ObjectiveTo investigate the mechanism by which Feixin decoction treats hypoxic pulmonary hypertension （HPH） by regulating the peroxisome proliferator-activated receptor gamma （PPARγ）/nuclear factor-kappa B （NF-κB）/NOD-like receptor pyrin domain containing 3 （NLRP3） signaling pathway. MethodsForty-eight male SD rats were randomly allocated into normal， hypoxia， and low-， medium- and high-dose （5.85， 11.7， 23.4 g·kg^-1， respectively） Feixin decoction groups， with 8 rats in each group. Except the normal group， the remaining five groups were placed in a hypoxia chamber with an oxygen concentration of （10.0±0.5）% for 8 h per day， 28 days， and administrated with corresponding drugs during the modeling process. After 4 weeks of treatment， echocardiographic parameters ［pulmonary artery acceleration time （PAT）， pulmonary artery ejection time （PET）， right ventricular anterior wall thickness （RVAWd）， and tricuspid annular plane systolic excursion （TAPSE）］ were measured for each group. The right ventricular systolic pressure （RVSP） was measured by the right heart catheterization method， and the right ventricular hypertrophy index （RVHI） was calculated by weighing the heart. The pathological changes in pulmonary arterioles were observed by hematoxylin-eosin staining. The co-localization of α-smooth muscle actin （α-SMA） with NLRP3， N-terminal gasdermin D （N-GSDMD）， and cysteinyl aspartate-specific proteinase-1 （Caspase-1） in pulmonary arteries was detected by immunofluorescence. The protein levels of PPARγ， NF-κB， NLRP3， apoptosis-associated speck-like protein containing a CARD （ASC）， N-GSDMD， interleukin-1β （IL-1β）， interleukin-18（IL-18）， and cleaved Caspase-1 in the lung tissue was determined by Western blot. The ultrastructural changes in pulmonary artery smooth muscle cells （PASMCs） were observed by transmission electron microscopy. ResultsCompared with the normal group， the hypoxia group showed increased RVSP and RVHI （P<0.01）， decreased right heart function （P<0.01）， increased pulmonary vascular remodeling （P<0.01）， increased co-localization of α-SMA with NLRP3， N-GSDMD， and Caspase-1 in pulmonary arterioles （P<0.01）， up-regulated protein levels of NF-κB， NLRP3， ASC， N-GSDMD， IL-1β， IL-18， and cleaved Caspase-1 in the lung tissue （P<0.05， P<0.01）， a down-regulated protein level of PPARγ （P<0.05， P<0.01）， and pyroptosis in PASMCs. Compared with the hypoxia group， Feixin decoction reduced RVSP and RVHI， improved the right heart function and ameliorated pulmonary vascular remodeling （P<0.05， P<0.01）， decreased the co-localization of α-SMA with NLRP3， N-GSDMD， and Caspase-1 （P<0.05， P<0.01）， down-regulated the protein levels of NF-κB， NLRP3， ASC， N-GSDMD， IL-1β， IL-18， and cleaved Caspase-1 in the lung tissue （P<0.05， P<0.01）， up-regulated the protein level of PPARγ （P<0.05， P<0.01）， and alleviated pyroptosis in PASMCs. ConclusionFeixin decoction can ameliorate pulmonary vascular remodeling and right heart dysfunction in chronically induced HPH rats by regulating pyroptosis in PASMCs through the PPARγ/NF-κB/NLRP3 pathway.

V-ATPases are a class of multi-subunit protein complexes that utilize energy derived from ATP hydrolysis for mediating H + transport across cell membranes, which plays an important role in a range of life activities by acidifying the intracellular and extracellular environment. Variants of V-ATPase genes may lead to complete or partial loss of V-ATPase activity, which in turn may impair the ability of type A intercalated cells in renal tubules to pump H + into the tubular lumen, ultimately resulting in the onset of autosomal recessive distal renal tubular acidosis (dRTA). With the rapid development of molecular techniques, ATP6V0A4 and ATP6V1B1 have now been identified as the pathogenic genes for dRTA. Moreover, animal and cell experiments have substantiated the implication of V-ATPase subunit genes including ATP6V1C2 and ATP6V1G3 in the development of dRTA, though clinical evidence is still limited. This article has reviewed recent progress on the genetic and molecular mechanisms of V-ATPase subunit gene variants which can lead to dRTA, which may shed light on the diagnosis and treatment of this disease.

