Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl₄ and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.

Objective To investigate the incidence rate,clinical characteristics,and prognosis of neonatal stroke in Shenzhen,China.Methods Led by Shenzhen Children's Hospital,the Shenzhen Neonatal Data Collaboration Network organized 21 institutions to collect 36 cases of neonatal stroke from January 2020 to December 2022.The incidence,clinical characteristics,treatment,and prognosis of neonatal stroke in Shenzhen were analyzed.Results The incidence rate of neonatal stroke in 21 hospitals from 2020 to 2022 was 1/15 137,1/6 060,and 1/7 704,respectively.Ischemic stroke accounted for 75％(27/36);boys accounted for 64％(23/36).Among the 36 neonates,31(86％)had disease onset within 3 days after birth,and 19(53％)had convulsion as the initial presentation.Cerebral MRI showed that 22 neonates(61％)had left cerebral infarction and 13(36％)had basal ganglia infarction.Magnetic resonance angiography was performed for 12 neonates,among whom 9(75％)had involvement of the middle cerebral artery.Electroencephalography was performed for 29 neonates,with sharp waves in 21 neonates(72％)and seizures in 10 neonates(34％).Symptomatic/supportive treatment varied across different hospitals.Neonatal Behavioral Neurological Assessment was performed for 12 neonates(33％,12/36),with a mean score of(32±4)points.The prognosis of 27 neonates was followed up to around 12 months of age,with 44％(12/27)of the neonates having a good prognosis.Conclusions Ischemic stroke is the main type of neonatal stroke,often with convulsions as the initial presentation,involvement of the middle cerebral artery,sharp waves on electroencephalography,and a relatively low neurodevelopment score.Symptomatic/supportive treatment is the main treatment method,and some neonates tend to have a poor prognosis.

Objective To explore the anatomical basis and clinical effect of radical styloid process bone(membrance)flap pedicled with the recurrent branch of radial artery to styloid process for repairing carpal scaphoid fracture.Methods The equal lengths of the radial styloid process in 25 adult radial specimens were measured.A latex-perfused male adult upper limb specimen was dissected to observe the course and distribution of the recurrent branch of radial artery to styloid process.The clinical data of 15 patients with carpal scaphoid fracture repaired by transposition and implantation of radical styloid process bone(membrance)flap pedicled with the recurrent branch of radial artery to styloid process were retrospectively analyzed,and the therapeutic effect was analyzed.Results The length of the radial styloid process measured on 25 radial specimens was 11 to 16 mm.Dissection of the latex-perfused male adult upper limb specimens revealed:the radial artery in the snuffbox emitted a thicker dorsal carpal branch to the ulnar side at(1.2±0.2)cm below the styloid process,and then sent a branch proximally back to the styloid process.The fracture line of 15 patients disappeared after surgery,with a fracture healing rate of 100%,and a mean healing time of 12 weeks;the Krimmer wrist joint function score showed that 6 cases were excellent,7 cases were good,and 2 cases were acceptable,with excellent and good rate of 86.7%;patients had lower postoperative pain visual analogue scale scores compared with those before surgery,the difference was significant(P<0.05).Conclusion Measuring the radial styloid process of the physical specimen and observing the course and distribution of the recurrent branch of radial artery to styloid process in adult upper limb specimens can guide the formulation of surgical plan for the treatment of carpal scaphoid fractures in clinic.The transposition and implantation of radical styloid process bone(membrance)flap pedicled with the recurrent branch of radial artery to styloid process can effectively promote fracture healing,and reduce the risk of delayed healing,which has good postoperative recovery of wrist joint function and definite clinical effect in the treatment of carpal scaphoid fractures.

