ObjectiveTo investigate the effect and mechanism of Qingre Sanzhuo decoction in treating gouty arthritis （GA） combined with hyperuricaemia （HUA）. MethodsSixty male SD rats were randomized into normal， model， colchicine （0.5 mg·kg^-1）， and low-， medium-， and high-dose （17， 34， 68 g·kg^-1， respectively） Qingre Sanzhuo decoction groups （n=10）. The rats in other groups except the normal group were treated with the modified method for the modeling of GA combined with HUA. The drug intervention groups were administrated with corresponding drugs by gavage in the afternoon every day and the normal group and the model group were administrated with an equal volume of sterile normal saline by gavage. The level of uric acid （SUA） in the serum was measured 2 h after the last administration. The degree of ankle joint swelling was calculated 0.5， 12， 24， 48 h after modeling， and joint inflammation was scored. The pathological changes of ankle joints were observed by hematoxylin-eosin staining， and the serum levels of tumor necrosis factor-α （TNF-α）， interleukin-1β （IL-1β）， C reactive protein （CRP）， and interleukin-18 （IL-18） were measured by enzyme-linked immunosorbent assay. Real-time PCR was performed to determine the mRNA levels of NOD-like receptor protein 3 （NLRP3）， apoptosis-associated speck-like protein containing CARD （ASC）， cysteinyl aspartate-specific protease-1 （Caspase-1）， gasdermin D （GSDMD）， and nuclear factor-kappa B （NF-κB） in the synovial tissue of ankle joints. Western blot was employed to determine the protein levels of NLRP3， ASC， and Caspase-1 in ankle joints. The immunohistochemical method was used to detect the expression of GSDMD and NF-κB in the synovial tissue of ankle joints. ResultsCompared with the normal group， the model group showed increased SUA in the serum （P<0.05）， ankle joint swelling and joint inflammation （P<0.05）， increased number of blood vessels in the synovium， inflammatory cell foci in the synovial bursa， elevated serum levels of TNF-α， IL-1β， CRP， and IL-18 （P<0.05）， and up-regulated mRNA and protein levels of NLRP3， ASC， Caspase-1， GSDMD， and NF-κB in the synovial tissue of ankle joints （P<0.05）. Compared with the model group， the medium- and high-dose Qingre Sanzhuo decoction groups showed reduced SUA in the serum （P<0.05）， alleviated ankle joint swelling and joint inflammation （P<0.05）， lowered serum levels of TNF-α， IL-1β， CRP， and IL-18 （P<0.05）， and down-regulated mRNA and protein levels of NLRP3， ASC， Caspase-1， GSDMD， and NF-κB in the synovial tissue of ankle joints （P<0.05）. However， in terms of ameliorating the pathological changes of ankle joints， only the high-dose Qingre Sanzhuo decoction group showed normal morphology of the synovial membrane of ankle joints and no obvious lesion in the articular cartilage. ConclusionQingre Sanzhuo decoction may play a role in preventing and controlling GA combined with HUA by down-regulating the activity of NLRP3/ASC/Caspase-1 pathway and inhibiting the expression of inflammatory cytokines， such as TNF-α， IL-1β， CRP， and IL-18.

Trauma is the main cause of death and disability. Patients with severe trauma have hemorrhagic shock, traumatic coagulopathy and other diseases, which increase the risk of death. Platelets are important in the hemostatic response, but their function is rapidly dysregulated in trauma patients, leading to traumatic coagulopathy, blood loss, and early death. In addition to their role in hemostasis, platelets act as coordinators of the initial immune response, which can lead to immunothrombosis, organ dysfunction, and increased late mortality. At present, the treatment of post traumatic platelet dysfunction is mainly based on early hemostasis, and late prevention and treatment of thrombosis and organ dysfunction. In this review, the characteristics, underlying mechanisms, diagnosis and treatment strategies of platelet dysfunction in different periods are summarized, to provide ideas for studying the mechanism of platelet dysfunction after trauma and the treatment strategy for trauma patients.
Humans ; Wounds and Injuries/therapy* ; Blood Platelets/metabolism* ; Blood Platelet Disorders/etiology* ; Animals ; Hemostasis

