VIP

Abstract

Understanding neuron subclasses and their functional consequences can contribute to understanding brain circuits. A scheme long used to classify GABAergic neurons in the neocortex is based on expression of three calcium-binding proteins (CBPs): parvalbumin (PV), calbindin D-28K (CB), and calretinin (CR). Because CB and CR are frequently co-expressed by individual neurons in rodents, this scheme has been replaced by one based on PV and two signaling peptides: somatostatin (SST) and vasoactive intestinal peptide (VIP). In macaques, however, CBPs are generally not co-expressed, and so their use has persisted despite suggestions that the underlying populations are not, in fact, entirely GABAergic. We set out to quantitatively evaluate CBPs as a classification scheme for GABAergic neurons in early and mid-level visual regions in macaque cortex. Combining immunohistochemistry and in situ hybridization, we find that up to half of neurons expressing CBPs are likely not GABAergic. Furthermore, contrary to what has been previously suggested, the GABAergic subpopulations cannot be distinguished based on staining intensity. Thus, the CBP-based classification scheme is not valid, at least as it has traditionally been used. Instead, we find support for co-labeling CB and CR neurons with SST and VIP, an approach that can identify GABAergic subpopulations within the CBP classes; or simply adopting the PV/SST/VIP scheme. We discuss the functional implications of expressing these various cell type markers, and how consideration of marker functions can support proper selection of a classification scheme for a given experimental purpose.

Abstract

In this study, loperamide hydrochloride (LOP) was used to establish a rat model of functional constipation (FC) to explore the mechanism of Atractylodes macrocephala insoluble dietary fiber (AMDF) in improving FC. The results showed that AMDF could increase the fecal water content and small intestinal advancement rate of FC rats, raise the levels of gastrin (GAS), vasoactive intestinal peptide (VIP), and substance P (SP) in serum, reduce the level of somatostatin (SS), reduce the levels of IL-6, TNF-α, and NO in serum, and alleviate the pathological state of colon tissue. The 16S rDNA sequencing results revealed that AMDF could enhance the diversity of the intestinal microbiota and restore the ratio of Firmicutes/Bacteroides (F/B). Metabolomics results show that AMDF treatment can regulate bile secretion, primary bile acid biosynthesis, amino acid metabolic signaling pathways, etc. Meanwhile, AMDF could inhibit the activation of the NF-κB signaling pathway in colon tissue and alleviate intestinal inflammation in FC rats. In conclusion, the research results showed that AMDF can improve the intestinal microbiota and metabolism, and inhibit the intestinal inflammatory response, achieving the effect of relieving FC.

Abstract

Sarcopenia is increasingly recognised as a systemic metabolic disorder involving lipid dysregulation, adipose tissue dysfunction, and adipokine imbalance. However, there is a lack of quantitative synthesis with sex-specific analyses.

Abstract

Previous research on traditional exercise interventions for chronic heart failure (CHF) has primarily concentrated on single exercise modalities in isolation, providing scant insight into the ideal exercise regimen for this patient population. This study aims to assess the effects of 6 traditional exercise therapies - specifically Liuzijue, Tai Chi, Baduanjin, yoga, Wuqinxi, and meditation - on CHF outcomes using the Minnesota living with heart failure questionnaire (MLHFQ), six-minute walk test (6MWT), N-terminal pro-brain natriuretic peptide (NT-proBNP), and left ventricular ejection fraction (LVEF).

Abstract

Constipation has emerged as an important public health concern, and novel therapeutic approaches, such as those, are attracting increasing attention. However, the effects and mechanisms of Bifidobacterium breve (B. breve) and Lacto-N-neotetraose (LNnT) in relieving constipation remain incompletely understood. Moreover, the potential synergistic effects of B. breve and LNnT in alleviating constipation are still unclear. In this study, we used 4-wk-old female BALB/c mice (n = 60), which were randomly assigned to normal control (NC) group, model control (MC) group, LNnT group, B. breve group, and B. breve+LNnT group. We evaluated the effects of B. breve+LNnT on defecation performance and intestinal mucus secretion. We also analyzed gut microbiota composition and metabolic functions. Additionally, an independent cohort of 45 mice was used to assess the effect of gut microbiota and microbiota-derived metabolites on constipation. The results demonstrated that B. breve+LNnT increased the gastrointestinal transit rate and fecal water content while reducing whole-gut transit time. It also elevated serum concentrations of gastrin (GAS) and motilin (MLT) while decreasing those of vasoactive intestinal peptide (VIP) and nitric oxide (NO). Mice receiving B. breve+LNnT showed increased intestinal mucus content, a more organized mucus layer structure, and higher expression of mucus-related genes (Muc2, Agr2, Muc1, Muc4, Muc13). Additionally, B. breve+LNnT increased gut microbiota diversity and enriched potentially beneficial microbiota, including Ruminococcus, Bifidobacterium, Tyzzerella, and Roseburia. Consistently, levels of the acetate and propionate were elevated in the B. breve+LNnT group. Correlation analysis indicated positive associations between these microbiota and acetate. Finally, we explored the role of gut microbiota, acetate, and propionate in constipation. We found that the alleviation of constipation by B. breve+LNnT depended on the presence of gut microbiota and was associated with microbiota-derived acetate.