【Objective】 To evaluate the differential miRNA expression of breast milk exosome in premature and full-term groups, and to analyze the regulatory pathways by bioinformatics, so as to provide guidance and scientific basis for the growth and development of premature infants and the prevention and treatment of related diseases. 【Methods】 From August 2020 to June 2021, breast milk samples from 13 premature (premate group) and 9 full-term infants(full-term group) in the Department of Child Health Care of the Second Affiliated Hospital of Nanjing Medical University were collected to extract exosomes. The miRNAs of two groups of breast milk exosomes were sequenced by high-throughput sequencing. According to the sequencing results, miRNA expression profiles of milk exosome were analyzed. Biological function software was used to carry out GO and KEGG pathway analysis of differential miRNA. 【Results】 The expression of miRNA in human milk exosomes was rich, especially hsa-miR-148a-3p,hsa-let-7b-5p, hsa-let-7g-5p, hsa-miR-22-3p, hsa-miR-99a-5p, hsa-miR-200, hsa-miR-146b-5p and hsa-miR-26a-5p were relatively high expressed in preterm group and full-term group. Differential expression analysis showed that compared with full-term infant breast milk, 7 miRNAs were up-regulated(log2|fold change|=2.803, 2.714, 1.632, 2.360, 1.350, 3.387, 2.137, respectively), and 5 miRNAs were down-regulated(log2|fold change|=-2.553, -2.197, -2.771, -1.395, -1.136, respectively)(|fold change>2|, P<0.05) in breast milk for preterm infants. In these differential expressed miRNAs, down-regulated miR-29b(P=0.001) and up-regulated miR-133a-3p(P=0.004) were associated with inflammation, and up-regulated miR-126-5p(P=0.021) and miR-126-3p(P=0.041) were associated with lipid metabolism. The fatty acid biosynthesis pathway was obviously enriched in preterm group. MiR-7-5p, miR-29b-3p and miR-100-5p played a role in the fatty acid synthesis pathway. 【Conclusions】 Exosomal miRNAs are rich in breast milk, and have significant differences between preterm and full-term infants′ mothers. The differentially expressed miRNA in preterm infants treast milk may be related to inflammation and promote the growth and development of preterm infants through the fatty acid biosynthesis pathway.

Krüppel-like transcription factor 2 (KLF2) plays a key regulatory role in endothelial inflammation, thrombosis, angiogenesis and macrophage inflammation and polarization, and up-regulation of KLF2 expression has the potential to prevent and treatment atherosclerosis. In this study, trichostatin C (TSC) was obtained from the secondary metabolites of rice fermentation of Streptomyces sp. CPCC 203909 as a KLF2 up-regulator by using a high throughput screening model based on a KLF2 promoter luciferase reporter assay. TSC significantly inhibited the adhesion of tumor necrosis factor-α (TNFα) induced monocytes (THP-1) to human umbilical vein endothelial cells (HUVECs). Western blot results showed that TSC decreased TNFα induced the protein expression increase of vascular cell adhesion molecule-1 (VCAM-1), and thereby inhibited endothelial inflammation. The results of histone deacetylase (HDAC) overexpression and molecular docking experiments showed that TSC upregulated the expression of KLF2 by inhibiting subtypes of HDAC 4/5/7. In conclusion, this study suggests that TSC up-regulates the expression of KLF2 through inhibiting HDAC 4/5/7 and thus inhibits TNFα induced endothelial inflammation, and it has the potential to prevent and treat atherosclerosis.

Objective:To investigate the expression and clinical significance of Beclin-1 and cytochromes C (CytC) in patients with hand, foot and mouth disease (HFMD).Methods:Sixty children with HFMD were classified into two groups of severe group and common group with 30 cases in each group. Another thirty children who underwent circumcision and had no underlying disease were selected as control group. Serum Beclin-1, CytC and S100B levels were detected before and after treatment. The levels of Beclin-1 and CytC in cerebrospinal fluid (CSF) of children with severe HFMD were detected before and after treatment. Receiver operating characteristic (ROC) curve was used to evaluate the prediction efficiency of Beclin-1 and CytC for the severity of HFMD.Results:Serum Beclin-1 and CytC levels in the severe group were higher than those in the other two groups ( P<0.01), and the common group showed significantly increased serum Beclin-1 and CytC levels as compared with the control group ( P<0.01). After treatment, the serum Beclin-1 and CytC levels decreased in both severe and common groups ( P<0.05). Compared with the common group, the severe group had remarkable increases in the levels of Beclin-1 and CytC in CSF ( P<0.01), which decreased significantly after treatment ( P<0.01). Serum Beclin-1 and CytC levels were positively correlated with the level of S100B protein. In the prediction of severe HFMD, serum CytC had the highest Youden value of 0.533 at the cut-off value of 38.785 ng/ml with a sensitivity of 56.67% and a specificity of 96.67%; serum Beclin-1 had the highest Youden value of 0.467 at the cut-off value of 6.560 ng/ml with a sensitivity of 46.67% and a specificity of 100.00%. Combined measurements of these two parameters had the highest predictive value for severe HFMD with a sensitivity of 76.67% and a specificity of 96.67%. Conclusions:Serum Beclin-1 and CytC levels were conducive to predict the severity and treatment outcomes of HFMD. Combined measurements of these two parameters had a higher predictive value for severe HFMD.