PURPOSE: To investigate the regulatory role of nerve injury-induced protein 1 (NINJ1) in the anti-inflammatory function of human umbilical cord mesenchymal stem cells (hUC-MSCs) co-stimulated by interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). METHODS: hUC-MSCs were expanded in vitro using standard protocols, with stem cell characteristics confirmed by flow cytometry and multilineage differentiation assays. The immunomodulatory properties and cellular activity of cytokine-co-pretreated hUC-MSCs were systematically evaluated via quantitative reverse transcription RT-qPCR, lymphocyte proliferation suppression assays, and Cell Counting Kit-8 viability tests. Transcriptome sequencing, Western blotting and small interfering RNA interference were integrated to analyze the regulatory mechanisms of NINJ1 expression. Functional roles of NINJ1 in pretreated hUC-MSCs were elucidated through gene silencing combined with lactate dehydrogenase release assays, Annexin V/Propidium Iodide apoptosis analysis, macrophage co-culture models, and cytokine Enzyme-Linked Immunosorbent Assay. Therapeutic efficacy was validated in a cecal ligation and puncture-induced septic mouse model: 80 mice were randomly allocated into 4 experimental groups (n=20/group): sham group (laparotomy without cecal ligation); phosphate-buffered saline-treated group (cecal ligation and puncture (CLP) + 0.1 mL phosphate-buffered saline); hUC-MSCs (small interfering RNA (siRNA)-interferon-gamma and tumor necrosis factor-alpha co-stimulation (IT))-treated group (CLP + hUC-MSCs transfected with scrambled siRNA); and hUC-MSCs (siNINJ1-IT)-treated group (CLP + hUC-MSCs with NINJ1-targeting siRNA). RESULTS: hUC-MSCs demonstrated compliance with International Society for Cellular Therapy criteria, confirming their stem cell identity. IFN-γ/TNF-α co-pretreatment enhanced the immunosuppressive capacity of hUC-MSCs, accompanied by the reduction of cellular viability, while concurrently upregulating pro-inflammatory cytokines such as interleukin-6 and interleukin-1β. This co-stimulation significantly elevated NINJ1 expression in hUC-MSCs, whereas genetic silencing of NINJ1 effectively suppressed pro-inflammatory cytokine production and attenuated damage-associated molecular patterns release through inhibition of programmed plasma membrane rupture. Furthermore, the NINJ1 interference potentiated the ability of cytokine-pretreated hUC-MSCs to suppress LPS-induced pro-inflammatory responses in RAW264.7 macrophages. In cecal ligation and puncture-induced sepsis model, NINJ1-silenced hUC-MSCs exhibited enhanced therapeutic efficacy, manifested by reduced systemic inflammation and multi-organ damage. CONCLUSION Our findings shed new light on the immunomodulatory functions of cytokine-primed MSCs, offering groundbreaking insights for developing MSC-based therapies against inflammatory diseases via interfering the expression of NINJ1.
Mesenchymal Stem Cells/drug effects* ; Animals ; Interferon-gamma/pharmacology* ; Tumor Necrosis Factor-alpha/pharmacology* ; Humans ; Mice ; Umbilical Cord/cytology* ; Cells, Cultured ; Apoptosis ; Male

Objective:To analyze the relevant factors affecting postnatal glucose metabolism in pregnant women with gestational diabetes and construct a nomogram prediction model.Methods:Using a retrospective study method, 210 cases of gestational diabetes patients admitted to Danyang People′s Hospital from March 2019 to November 2021 were selected as the study subjects, and they were divided into 125 cases of normal group and 85 cases of abnormal group according to the postnatal glucose metabolism. The predictive value was analyzed using the subject work characteristics (ROC) curve experiment; the risk factors affecting abnormal postpartum glucose metabolism in pregnant women with gestational diabetes mellitus were analyzed using Logistic regression experiment; and the clinical efficacy of the column-line diagram model was verified using internal data.Results:There was no statistically significant difference between the two groups when comparing the general information such as age ( P>0.05); compared with the normal group, the abnormal group had higher values of total cholesterol (TG), postprandial 2 h blood glucose (OGTT 2 h), glycosylated hemoglobin, and pre-pregnancy body mass index (BMI): (4.23 ± 1.35) mmol/L vs. (3.65 ± 1.50) mmol/L, (9.36 ± 1.25) mmol/L vs. (8.20 ± 1.51) mmol/L, (8.31 ± 2.96)% vs. (6.73 ± 2.23)%, (24.96 ± 4.21) kg/m 2 vs. (23.20 ± 3.25) kg/m 2, and those with a family history of diabetes mellitus were higher: 47.06%(40/85) vs. 20.80%(26/125), there were statistical differences ( P<0.05); the area under the curve (AUC) of TG, OGTT 2 h, glycated hemoglobin, and pre-pregnancy BMI were 0.605, 0.720, 0.670, and 0.616, with optimal cut off values of 4.65 mmol/L, 8.33 mmol/L, 8.06%, and 25.27 kg/m 2; TG (>4.65 mmol/L), OGTT 2 h (>8.33 mmol/L), glycated hemoglobin (>8.06%), and preconception BMI (>25.27 kg/m 2), and family history of diabetes mellitus (yes) were risk factors for abnormal glucose metabolism in pregnant women ( P<0.05); the C-index of the risk of postpartum glucose metabolism in pregnant women with gestational diabetes mellitus predicted by the column chart model was 0.750 (95% CI 0.672 - 0.864). The model predicted that the threshold of the risk of postnatal glucose metabolism in pregnant women with gestational diabetes mellitus was >0.07. Conclusions:TG (>4.65 mmol/L ), OGTT 2 h (>8.33 mmol/L ), glycated haemoglobin (>8.06%), pre-pregnancy BMI (>25.27 kg/m 2), and family history of diabetes (yes) are risk factors for abnormal glucose metabolism in pregnant women, and the model constructed based on the variables have good predictive power.

