ObjectiveTo investigate the therapeutic effect of paeoniflorin on metabolic dysfunction-associated fatty liver disease （MASLD） combined with insulin resistance （IR）， and to elucidate its regulatory mechanisms on the Toll-like receptor 4 （TLR4）/nuclear transcription factor （NF）-κB-insulin receptor substrate 1 （IRS1） inflammation-insulin signaling axis. MethodsMASLD mouse model was established using a 60% high-fat diet. Mice were randomly assigned to a normal control group， a MASLD model group， and paeoniflorin groups （low dose： 25 mg·kg^-1·d^-1， medium dose： 50 mg·kg^-1·d^-1， high dose： 100 mg·kg^-1·d^-1）， receiving intragastric administration for consecutive 12 weeks. Concurrently， a palmitic acid/oleic acid （PA/OA）-induced lipid deposition model was established in HepG2 cells. Cell counting kit-8 （CCK-8） assay was performed to determine the optimal concentrations of PA/OA and paeoniflorin for intervention. Mice body weight， liver index， and serum levels of alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， triglycerides （TG）， and total cholesterol （TC） were measured. Fasting blood glucose （FBG） and fasting insulin （FINS） levels were measured， and the homeostatic model assessment of insulin resistance （HOMA-IR） was calculated， while an oral glucose tolerance test （OGTT） was performed to evaluate glucose metabolism. Hematoxylin and eosin （HE） staining was used to observe pathological changes and inflammatory cell infiltration in liver tissue， and oil red O staining was used to evaluate lipid droplet deposition in liver tissue and HepG2 cells. Potential targets were screened using network pharmacology and molecular docking. Western blot analysis was performed to detect the expression of HSP90AA1， TLR4， p-NF-κB p65， p-IRS1， and p-Akt proteins in liver tissue and HepG2 cells. ResultsCompared with the normal control group， mice in the MASLD model group exhibited significantly increased body weight， liver index， and serum levels of ALT， AST， TG， and TC， as well as markedly elevated FBG， FINS， and HOMA-IR， and impaired glucose tolerance （P<0.01）. HE staining revealed marked hepatic steatosis and inflammatory cell infiltration， while oil red O staining showed a significant increase in lipid droplet deposition. Compared with the MASLD model group， after intervention with various doses of paeoniflorin， the increase in body weight and liver index was reduced， serum ALT， AST， TG， and TC levels decreased， and FBG， FINS， and HOMA-IR were significantly lowered， with glucose tolerance markedly improved （P<0.05， P<0.01）， showing a certain dose-dependent trend. HE and oil red O staining results showed a marked reduction in hepatic steatosis and lipid deposition. In vitro experiments demonstrated that， compared with the control group， PA/OA treatment significantly induced increased lipid deposition in HepG2 cells. Compared with the model group， paeoniflorin intervention significantly reduced intracellular lipid droplets， and lipid deposition showed a dose-dependent decreasing trend. Mechanism studies indicated that， compared with the normal control group， the MASLD model group exhibited significantly elevated expression of TLR4， HSP90AA1， and p-NF-κB p65， while p-IRS1 （Ser307） expression was elevated and p-Akt （Ser473） expression was reduced （P<0.01）. Compared with the model group， the expression of the aforementioned proteins was significantly reversed in all treatment groups following intervention （P<0.05， P<0.01）. ConclusionPaeoniflorin significantly alleviates lipid deposition and insulin resistance in MASLD mice. Its mechanism of action may involve targeting HSP90AA1， TLR4， and NF-κB1 to regulate the TLR4/NF-κB-IRS1 inflammation-insulin signaling axis. This regulation suppresses inflammatory responses and restores insulin signaling， thereby ameliorating abnormalities in glucose and lipid metabolism.