Abstract

Defensive behaviors are essential for survival, relying on risk assessment to detect and respond to threats. The dorsal raphe nucleus (DRN), a brain region involved in sleep-wake regulation, contains dopaminergic neurons (DRNDA) with unclear roles in threat evaluation. A subset of these neurons expresses vasoactive-intestinal-peptide (VIP) and projects to two key regions for adaptive threat responses: the central amygdala (CeA) and the oval nucleus of the bed nucleus of the stria terminalis (ovBNST). We hypothesized that DRNVIP neurons modulate sleep-wake regulation and play a pivotal role in coordinating activity between the CeA and ovBNST, thereby influencing risk assessment and defensive response. We found that DRNVIP neurons form a distinct feedback loop with PKC-δ neurons in the CeA and ovBNST. These DRNVIP neurons release glutamate and modulate excitability in target regions. Selective ablation of DRNVIP neurons disrupts active-phase sleep architecture, enhances risk assessment behaviors that may reflect dysfunctional processing, and impairs defensive responses. Fiber-photometry revealed direct activation of the DRNVIP neurons during presentation of the visual threat-predictive cue in behaving mice. These results suggest that DRNVIP neurons regulate specific sleep phases and control defensive behaviors, acting as a neuronal alarm system that responds to threats.

Abstract

Two studies in Nature Immunology by Jakob, Sterczyk et al. and Pirzgalska et al. show that neuron-derived vasoactive intestinal peptide (VIP) regulates intestinal epithelial differentiation and orchestrates immune responses. Through its receptor VIPR1, VIP restrains secretory lineage expansion, balances type 1 and type 2 immunity, and establishes a neuro-epithelial circuit preserving gut barrier integrity.

Abstract

As the use of Traditional Chinese Medicine injections (TCMIs) for sepsis-induced myocardial dysfunction (SIMD) becomes increasingly diverse, this study aims to evaluate their efficacy, optimal combinations, and safety.

Abstract

Cerebral amyloid angiopathy (CAA) is a common small vessel disease characterized by Aβ deposition in cortical and leptomeningeal arteries, leading to lobar intracerebral hemorrhage and vascular cognitive impairment. Despite advances in diagnosis, prognosis remains highly heterogeneous, encompassing risks of recurrent hemorrhage and progressive cognitive decline. This review summarizes recent developments in imaging and fluid biomarkers for prognostic stratification in CAA. Imaging markers, including advanced MRI and molecular PET techniques, have evolved from traditional hemorrhagic indicators, such as cerebral micro-bleeds (CMBs) and cortical superficial siderosis (cSS), to non-hemorrhagic including white matter hyper-intensities (WMHs), and enlarged perivascular spaces (ePVS), which sensitively capture microstructural damage after using quantitative measures. Fluid biomarkers provide dynamic insights into vascular and neuronal injury, including altered plasma Aβ42/Aβ40 ratios, MMPs/TIMPs balance, and elevated neuro-filament light chain (NfL) and glial fibrillary acidic protein (GFAP) levels. Integrating these multi-modal indicators may enable individualized prediction of hemorrhagic and cognitive outcomes and inform precision management strategies. Future research should standardize quantification methods and validate multi-modal models across diverse CAA phenotypes to advance toward personalized prognostic frameworks.

Abstract

Late-stage cervical cancer often exhibits poor responses to radiotherapy and immunotherapy, but the key regulatory factors and mechanisms underlying these issues remain inadequately understood. In the current study, we reveal that the expression level of SPP1 correlates positively with pathological grading, and patients with higher SPP1 expression show poorer response to radiotherapy and worse clinical outcomes. Analysis of clinical dataset reveals that SPP1 expression is associated with M2-like polarization of tumor-associated macrophages, a process known to closely relate to resistance against tumor immunotherapy. In co-culture systems of cervical cancer cells and macrophages, either knockdown or overexpression of SPP1 can correspondingly inhibit or promote M2-like polarization. RNA-seq data analysis of SPP1 knockdown cervical cancer cell lines indicates that SPP1 enhances the expression of CCL2, a crucial factor that drives M2-like polarization of macrophage. In vivo experiments demonstrate that inhibiting SPP1 expression in cervical cancer effectively suppresses p-STAT3 expression level and M2-like polarization of macrophages, thereby alleviates cervical tumor progression. Our study elucidates the mechanism by which SPP1 contributes to progression of cervical cancer and provides a theoretical basis for the development of targeted therapeutic strategies aimed at advancing precision medicine.