Humans ; Albumins ; Albuminuria/urine* ; Blood Pressure ; China/epidemiology* ; Creatinine ; Risk Factors ; Aged

Objective To investigate the pharmacological effects of"Yajieshaba"on mice with alcohol-induced liver injury and to investigate the mechanism of the impact of"Yajieshaba"on the regulation of intestinal flora by 16S rDNA technology.Methods Healthy male KM mice were randomly divided into control,model,"Yajieshaba"low,medium,and high dose(0.39,1.17 and 3.51 g·kg-1)groups and Bifendatatum(2.93 mg·kg-1)groups,with eight mice in each group.After one week of pre-administration of"Yajieshaba",a mouse model of acute alcoholic liver injury was established by a single instillation of 56%alcohol,and the levels of AST and ALT in the serum of mice were measured,and the morphological changes of liver histology were observed by HE staining;secondly,faecal DNA was extracted from each group under aseptic operation,and 16S rDNA sequencing and differential analysis by alpha diversity and species composition at the phylum and genus levels were performed.Results The results showed that the biochemical indexes of liver function(ALT and AST)were significantly improved by"Yajieshaba",and the degree of liver damage was significantly reduced by HE staining.At the phylum level,it significantly decreased the abundance of Aspergillus and increased the quantity of Bacteroides;at the genus level,it significantly up-regulated the plenty of Bacteroides and Prevotella and downregulated a lot of Prevotella and Helicobacter.At the genus level,"Yajieshaba"significantly up-regulated the abundance of Bacillus spp.and Prevotella spp.and down-regulated the abundance of Prevotella spp.and Helicobacter spp.Conclusion"Yajieshaba"may play an anti-acute alcoholic liver injury effect by regulating the intestinal flora and metabolites.

Objective　Because occult hepatitis B virus (HBV) variants are highly transmissible and harmful, the investigation of HBsAg antigenic mutation, synthesis, and secretion will provide useful guidance for addressing clinical diagnosis and treatment of occult hepatitis B infection. Methods The HBV gene sequences of OBI patients were successfully cloned to obtain HBsAg single and multi-locus mutants. The protein similarity and stability of the wild-type and mutant structural model were analyzed using AlphaFold2.3 software, and the wild-type, single and multi-locus mutants were transfected into Huh7 cells to analyze the intra- and extracellular synthesis and secretion of different mutants. Results The single mutant loci Y100L, Y100C, and C139R showed smaller root mean squared deviation (RMSD) values compared to the wild type, while G145R had a larger RMSD value. Moreover, the Y100L mutation exhibited the smallest thermos-energetic difference (∆∆G), followed by Y100C, C139R, and G145R. The RMSD values of the three multi-locus mutants were less than 1 compared to the wild type, and the RMSD values of T63I/Y100L/Q101K were the smallest, followed by T125A/F158L/V224G and S113T/F220C. The synthesis, secretion, and secretion efficiency of Y100C, C139R, and G145R were significantly different from the wild-type (P<0.05); the intracellular synthesis and secretion efficiency of S113T/F220C were statistically different compared to the wild-type (P<0.05); the intracellular synthesis and secretion efficiency of T63I/Y100L/Q101K were statistically different compared to the wild type (P<0.05). Conclusion Some single-point mutants in the luminal region of the endoplasmic reticulum reduce the synthesis and secretion of HBsAg in hepatocytes. Certain multi-loci mutants combining the luminal region of the endoplasmic reticulum with other structural regions increase the synthesis of HBsAg in hepatocytes but reduce secretion efficiency.

