RWPH and RWPE. The biosynthesis of primary bile acids was enhanced by the presence of RWPH.ConclusionBoth RWPH and RWPE provided a protective effect against DCM by promoting autophagy, inhibiting apoptosis, and reversing both gut microbiota dysbiosis and metabolic dysregulation.

Objectives: To evaluate the role and therapeutic value of homocysteine (hcy)-inducible endoplasmic reticulum stress (ERS) protein with ubiquitin like domain 1 (Herpud1) in hcy-induced calci c aortic valve disease (CAVD).Background: The morbidity and mortality rates of calci c aortic valve disease (CAVD) remain high while treatment options are limited.Methods: In vivo , we use the low-density lipoprotein receptor (LDLR) and Herpud1 double knockout (LDLR-/-/Herpud1-/-) mice assessment of aortic valve calci cation lesions, ERS activation, autophagy, and osteogenic differentiation of aortic valve interstitial cells (AVICs). We used siRNA to knock down Herpud1 in cultured Primary AVICs were isolated from mice to further validate our ndings.Results: Herpud1 was highly expressed in calci ed human and mouse aortic valves as well as primary aortic valve interstitial cells (AVICs). Herpud1 de ciency inhibited hcy-induced CAVD in vitro and in vivo.Herpud1 silencing activated cell autophagy, which subsequently inhibited hcy-induced osteogenic differentiation of AVICs. Hcy increased Herpud1 expression through the ERS pathway and promoted CAVD progression. ERS inhibitor 4-phenyl butyric acid (4-PBA) signi cantly attenuated aortic valve calci cation in high methionine diet-fed low-density lipoprotein receptor -/-(LDLR -/-) mice by suppressing ERS and subsequent Herpud1 biosynthesis.Conclusions: These ndings identify a previously unknown mechanism of Herpud1 upregulation in CAVD progression, suggesting that Herpud1 silencing or inhibition is a viable therapeutic strategy for arresting CAVD progression. HighlightsHomocysteine (hcy) promotes aortic valvular calci cation in vivo and in vitro.Herpud1 is upregulated in the lea ets of mice and humans with CAVD. Herpud1 de ciency inhibited hcy-induced CAVD in vitro and in vivo.Herpud1 silencing activates cell autophagy, inhibiting osteogenic differentiation of primary aortic valve interstitial cells (AVICs) induced by hcy. 4-Phenyl butyric acid, a compound that suppresses ERS and subsequent Herpud1 biosynthesis, signi cantly decreased AVIC calci cation in vitro after hcy stimulation and mitigated the severity of aortic valve brosis and calci cation in a murine model of CAVD.

BackgroundThe high prevalence of patent foramen ovale (PFO) in cryptogenic stroke suggested a stroke-causing role for PFO. As risk factors for recurrence of such stroke are not recognized, clinicians cannot sufficiently identify, treat, and follow-up high-risk patients. Therefore, this study aimed to establish a prediction model for PFO-related stroke recurrence.MethodsThis study included 392 patients with PFO-related stroke in a training set and 164 patients with PFO-related stroke in an independent validation set. In the training set, independent risk factors for recurrence identified using forward stepwise Cox regression were included in nomogram 1, and those identified using least absolute shrinkage and selection operator(LASSO)regression were included in nomogram 2. Nomogram performance and discrimination were assessed using the concordance index (C-index), area under the curve (AUC), calibration curve, and decision curve analyses (DCA). The results were also validated in the validation set.ResultsNomogram 1 was based on homocysteine (Hcy), high-sensitivity C-reactive protein (hsCRP), and albumin (ALB), and nomogram 2 was based on age, diabetes, hypertension, right-to-left shunt, ALB, prealbumin, hsCRP, and Hcy. The C-index of nomogram 1 was 0.861, which was not significantly different from that of nomogram 2 (0.893). The 2- and 5-year AUCs of nomogram 1 were 0.863 and 0.777, respectively. In the validation set, nomogram 1 still had good discrimination (C-index, 0.862; 2-year AUC, 0.839; 5-year AUC, 0.990). The calibration curve showed good homogeneity between the prediction by nomogram 1 and the actual observation. DCA demonstrated that nomogram 1 was clinically useful. Moreover, patients were successfully divided into two distinct risk groups (low and high risk) for recurrence rate by nomogram 1.ConclusionsNomogram 1, based on Hcy, hsCRP, and ALB levels, provided a more clinically realistic prognostic prediction for patients with PFO-related stroke. This model could help patients with PFO-related stroke to facilitate personalized prognostic evaluations.

Objectives: To evaluate the role and therapeutic value of homocysteine (hcy)-inducible endoplasmic reticulum stress (ERS) protein with ubiquitin like domain 1 (Herpud1) in hcy-induced calcific aortic valve disease (CAVD). Background: The morbidity and mortality rates of calcific aortic valve disease (CAVD) remain high while treatment options are limited.Methods: In vivo , we use the low-density lipoprotein receptor (LDLR) and Herpud1 double knockout (LDLR-/-/Herpud1-/-) mice assessment of aortic valve calcification lesions, ERS activation, autophagy, and osteogenic differentiation of aortic valve interstitial cells (AVICs). We used siRNA to knock down Herpud1 in cultured Primary AVICs were isolated from mice to further validate our findings. Results: Herpud1 was highly expressed in calcified human and mouse aortic valves as well as primary aortic valve interstitial cells (AVICs). Herpud1 deficiency inhibited hcy-induced CAVD in vitro and in vivo. Herpud1 silencing activated cell autophagy, which subsequently inhibited hcy-induced osteogenic differentiation of AVICs. Hcy increased Herpud1 expression through the ERS pathway and promoted CAVD progression. ERS inhibitor 4-phenyl butyric acid (4-PBA) significantly attenuated aortic valve calcification in high methionine diet–fed low-density lipoprotein receptor-/- (LDLR-/-) mice by suppressing ERS and subsequent Herpud1 biosynthesis. Conclusions: These findings identify a previously unknown mechanism of Herpud1 upregulation in CAVD progression, suggesting that Herpud1 silencing or inhibition is a viable therapeutic strategy for arresting CAVD progression.

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