Abstract

Control of synaptic inhibition at the network level is essential for neuronal computation; however, the mechanism by which inhibitory I → I synapses between interneurons adjust their strength remains unclear. Here, we describe a non-Hebbian form of inhibitory long-term depression (iLTD) that operates at vasoactive intestinal peptide (VIP) interneuron inputs onto stratum oriens interneurons in the hippocampal CA1 region.

Abstract

Glyphosate (Gly) is the most commonly used herbicide in the world. Glyphosate and its main degradation product, aminomethylphosphonic acid (AMPA), are often detected in aquatic environments and may pose a threat to the health of aquatic organisms. It is well established that Gly is mainly enriched in the intestine and degraded into AMPA. However, it remains unclear whether they disrupt the gut microbiota and cause liver health effects, as well as whether they have a synergistic effect with antibiotics. We investigated herein the effects of zebrafish exposure to Gly, AMPA and oxytetracycline (OTC) alone or in combination on the gut-liver axis. Our results suggest that Gly, AMPA, and OTC induce lipid accumulation, inflammatory response and oxidative damage in the liver, which is associated with a higher Firmicutes/Bacteroidetes ratio in the intestine and a higher levels of lipopolysaccharide in serum. Compared with the single exposure groups (OTC, Gly, and AMPA), the toxic effects of the gut-liver axis were more severe in the combined exposure groups (Gly+OTC, AMPA+OTC). Our results indicate that the health risks posed by Gly, AMPA and OTC through the gut microbiota of aquatic organisms are a neglected hot spots.

Abstract

Noise correlations-synchronized firing fluctuations among neurons-critically influence sensory processing, yet their regulatory mechanisms remain unclear. We investigated how V1 inhibitory neuron subtypes regulate noise correlations and visual encoding in mice using optogenetics and electrophysiology. Suppression of parvalbumin-positive (PV+) or somatostatin-positive (SOM+) neurons increased noise correlations, whereas suppression of vasoactive intestinal peptide-positive (VIP+) neurons decreased them, reflecting their distinct inhibitory roles. These changes correlated with altered orientation-discrimination performance. Our linear regression model, integrating noise correlations with neuronal discriminability, successfully predicted individual animals' behavioral performance, demonstrating their synergistic influence on visual perception. These findings elucidate how inhibitory circuits regulate noise correlations and sensory processing, indicating potential therapeutic targets for sensory-processing disorders.

Abstract

In mammals, the suprachiasmatic nucleus (SCN) functions as the primary driver of circadian rhythm. Although individual SCN neurons exhibit cell-autonomous oscillations, intercellular communication-mediated by neural peptides such as vasoactive intestinal polypeptide (VIP)-synchronizes their rhythms. However, the precise molecular mechanism by which VIP facilitates SCN synchronization remains elusive. Here, we introduce an automated ex vivo culture system, termed 'brain-slice-in-a-chamber' (BaSIC), tailored for SCN slices, as well as dissociated cells culture. This apparatus automates medium exchange and ensures optimal control over temperature and humidity, ensuring a stable internal environment conducive to tissue culture. Furthermore, BaSIC enables real-time observation of tissue responses to diverse but programmed stimuli. Using BaSIC, we demonstrate that VIP pulsing rapidly resets the circadian rhythm by synchronizing both phase and amplitude through a swift reduction of Period 2 (PER2) protein. Mathematical modeling, coupled with experimental validation, further suggests that VIP promotes the rapid reduction of PER2. Our findings, facilitated by BaSIC, provide new insights into SCN neuron synchronization, paving the way for advanced studies in chronobiology, with potential therapeutic applications for circadian disorders.