Respiratory syncytial virus (RSV) is an enveloped, negative-sense, single-stranded RNA virus of the Orthopneumovirus  genus of the Pneumoviridae family in the order Mononegavirales. RSV can cause acute upper and lower respiratory tract infections, sometimes with extrapulmonary complications. The disease burden of RSV infection is enormous, mainly affecting infants and older adults aged 75 years or above. Currently, treatment options for RSV are largely supportive. Prevention strategies remain a critical focus, with efforts centered on vaccine development and the use of prophylactic monoclonal antibodies. To date, three RSV vaccines have been approved for active immunization among individuals aged 60 years and above. For children who are not eligible for these vaccines, passive immunization is recommended. A newly approved prophylactic monoclonal antibody, Nirsevimab, which offers enhanced neutralizing activity and an extended half-life, provides exceptional protection for high-risk infants and young children. This review provides a comprehensive and detailed exploration of RSV's virology, immunology, pathogenesis, epidemiology, clinical manifestations, treatment options, and prevention strategies.
Humans ; Respiratory Syncytial Virus Infections/prevention & control* ; Respiratory Syncytial Viruses/pathogenicity* ; Respiratory Syncytial Virus, Human/pathogenicity* ; Antiviral Agents/therapeutic use*

Metastasis accounts for 90% of breast cancer deaths, where the lethality could be attributed to the poor drug accumulation at the metastatic loci. The tolerance to chemotherapy induced by breast cancer stem cells (BCSCs) and their particular redox microenvironment further aggravate the therapeutic dilemma. To be specific, therapy-resistant BCSCs can differentiate into heterogeneous tumor cells constantly, and simultaneously dynamic maintenance of redox homeostasis promote tumor cells to retro-differentiate into stem-like state in response to cytotoxic chemotherapy. Herein, we develop a specifically-designed biomimic platform employing neutrophil membrane as shell to inherit a neutrophil-like tumor-targeting capability, and anchored chemotherapeutic and BCSCs-differentiating reagents with nitroimidazole (NI) to yield two hypoxia-responsive prodrugs, which could be encapsulated into a polymeric nitroimidazole core. The platform can actively target the lung metastasis sites of triple negative breast cancer (TNBC), and release the escorted drugs upon being triggered by the hypoxia microenvironment. During the responsiveness, the differentiating agent could promote transferring BCSCs into non-BCSCs, and simultaneously the nitroimidazole moieties conjugated on the polymer and prodrugs could modulate the tumor microenvironment by depleting nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) and amplifying intracellular oxidative stress to prevent tumor cells retro-differentiation into BCSCs. In combination, the BCSCs differentiation and tumor microenvironment modulation synergistically could enhance the chemotherapeutic cytotoxicity, and remarkably suppress tumor growth and lung metastasis. Hopefully, this work can provide a new insight in to comprehensively treat TNBC and lung metastasis using a versatile platform.

As a neurological disorder in the brain, epilepsy is not only associated with abnormal synchronized discharging of neurons, but also inseparable from non-neuronal elements in the altered microenvironment. Anti-epileptic drugs (AEDs) merely focusing on neuronal circuits frequently turn out deficient, which is necessitating comprehensive strategies of medications to cover over-exciting neurons, activated glial cells, oxidative stress and chronic inflammation synchronously. Therefore, we would report the design of a polymeric micelle drug delivery system that was functioned with brain targeting and cerebral microenvironment modulation. In brief, reactive oxygen species (ROS)-sensitive phenylboronic ester was conjugated with poly-ethylene glycol (PEG) to form amphiphilic copolymers. Additionally, dehydroascorbic acid (DHAA), an analogue of glucose, was applied to target glucose transporter 1 (GLUT1) and facilitate micelle penetration across the blood‒brain barrier (BBB). A classic hydrophobic AED, lamotrigine (LTG), was encapsulated in the micelles via self-assembly. When administrated and transferred across the BBB, ROS-scavenging polymers were expected to integrate anti-oxidation, anti-inflammation and neuro-electric modulation into one strategy. Moreover, micelles would alter LTG distribution in vivo with improved efficacy. Overall, the combined anti-epileptic therapy might provide effective opinions on how to maximize neuroprotection during early epileptogenesis.