ObjectiveTo investigate the therapeutic effect of paeoniflorin on metabolic dysfunction-associated fatty liver disease （MASLD） combined with insulin resistance （IR）， and to elucidate its regulatory mechanisms on the Toll-like receptor 4 （TLR4）/nuclear transcription factor （NF）-κB-insulin receptor substrate 1 （IRS1） inflammation-insulin signaling axis. MethodsMASLD mouse model was established using a 60% high-fat diet. Mice were randomly assigned to a normal control group， a MASLD model group， and paeoniflorin groups （low dose： 25 mg·kg^-1·d^-1， medium dose： 50 mg·kg^-1·d^-1， high dose： 100 mg·kg^-1·d^-1）， receiving intragastric administration for consecutive 12 weeks. Concurrently， a palmitic acid/oleic acid （PA/OA）-induced lipid deposition model was established in HepG2 cells. Cell counting kit-8 （CCK-8） assay was performed to determine the optimal concentrations of PA/OA and paeoniflorin for intervention. Mice body weight， liver index， and serum levels of alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， triglycerides （TG）， and total cholesterol （TC） were measured. Fasting blood glucose （FBG） and fasting insulin （FINS） levels were measured， and the homeostatic model assessment of insulin resistance （HOMA-IR） was calculated， while an oral glucose tolerance test （OGTT） was performed to evaluate glucose metabolism. Hematoxylin and eosin （HE） staining was used to observe pathological changes and inflammatory cell infiltration in liver tissue， and oil red O staining was used to evaluate lipid droplet deposition in liver tissue and HepG2 cells. Potential targets were screened using network pharmacology and molecular docking. Western blot analysis was performed to detect the expression of HSP90AA1， TLR4， p-NF-κB p65， p-IRS1， and p-Akt proteins in liver tissue and HepG2 cells. ResultsCompared with the normal control group， mice in the MASLD model group exhibited significantly increased body weight， liver index， and serum levels of ALT， AST， TG， and TC， as well as markedly elevated FBG， FINS， and HOMA-IR， and impaired glucose tolerance （P<0.01）. HE staining revealed marked hepatic steatosis and inflammatory cell infiltration， while oil red O staining showed a significant increase in lipid droplet deposition. Compared with the MASLD model group， after intervention with various doses of paeoniflorin， the increase in body weight and liver index was reduced， serum ALT， AST， TG， and TC levels decreased， and FBG， FINS， and HOMA-IR were significantly lowered， with glucose tolerance markedly improved （P<0.05， P<0.01）， showing a certain dose-dependent trend. HE and oil red O staining results showed a marked reduction in hepatic steatosis and lipid deposition. In vitro experiments demonstrated that， compared with the control group， PA/OA treatment significantly induced increased lipid deposition in HepG2 cells. Compared with the model group， paeoniflorin intervention significantly reduced intracellular lipid droplets， and lipid deposition showed a dose-dependent decreasing trend. Mechanism studies indicated that， compared with the normal control group， the MASLD model group exhibited significantly elevated expression of TLR4， HSP90AA1， and p-NF-κB p65， while p-IRS1 （Ser307） expression was elevated and p-Akt （Ser473） expression was reduced （P<0.01）. Compared with the model group， the expression of the aforementioned proteins was significantly reversed in all treatment groups following intervention （P<0.05， P<0.01）. ConclusionPaeoniflorin significantly alleviates lipid deposition and insulin resistance in MASLD mice. Its mechanism of action may involve targeting HSP90AA1， TLR4， and NF-κB1 to regulate the TLR4/NF-κB-IRS1 inflammation-insulin signaling axis. This regulation suppresses inflammatory responses and restores insulin signaling， thereby ameliorating abnormalities in glucose and lipid metabolism.

Zika virus(ZIKV),a flavivirus transmitted primarily through the bites of Aedes mosquitoes,led to a major public health crisis in the 2015 Brazilian outbreak.The World Health Organization(WHO)subsequently designated the Brazilian ZIKV epi-demic as a Public Health Emergency of International Concern(PHEIC)in 2016,because of its devastating consequences.Congenital Zika syndrome(CZS),a distinctive constellation of teratogenic effects caused by intrauterine ZIKV infection,is characterized by mi-crocephaly,ocular lesions,cortical calcifications,congenital contractures,and multisystem developmental anomalies.CZS poses sub-stantial risks to neonatal survival and long-term health outcomes.Despite containment efforts,ZIKV remains prevalent across multiple endemic regions,thus underscoring persistent threats to maternal-fetal health.Systematic longitudinal monitoring of CZS cohorts,inte-grated with interdisciplinary approaches bridging clinical assessments and mechanistic studies,is imperative to elucidate the pathogen-esis and advance therapeutic strategies.To inform future investigations and identify novel research directions in CZS pathobiology,this review synthesizes recent advances in three key domains:clinical characterization of CZS manifestations,development of CZS animal models,and breakthroughs in molecular mechanisms underlying ZIKV-induced teratogenesis.