Abstract

Fecal coprolites preserve ancient microbiomes and are a potential source of extinct but highly efficacious antimicrobial peptides (AMPs). Here, we develop AMPLiT (AMP Lightweight Identification Tool), an efficient tool deployable to portable hardware for AMP screening in metagenomic datasets. AMPLiT demonstrates AUPRC performances of 0.9486 ± 0.0003 and reasonable overall training time of 3200 ± 53 s. By computationally utilizing AMPLiT, we analyze seven ancient human coprolite metagenomes, identifying 160 AMP candidates. Of 40 representative peptides synthesized, 36 (90%) peptides demonstrate measurable antimicrobial activity at 100 μM or less in vitro. Strikingly, approximately two-thirds of these peptides are sourced from Segatella copri, a dominant ancient gut commensal that is conspicuously underrepresented in modern populations, particularly those with Westernized lifestyles. Representative S. copri-derived AMPs exhibit disruptions against membranes of pathogenic bacteria, coupled with low cytotoxicity and hemolytic risk. In vivo, lead peptides demonstrate potent antibacterial and wound-healing efficacy comparable to traditional antibiotics, especially in combating gram-positive pathogens. Our findings highlight the ancient gut microbiomes as sources of novel AMPs, offering valuable insights into the historical role of S. copri in human health and its decline in contemporary populations.

Abstract

Spinal cord injury (SCI) repair remains a significant clinical challenge due to the imbalance of inflammatory microenvironment and insufficient neural regenerative ability. Current therapeutic approaches, such as pharmaceuticals, stem cell transplantation, and inorganic biomaterials, are limited by insufficient supply, poor bioactivity, and immunogenicity, severely limiting their clinical translation. To address these issues, we developed a biomimetic dual-engineered nanovesicles (Treg-Exo-IKVAV) by conjugating a neuroprotective IKVAV peptide motif with Treg-derived exosomes (Treg-Exo) using click chemistry. This system synergistically integrates the intrinsic immunomodulatory properties of Treg-Exo (early-stage anti-inflammation) with the neural regenerative capability of IKVAV, enabling spatiotemporally sequential regulation of neuro-regeneration. In vitro studies demonstrated that Treg-Exo-IKVAV suppressed macrophage-induced inflammatory responses by reprogramming macrophage polarization. Furthermore, Treg-Exo-IKVAV exerts dual direct and immunoregulatory effects on promoting neuronal differentiation of stem cells (NSCs). In vivo experiments revealed that Treg-Exo-IKVAV via tail vein injection precisely targeted and accumulated at the injured site. Subsequently, the functional assessments showed that Treg-Exo-IKVAV significantly enhanced motor functional recovery in SCI mice. Mechanistically, these nanovesicles reshaped the neuro-immune microenvironment through a two-phase mechanism: initial suppression of inflammation via Treg-derived anti-inflammatory signaling followed by activation of neuro-regenerative pathways mediated by IKVAV. This integrated "exosome-peptide" nanocomposite combining immunomodulation and neuronal regeneration provides a highly efficient and safe therapeutic solution for SCI.

Abstract

Serine/threonine phosphatase 1 (PP1) and phosphatase 2A (PP2A) play important roles in mediating cellular signaling in different tissues to different stimuli, including in protein synthesis, growth, cell cycle regulation, and secretion. However, their roles in various pancreatic exocrine functions, such as pancreatic acinar fluid/electrolyte secretion, is still unclear. Therefore, in the present study, we examined the ability of vasoactive intestinal peptide (VIP) and secretin, which stimulate cAMP generation in pancreatic acini, to activate serine/threonine phosphatase 1 (PP1) and phosphatase 2A (PP2A), the signaling cascades involved, and their possible role in activating sodium-potassium adenosine triphosphatase (Na+-K+-ATPase). Our results demonstrate that VIP and secretin activate PP1 and PP2A. However, they differ in their signaling cascades. Both VIP and secretin stimulate PP1 through cAMP-stimulated activation of protein kinase A (PKA) and exchange protein directly activated by cAMP (EPAC). However, VIP stimulates PP2A through the activation of cAMP-mediated EPAC, whereas secretin does it through activation of PKA. Despite these differences, in cAMP effect on activation, both VIP and secretin activate PP2A through a p21-activated kinase 4 (PAK4)-mediated mechanism, without involvement of PAK2. Furthermore, PP1 and PP2A activation is needed for Na+-K+-ATPase activation, which mediates pancreatic acinar fluid and electrolyte secretion. These results support the conclusion that PP1 and PP2A play an important role in pancreatic acinar fluid and electrolyte secretion, mediated by a PAK4-dependent mechanism, which when combined with their recently described roles in pancreatic enzyme secretion, pancreatitis, and pancreatic acinar growth and cancer, demonstrate the important roles they play in both physiological and pathological responses in the exocrine pancreas, similar to their previously established roles in the endocrine pancreas.NEW & NOTEWORTHY The roles of the serine/threonine phosphatase 1/2A in mediating fluid/electrolyte secretion by pancreatic acinar cells remains unclear. This study demonstrates that PP1/PP2A are activated vasoactive intestinal peptide (VIP)/secretin in pancreatic acini. VIP/secretin both activate PP1/PP2A but differed for their ability to activate exchange protein directly activated by cAMP (EPAC) and protein kinase A (PKA). VIP/secretin require PAK4, not PAK2, activation to stimulate PP2A, not PP1; however, PP1/PP2A activation stimulate sodium-potassium adenosine triphosphatase (Na+-K+-ATPase) activity. This study shows that PP1/PP2A play important roles in VIP-secretin-stimulated pancreatic acinar fluid/electrolyte secretion.