OBJECTIVE: To investigate the effect of internal external fixator assisted O-arm navigation imaging in the treatment of unstable pelvic fractures. METHODS: From May 2019 to November 2019, 15 patients with unstable pelvic fractures were treated by intraoperative O-arm navigation imaging using INFIX technology. There were 6 males and 9 females. The age ranged from 24 to 66 years old. The course of disease ranged from 2 to 14 days. According to Tile classification, there were 1 case of B1 type, 8 cases of B2 type, 3 cases of C1 type, and 3 cases of C2 type. According to Young-Burgess classification, there were 8 cases of LC, 1 case of APC, 4 cases of VS, 2 cases of CM. Preoperative routine pelvic anteroposterior film, entrance position, exit position and pelvic CT three-dimensional reconstruction were performed. Intraoperative O-arm navigation system three-dimensional reconstruction and triplane scanning imaging were used to evaluate the effect of intraoperative reduction. The anterior pelvic ring was fixed with internal external fixator, and the posterior ring was fixed with sacroiliac screw, plate screw or lumbar iliac screw. The operation time, intraoperative bleeding and nail placement were observed and recorded. The quality of fracture reduction was evaluated by Matta standard, and the postoperative function was evaluated by Majeed function score. RESULTS: Wound healing was good in all patients without vascular, nerve and local irritation complications. All the 15 patients were followed up for 10 to 16 months. The fracture reduction was evaluated according to the Matta scoring standard, 9 cases were excellent results, 5 cases were good, and 1 case was medium. The Majeed functional score was 0 to 95 points. CONCLUSION The built-in external fixator assisted O-arm navigation imaging system in the treatment of unstable pelvic fractures. The reduction effect is evaluated in advance, the operation time is shortened, and the accuracy of internal fixation is improved. The operation is simple, safe and less bleeding. The operation is in line with the principles of minimally invasive medical treatment and precision medical treatment in orthopedics, which is conducive to the recovery of patients' postoperative function and rapid recovery.
Adult ; Aged ; Bone Plates ; Female ; Fracture Fixation, Internal/methods* ; Fractures, Bone/surgery* ; Humans ; Imaging, Three-Dimensional ; Male ; Middle Aged ; Surgery, Computer-Assisted ; Tomography, X-Ray Computed ; Young Adult

Objective: To compare the efficacy and safety of prolonged dual antiplatelet therapy (DAPT>1 year) in patients with stable coronary artery disease (CAD) and diabetes who were event-free at 1 year after percutaneous coronary intervention (PCI) with drug-eluting stent (DES) in a large and contemporary PCI registry. Methods: A total of 1 661 eligible patients were selected from the Fuwai PCI Registry, of which 1 193 received DAPT>1 year and 468 received DAPT ≤1 year. The primary endpoint was major adverse cardiac and cerebrovascular event (MACCE) and Bleeding Academic Research Consortium (BARC) type 2, 3 or 5 bleeding, MACCE was defined as a composite of all-cause death, myocardial infarction or stroke. Multivariate Cox regression analysis and inverse probability of treatment weighting (IPTW) Cox regression analysis were performed. Results: After a median follow-up of 2.5 years, patients who received DAPT>1 year were associated with lower risks of MACCE (1.4% vs. 3.2%; hazard ratio (HR) 0.412, 95% confidence interval (CI) 0.205-0.827) compared with DAPT ≤1 year, which was primarily caused by the lower all-cause mortality (0.1% vs. 2.6%; HR 0.031, 95%CI 0.004-0.236). Risks of cardiac death (0.1% vs. 1.5%; HR 0.051, 95%CI 0.006-0.416) and definite/probable ST (0.3% vs. 1.1%; HR 0.218, 95%CI 0.052-0.917) were also lower in patients received DAPT>1 year than those received DAPT ≤ 1 year. No difference was found between the two groups in terms of BARC type 2, 3, or 5 bleeding (5.3% vs. 4.1%; HR 1.088, 95%CI 0.650-1.821). Conclusions: In patients with stable CAD and diabetes who were event-free at 1 year after PCI with DES, prolonged DAPT (>1 year) provides a substantial reduction in ischemic cardiovascular events, including MACCE, all-cause mortality, cardiac mortality, and definite/probable ST, without increasing the clinically relevant bleeding risk compared with ≤ 1-year DAPT. Further well-designed, large-scale randomized trials are needed to verify the beneficial effect of prolonged DAPT in this population.
Coronary Artery Disease/therapy* ; Diabetes Mellitus, Type 2 ; Drug Therapy, Combination ; Drug-Eluting Stents ; Hemorrhage ; Humans ; Percutaneous Coronary Intervention ; Platelet Aggregation Inhibitors/therapeutic use* ; Risk Assessment ; Treatment Outcome