Dry eye disease (DED) is a prevalent and intractable ocular disease induced by a variety of causes. Elevated sphingomyelin (SM) levels and pro-inflammatory cytokines were detected on the ocular surface of DED patients, particularly in the meibomian glands. Sphingomyelin synthase 2 (SMS2), one of the proteins involved in SM synthesis, would light a novel way of developing a DED therapy strategy. Herein, we report the design and optimization of a series of novel thiophene carboxamide derivatives to afford 14l with an improved highly potent inhibitory activity on SM synthesis (IC_{50, SMS2} = 28 nmol/L). Moreover, 14l exhibited a notable protective effect of anti-inflammation and anti-apoptosis on human corneal epithelial cells (HCEC) under TNF-α-hyperosmotic stress conditions in vitro, with an acceptable ocular specific distribution (corneas and meibomian glands) and pharmacokinetics (PK) profiles (t _{1/2, cornea} = 1.11 h; t _{1/2, meibomian glands} = 4.32 h) in rats. Furthermore, 14l alleviated the dry eye symptoms including corneal fluorescein staining scores and tear secretion in a dose-dependent manner in mice. Mechanically, 14l reduced the mRNA expression of Tnf-α, Il-1β and Mmp-9 in corneas, as well as the proportion of very long chain SM in meibomian glands. Our findings provide a new strategy for DED therapy based on selective SMS2 inhibitors.

Zika virus(ZIKV),a flavivirus transmitted primarily through the bites of Aedes mosquitoes,led to a major public health crisis in the 2015 Brazilian outbreak.The World Health Organization(WHO)subsequently designated the Brazilian ZIKV epi-demic as a Public Health Emergency of International Concern(PHEIC)in 2016,because of its devastating consequences.Congenital Zika syndrome(CZS),a distinctive constellation of teratogenic effects caused by intrauterine ZIKV infection,is characterized by mi-crocephaly,ocular lesions,cortical calcifications,congenital contractures,and multisystem developmental anomalies.CZS poses sub-stantial risks to neonatal survival and long-term health outcomes.Despite containment efforts,ZIKV remains prevalent across multiple endemic regions,thus underscoring persistent threats to maternal-fetal health.Systematic longitudinal monitoring of CZS cohorts,inte-grated with interdisciplinary approaches bridging clinical assessments and mechanistic studies,is imperative to elucidate the pathogen-esis and advance therapeutic strategies.To inform future investigations and identify novel research directions in CZS pathobiology,this review synthesizes recent advances in three key domains:clinical characterization of CZS manifestations,development of CZS animal models,and breakthroughs in molecular mechanisms underlying ZIKV-induced teratogenesis.

Ocular fundus diseases is a kind of ophthalmic diseases that occur in the vitreous, retina, choroid and optic nerve, including a series of pathophysiological changes such as inflammation, exudation and proliferation. Because of high morbidity and high blindness rate, ocular fundus diseases has been paid more and more attention from medical community. With the continuous deepening of research on its etiology, anatomy and pathological mechanism in recent years, clinicians have obtained more abundant treatment methods than in the past, and the medical treatment of ocular fundus diseases have made many phased progress. However, due to its wide spectrum of diseases and complex pathological mechanism, clinicians still need to further explore more effective treatment methods, and improve the effect of diagnosis and treatment to ocular fundus diseases.

Objective:To investigate the characteristics of new mutations of CCM1 gene in a family with familial multiple cerebral cavernous malformation (CCM). Methods:A family with familial multiple CCM diagnosed in our hospital in 2013 and followed up for a long time were selected in our study. Peripheral blood samples and/or pathological tissue samples of some patients and healthy subjects in this family were collected for full exon sequencing of genomic DNA. Combined with the databases of Clin Var, HGMD and ExAC, the possible pathogenic genes in this family were screened by bioinformatics analysis; the three-dimensional structure prediction analysis of protein products was performed and Sanger sequencing was used to verify the pathogenic genes.Results:Whole exon sequencing showed that a novel deletion-frameshift mutation (c.1635delA) in CCM1 gene was noted in these patients, and this mutation leaded to deletion of reference nucleobase "T" ; this deletion had not been reported; while no above mutation was noted in the healthy subjects. Sanger sequencing showed that deletion of nucleobase "A" was noted in 1635 locus, No. 15 exon of CCM1 gene; this deletion would result in changes of CCM1 gene reading frame, which leaded to premature appearance of termination codon TAG at nucleotide of position 1652-1654. Three-dimensional structure prediction analysis showed that this new mutation might lead to the lack of Ferm-3 domain in the C-terminal of KRIT1 protein. Conclusion:The new deletion-frameshift mutation (c.1635delA) of CCM1 gene in this family leads to familial multiple CCM.