Abstract

Hepatocellular carcinoma (HCC) remains the most common primary liver cancer, with a high incidence and mortality rate. Remarkable progress has been made in cancer treatment in recent years; however, most patients with HCC still receive limited benefits from current treatment options. Therefore, there is an urgent need to explore novel and effective therapeutic strategies. Here, a novel combination therapy consisting of the calcineurin inhibitor cyclosporine A (CsA) and the flavone-naphthalimide-polyamine derivative 6c was identified. The combination of CsA and 6c inhibited cell viability and colony formation and induced GSDME-dependent pyroptosis. Mechanistically, RNA sequencing revealed that CsA and 6c synergistically activated the RIG-I-like receptor (RLR) signaling pathway. Moreover, the combination of CsA and 6c promoted RIG-I and MDA5 expression, TBK1 and IRF3 phosphorylation, and downstream target gene expression. RIG-I deletion attenuated the combination treatment-induced inhibition of cell growth, pyroptosis, and expression of IFN-stimulated genes (ISGs). Furthermore, combination treatment induced the downregulation of LDHA expression, leading to increased reactive oxygen species (ROS) generation. LDHA overexpression and ROS removal reversed the inhibitory effect of the combination treatment on HCC. Finally, combination of CsA and 6c suppressed tumor growth and pulmonary metastasis in vivo. Overall, our study suggests a novel synergistic treatment combination with a comprehensive mechanistic exploration, demonstrating that it is a promising strategy for HCC treatment via targeting RIG-I-like receptor signaling.

Abstract

Chronic stress is a major risk factor contributing to cellular changes in the brain that precipitate the emergence of various behavioral changes, including anxiety and anhedonia-symptoms relevant to mood disorders including major depression-however the sequence and trajectory of early molecular changes is poorly characterized. Using the chronic restraint stress (CRS) model in mice (N = 6-8/sex/group), we assessed the impact of 0, 7, 14, 21, 28, or 35 days of CRS at the behavioral level on the emergence of anxiety-like and anhedonia-like phenotypes. While 7 days of CRS was sufficient to induce anxiety-like behaviors in the PhenoTyper test, anhedonia-like deficits in the sucrose consumption test were only observed after 35 days of CRS. We also investigated the underlying molecular changes in the prefrontal cortex, a limbic brain region highly sensitive to stress, using Western blot and qPCR. We found that protein or RNA levels of several markers known to be implicated in the pathology of depression, and markers of synapses (post synaptic density protein 95 (PSD95), synapsin-1 (SYN1), vesicular glutamate transporter-1 (VGLUT1), and gephyrin (GPHN)); GABAergic inhibitory interneurons (somatostatin (SST), parvalbumin (PV), glutamic acid decarboxylase-67 (GAD67), and vasoactive intestinal peptide (VIP)); and astroglia (glial fibrillary acidic protein (GFAP), glutamate transporter-1 (GLT1), and glutamine synthase (GS)) were gradually reduced by CRS. Interestingly, all three astroglial markers were negatively correlated with anhedonia-like behaviors, while SYN1 and GPHN negatively correlated with anxiety-like behaviors. GLT1, VGLUT1, SYN1, and GAD67 negatively correlated with Z-emotionality scores. Exploratory between-marker correlations and integrative network analyses revealed that CRS effects might be driven by different compartments (synaptic, GABAergic and astroglial) depending on sex. Our study demonstrates that CRS induces dynamic changes that can be observed at the behavioral and molecular levels, and that male and female mice, while exhibiting similar symptoms, may experience different underlying pathologies.