The emergence of SARS-CoV-2 variants of concern and repeated outbreaks of coronavirus epidemics in the past two decades emphasize the need for next-generation pan-coronaviral therapeutics. Drugging the multi-functional papain-like protease (PLpro) domain of the viral nsp3 holds promise. However, none of the known coronavirus PLpro inhibitors has been shown to be in vivo active. Herein, we screened a structurally diverse library of 50,080 compounds for potential coronavirus PLpro inhibitors and identified a noncovalent lead inhibitor F0213 that has broad-spectrum anti-coronaviral activity, including against the Sarbecoviruses (SARS-CoV-1 and SARS-CoV-2), Merbecovirus (MERS-CoV), as well as the Alphacoronavirus (hCoV-229E and hCoV-OC43). Importantly, F0213 confers protection in both SARS-CoV-2-infected hamsters and MERS-CoV-infected human DPP4-knockin mice. F0213 possesses a dual therapeutic functionality that suppresses coronavirus replication via blocking viral polyprotein cleavage, as well as promoting antiviral immunity by antagonizing the PLpro deubiquitinase activity. Despite the significant difference of substrate recognition, mode of inhibition studies suggest that F0213 is a competitive inhibitor against SARS2-PLpro via binding with the 157K amino acid residue, whereas an allosteric inhibitor of MERS-PLpro interacting with its 271E position. Our proof-of-concept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anti-coronavirus agents. The orally administered F0213 may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and future coronavirus outbreaks.
Animals ; Coronavirus Papain-Like Proteases/antagonists & inhibitors* ; Cricetinae ; Humans ; Mice ; Pandemics ; SARS-CoV-2/enzymology* ; COVID-19 Drug Treatment

Xiao Xumingtang in The Catalogue of Famous Ancient Classics （The First Batch） issued by the National Administration of Traditional Chinese Medicine is derived from the Important Prescriptions Worth a Thousand Gold for Emergency （Bei Ji Qian Jin Yao Fang） written by SUN Si-miao in the Tang dynasty. The present study systematically explored the origin， development， historical evolution， and clinical application of Xiao Xumingtang. As revealed by the results， Xiao Xumingtang as well as its analogues are primary prescriptions indicated for apoplexy before the Tang and Song dynasties and serve as the benchmark for the treatment of apoplexy. After the Song dynasty， due to the changes in the understanding of the pathogenesis of apoplexy and the limitations of the understanding of Xiao Xumingtang， its clinical application to apoplexy gradually decreased. In modern times， it has been re-recognized and applied， during which its clinical applications have undergone great changes. Its clinical applications are extensive， involving a variety of diseases related to the brain and nervous systems， such as stroke and its sequelae， peripheral facial paralysis， rheumatoid arthritis， hypertension， and other diseases related to the motor nervous system. Its primary indications are stroke and its sequelae， followed by peripheral facial paralysis. Other new indications are gradually found. This study is expected to provide references for the clinical application of Xiao Xumingtang and the transformation of new drugs.