Abstract

Recurrent spontaneous abortion (RSA), often linked to defective endometrial stromal cell (ESC) decidualization, lacks effective metabolism-targeted therapies. Here, we identify the in situ synthesis of trimethylamine N-oxide (TMAO) in human decidua as a critical safeguard. Metabolomics revealed significantly lower TMAO levels in decidual tissues of individuals experiencing RSA. Mechanistically, cyclic AMP (cAMP)-protein kinase A (PKA)-cAMP-responsive element-binding protein 1 (CREB1) signaling upregulated flavin-containing monooxygenase 3 (FMO3) in ESCs, driving local TMAO accumulation. TMAO directly bound the C terminus of 14-3-3η, enhancing its interaction with phosphoinositide-dependent protein kinase 1 (PDK1) to relieve PDK1-mediated suppression of forkhead box protein O1 (FOXO1). This promoted FOXO1 nuclear translocation and the activation of decidualization markers. Through mouse models employing dietary choline restriction, and FMO3 inhibition via pharmacological or genetic knockout, we demonstrated that endometrial TMAO deficiency impairs decidualization and increases pregnancy loss. Strikingly, TMAO restored decidualization capacity in 15% of patient-derived ESCs with inherent dysfunction. Our findings unveil endometrial TMAO synthesis as a metabolic checkpoint for decidualization and propose it as a therapeutic candidate for RSA.

Abstract

To investigate factors influencing pulsed-wave Doppler transmitral flow profiles and evaluate their diagnostic value in dogs with myxomatous mitral valve disease (MMVD).

Abstract

Based on the model of spleen deficiency, this study investigated the medicinal properties of spleen meridian tropism of Ganoderma lucidum spores and their efficacy of strengthening the spleen. Fifty SPF Kunming mice were randomly divided into a control group, a model group, an Atractylodes macrocephala group(1.1 g·kg~(-1)), a low-dose G. lucidum spores group(0.55 g·kg~(-1)), and a high-dose G. lucidum spores group(1.1 g·kg~(-1)). The mouse spleen deficiency model was established by fasting every other day, having adequate feed on the other days, and performing exhausted swimming every day for 21 consecutive days. From the first day of modeling, deionized water was given to mice in the control group and the model group in the morning of each day, and the corresponding medicine was given to the rest of the groups, with the medicines administered for 21 consecutive days. The physical signs and behavior, digestive function, energy metabolism, and immune regulation related symptoms of the mice were detected. The results showed that G. lucidum spores could improve the symptoms of spleen deficiency in mice, such as emaciation, lack of luster of fur, reduced food intake, huddling and laziness, make stools shaped and activity increased, enhance the body mass of the mice, increase their grip strength, and prolong the time of exhausted swimming. G. lucidum spores significantly increased serum D-xylose level, enhanced motilin(MTL) and gastrin(GAS) secretion, and decreased cholecystokinin(CCK), vasoactive intestinal peptide(VIP), and somatostatin(SST) mRNA expression levels in mice with spleen deficiency syndrome. G. lucidum spores elevated the levels of hepatic glycogen(LG), muscle glycogen(MG), and adenosine triphosphate(ATP), enhanced the activities of Na~+-K~+-ATPase, Ca~(2+)-Mg~(2+)-ATPase, lactate dehydrogenase(LDH), mitochondrial respiratory enzyme Ⅰ, mitochondrial respiratory enzyme Ⅳ, and ATPase, and reduced the accumulation of free fatty acid(FFA) and lactic acid(LA). G. lucidum spores increased thymus index, spleen index, elevated immunoglobulin A(IgA), immunoglobulin M(IgM), and immunoglobulin G(IgG) levels, decreased interleukin-6(IL-6), interleukin-1 beta(IL-1β), and tumor necrosis factor-α(TNF-α) levels, and improved splenic histopathological changes. The above results indicate that G. lucidum spores can improve the physical signs and behavior, digestive function, energy metabolism, and immune regulation of mice with spleen deficiency and have the medicinal properties of spleen meridian tropism and efficacy of strengthening the spleen.

Abstract

Network Meta-analysis was performed to evaluate the efficacy and safety of different traditional Chinese medicine(TCM) injections combined with conventional western medicine in the treatment of patients with coronary heart disease complicated with heart failure. Computer searches were conducted in CNKI, Wanfang, VIP, SinoMed, PubMed, EMbase, Cochrane Library, and Web of Science databases for randomized controlled trial(RCT) of TCM injections from database establishment to December 15, 2024. Literature meeting inclusion criteria were evaluated using the Cochrane risk of bias tool, with network Meta-analysis performed by RevMan 5.4 and Stata 16 software. 237 RCTs were finally included, involving 22 730 total samples and 17 TCM injections. RESULTS:: show:(1) clinical total effective rate improvement, the top three surface under the cumulative ranking curve(SUCRA) rankings were Shuxuetong Injection + conventional western medicine, Sodium Tanshinone Ⅱ_A Sulfonate Injection + conventional western medicine, and Shuxuening Injection + conventional western medicine.(2) Left ventricular ejection fraction(LVEF) improvement, the top three SUCRA rankings were Xuesaitong Injection + conventional western medicine, Shenqi Fuzheng Injection + conventional western medicine, and Ginkgo Leaf Extract and Dipyridamole Injection + conventional western medicine.(3) Brain natriuretic peptide(BNP) reduction, the top three SUCRA rankings were Sofren Injection + conventional western medicine, Shenmai Injection + conventional western medicine, and Shuxuetong Injection + conventional western medicine.(4) N-terminal pro-brain natriuretic peptide(NT-proBNP) reduction, the top three SUCRA rankings were Shengmai Injection + conventional western medicine, Yiqi Fumai Injection + conventional western medicine, and Xinmailong Injection + conventional western medicine.(5) TCM syndrome efficacy improvement, the top three SUCRA rankings were Shenmai Injection + conventional western medicine, Xinmailong Injection + conventional western medicine, and Shenfu Injection + conventional western medicine.(6) Left ventricular end-diastolic diameter(LVEDD) reduction, the top three SUCRA rankings were Salvianolic Acids for Injection + conventional western medicine, Yiqi Fumai Injection + conventional western medicine, and Tanshinone Ⅱ_A Sodium Sulfonate Injection + conventional western medicine.(7) Cardiac output(CO) improvement, the top three SUCRA rankings were Shenqi Fuzheng Injection + conventional western medicine, Salvianolic Acids for Injection + conventional western medicine, and Shengmai Injection + conventional western medicine.(8) 6 min walk test(6MWT) improvement, the top three SUCRA rankings were Danhong Injection + conventional western medicine, Shenmai Injection + conventional western medicine, and Shenfu Injection + conventional western medicine.(9) High-sensitivity C-reactive protein(hs-CRP) reduction, the top three SUCRA rankings were Shenfu Injection + conventional western medicine, Xinmailong Injection + conventional western medicine, and Shengmai Injection + conventional western medicine. The results show that TCM injections combined with conventional western medicine can improve clinical efficacy in patients with coronary heart disease complicated with heart failure. However, given large differences in literature quality and study numbers, the above conclusions need to be verified by more high-quality clinical RCT.

Abstract

Chronic kidney disease (CKD), especially when comorbid with diabetes, represents a significant global health burden with limited therapeutic options. Ramulus Mori (Sangzhi) Alkaloids (SZ-A) is a natural alkaloid formulation approved in China for type 2 diabetes management, but its potential renoprotective role remains largely unexplored.

Abstract

Eosinophilic granulomatosis with polyangiitis (EGPA) and severe eosinophilic asthma (SEA) share a Type 2 (T2) inflammatory signature but exhibit distinct pathophysiology. We hypothesized that EGPA involves additional inflammatory mechanisms, beyond T2 immunity, that drive its systemic manifestations and treatment resistance. Using single-cell RNA sequencing, we identify interferon (IFN-I)-driven inflammation in EGPA, in contrast to TNF predominant pathway activation in SEA. IL1B+MX1+ neutrophils in EGPA express IFN-stimulated genes and promote tertiary lymphoid structure formation with autoantibody production. In addition, other IFN-activated granulocytes, including APOC1+ eosinophils, SCN7A+ mast cells, and basophils, further contribute to immune dysregulation in EGPA, unlike TNF activated granulocytes in SEA. Longitudinal single-cell analysis of EGPA reveals an IGF1+ macrophage population linked to EGPA relapse. In animal models of both conditions, IGF1 blockade attenuates T2 inflammation, mucin production, and goblet cell hyperplasia, highlighting IGF1 as a possible therapeutic target in T2 inflammation disease.

Abstract

VIPoma is a rare neuroendocrine tumor (NET) that is challenging to diagnose. While VIP concentrations are elevated in VIPoma, the optimal threshold for diagnostic purposes is not well defined. We aimed to study this in a single-institution population. We obtained results from vasoactive intestinal peptide (VIP) tests from 2011 to 2023 and reviewed the medical record of patients who had concentrations greater than our established assay-specific reference limit of 75 pg/mL. We compared plasma VIP concentrations between patient cohorts with and without VIPoma and determined the optimal threshold for VIP concentrations to predict a VIPoma in this population. Seventy-six patients met the selection criteria. Of these, nine cases of VIPoma were diagnosed. All patients had chronic diarrhea, and five patients had a previous diagnosis of a pancreatic neuroendocrine tumor (PNET). VIP concentrations drawn for acute/episodic diarrhea or flushing/diaphoresis did not lead to a diagnosis of a VIPoma. Mean VIP concentration was increased in patients with a VIPoma relative to those without, but the difference was not statistically significant (508 pg/mL vs 223 pg/mL, P = 0.31). Using the threshold of 75 pg/mL, the positive predictive value for a VIPoma was 12%. The optimal VIP threshold was 442 pg/mL (OR: 11.96, 95% CI: 2.00-79.69, P = 0.01), with statistically significant odds ratios starting at 200 pg/mL. Our findings suggest that elevated VIP concentrations are not predictive for a VIPoma and most patients with elevated VIP do not have a VIPoma. We recommend that VIP only be drawn in certain clinical scenarios to avoid unnecessary medical investigations.

Abstract

Alcohol use disorder (AUD) is highly prevalent and associated with substantial morbidity and mortality. While there are currently three FDA-approved medications for AUD, none specifically target the withdrawal/negative affect stage of AUD, underscoring the need to understand the underlying neurobiological adaptations associated with this critical stage of the addiction cycle. One key region involved in alcohol withdrawal and negative affect is the prelimbic cortex, a subregion of the medial prefrontal cortex. In the present study, we used male and female PV, SOM, and VIP reporter mice to examine cellular and synaptic adaptations in all three major classes of prelimbic cortex interneurons following 72-hour withdrawal from a continuous-access to two-bottle choice model of alcohol. We found that alcohol withdrawal increased PV interneuron excitability in the male cohort but reduced it in the female cohort. In SOM interneurons, withdrawal increased the action potential threshold in males, whereas in VIP interneurons it hyperpolarized the resting membrane potential and reduced membrane resistance in females. Withdrawal also altered synaptic transmission: it enhanced glutamate release onto SOM and VIP interneurons in males but reduced glutamate release onto SOM interneurons in females, and it decreased GABA release onto PV interneurons in males. Together, these findings reveal alcohol withdrawal-induced adaptations in both intrinsic properties and synaptic inputs across prelimbic interneurons, with several patterns differing across the male and female cohorts studied.

Abstract

The central circadian clock of the suprachiasmatic nucleus (SCN) comprises a network of diverse neuronal and glial cell types, yet its operating mechanism remains elusive. Here, by monitoring cellular calcium rhythms in vivo using dual-color fiber photometry in mice lacking vasoactive intestinal polypeptide (VIP), we demonstrate that arginine vasopressin (AVP) neurons oscillate intrinsically with a short period and reduced amplitude. This indicates that VIP normally amplifies and phase-delays the AVP neuronal rhythm each day, thereby lengthening its period to approximately 24 h in constant darkness. Consistently, the behavioral circadian period is shortened by AVP neuron-specific VIP receptor dysfunction and lengthened by AVP neuron-specific blockade of neurotransmitter release. VIP neurons and other SCN cell types occasionally exhibit weak, unstable, long-period calcium rhythms only when the AVP neuronal oscillation is attenuated due to VIP deficiency or AVP neuron-specific Bmal1 deletion. Given that AVP neurons serve as the primary pacesetter cells of the SCN ensemble rhythm, these results indicate that an SCN neuronal feedback loop (SNFL), composed of the AVP cellular oscillator and VIPergic signaling, is essential for generating robust circadian rhythms.

Abstract

The incidence of heart failure (HF) following percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI) remains relatively high, severely impairing long-term prognosis and quality of life. In recent years, advances in biomarker identification and imaging technologies have driven growing research into developing HF risk prediction models for AMI patients post-PCI. However, significant heterogeneity exists across current studies in terms of model construction methods, variable selection, and validation strategies, and the predictive performance and clinical utility of these models have not been systematically evaluated.

Abstract

Sensory cortices are not silent in the absence of sensory inputs but generate spontaneous activity intrinsic to the cortical circuit referred to as default-mode activity. Here, we report that spontaneous activity of excitatory and inhibitory neuronal types in layer 2/3 of the adult primary visual cortex (V1) exhibits quite stable default-mode local network architectures, which undergo rapid and selective restructuring following bilateral enucleation (EN), a model of adult-onset blindness. Spontaneous activity of both pyramidal (Pyr) and parvalbumin (PV) neurons rapidly and persistently increased following EN, but the default-mode network architecture of only Pyr rapidly rearranged and stabilized. Vasoactive intestinal peptide (VIP) neuronal network also restructured rapidly after EN, but their spontaneous activity increase was delayed. Somatostatin (SOM) neuronal network was quite stable. Our results indicate that adult-onset blindness rapidly and selectively modifies the stable default-mode local network architectures of V1, independent of increases in spontaneous activity, reflecting rapid adaptation to vision loss.