Objective To monitor heart-related parameters of hypoxic pulmonary hypertension(PH)mouse models induced by hypoxia alone and hypoxia combined with vascular endothelial growth factor receptor inhibitor SU5416 using echocardiography,and to construct the prediction equation of right ventricular systolic pressure(RVSP).Twenty-four C57BL/6J male mice were randomly divided into simple hypoxia group(group A),hypoxia combined with SU5416 group(group B),control group(group C),each group 8 mice.Hypoxic PH models were constructed with hypoxia alone and hypoxia combined with SU5416 in group A and group B,respectively.Echocardiography was performed before and during modeling(2,3,4 weeks after interventions),and the relevant parameters were obtained.RVSP was measured using right heart catheterization after the last echocardiography.The changes of ultrasonic parameters were observed,the correlations of ultrasonic parameters 4 weeks after intervention with RVSP were observed,and linear equations for predicting RVSP were established.Results With time going,during modeling,pulmonary artery diameter(PAD),PAD/aorta diameter(AOD)and right ventricle anterior wall thickness(RVAWT)increased,while heart rate,pulmonary artery acceleration time(PAAT),PAAT/pulmonary artery ejection time(PAET)and tricuspid annular plane systolic excursion(TAPSE)decreased in group A and B(all P＜0.05).Three and 4 weeks after interventions,PAET,PAAT/PAET and TAPSE in group B decreased compared with those in group A(all P＜0.05).Four weeks after interventions,RVSP in group A and B were highly correlated with PAD/AOD,RVAWT,PAAT,PAAT/PAET and TAPSE(all P＜0.05).The linear regression equations of PAAT/PAET and TAPSE for predicting RVSP in simple hypoxic PH mice models included RVSP=-161.7 ×(PAAT/PAET)+63.85,as well as RVSP=-36.53 ×TAPSE+71.55,while of predicting RVSP in hypoxia combined with VEGFR-2 inhibitor PH mouse models were as follows:RVSP=-266.4 ×(PAAT/PAET)+91.59,RVSP=-69.14 × TAPSE+116.5.Conclusion Four weeks after inerventions,the phenotypes of hypoxic PH mouse models induced by hypoxia alone and hypoxia combined with SU5416 became obvious.Prediction equations of RVSP established based on PAAT/PAET and TAPSE obtained with echocardiography could provide references for relevant research.

We retrospectively analyzed the clinical data of seven patients (four men and three women) with primary hyperoxaluria (PH) type 1 (PH1) in the Department of Nephrology of Zhongda Hospital, Southeast University from January 2018 to October 2023. The mean age at disease onset was 32.1 (range: 26-42) years. The mean age at diagnosis was 40.6 (range: 28-51) years. All patients initially had kidney stones, and three patients were found to have renal insufficiency at the time of disease onset. Among them, two patients underwent hemodialysis immediately. Symptoms at the first visit included bone pain ( n=7), joint pain or deformity ( n=5), fatigue ( n=5), hypotension ( n=3), and subcutaneous nodules ( n=2). Four patients had a family history of PH. All patients had varying degrees of anemia (60-114 g/L), significant hypoalbuminemia (16.5-32.1 g/L), and hypercoagulable state (D-dimer: 2 230-12 781 μg/L). Seven patients received maintenance hemodialysis; their mean age was 37.7 (range: 26-50) years. The mean duration from disease onset to hemodialysis was 5.6 (range: 0-20) years. Five patients repeatedly experienced dialysis access dysfunction. Three patients underwent kidney transplantation before a diagnosis was made, and all transplanted kidneys lost function due to oxalate deposition. The mean follow-up duration was 14.43 (range: 4-38) months. Unfortunately, one patient died. All seven patients underwent computed tomography of the abdomen. All patients suffered skeletal abnormalities, bilateral nephrolithiasis, and nephrocalcinosis. Six patients carried AGXT gene mutations, including four compound heterozygous mutations and two pure homozygous mutations.The mutation sites included: c.823-824dup.AG (p.S275Rfs*38)(exon 8), c.815-816ins.GA (p.S275Rfs*38)(exon 8), c.595G>A (p.G199S) (exon 5), c.32C>G (p.P11R) (exon 1), and c.638C>T (p.A213V)(exon 6). According to the American College of Medical Genetics and Genomics guidelines, two loci were identified as likely pathogenic variants, seven were identified as pathogenic variants, and one locus was identified as having uncertain significance. In addition, patients 1 and 4 underwent skin biopsy, patient 2 underwent renal transplant biopsy, and patient 3 underwent bone marrow biopsy. Interestingly, significant oxalate deposition was found in the tissues. Therefore, PH1 is a rare autosomal recessive inherited disease. This study not only enhanced the understanding of the clinical characteristics of PH1 patients but also had great significance in early diagnosis and treatment of the disease.

By analyzing the of genetic testing data of patients with renal polycystic kidney disease and their relatives, this study aims to identify unreported novel gene mutation sites associated with autosomal dominant polycystic kidney disease (ADPKD). Structural prediction software was employed to investigate protein structural changes before and after mutations, explore genotype-phenotype correlations, and enrich the ADPKD gene database. In this single-center retrospective study, patients with multiple renal cysts diagnosed from January 2019 to February 2023 at the Zhong Da Hospital Southeast University were included. Genetic and clinical data of patients and their families were collected. Unreported novel gene mutation sites associated with ADPKD were identified. The AlphaFold v2.3.1 software was used to predict protein structures. Changes in protein structure before and after mutations were compared to explore genotype-phenotype correlations and enrich the ADPKD gene database. Twelve mutated genes associated with renal cysts were detected in 52 families. Nineteen novel gene mutation sites associated with ADPKD were identified, including 17 mutations in the PKD1 gene (one splicing mutation, seven frameshift mutations, four nonsense mutations, one whole-codon insertion, and four missense mutations); one ALG9 missense mutation; and one chromosomal structural variation. Truncating mutations in the PKD1 gene were correlated with a more severe clinical phenotype, while non-truncating mutations were associated with greater clinical heterogeneity. Numerous novel gene mutation sites associated with ADPKD remain unreported. Therefore, it is essential to analyze the pathogenicity of these novel mutation sites, establish genotype-phenotype correlations, and enrich the ADPKD gene database.

Objective:To analyze the mutation pathogenicity of the novel compound heterozygous mutation in the PKHD1 gene causing autosomal recessive polycystic kidney disease (ARPKD) family, expand the PKHD1 gene mutation database, and explore the genotype-phenotype correlations of PKHD1 gene mutation causing ARPKD. Methods:Clinical data and peripheral blood of a patient with ARPKD caused by the novel compound heterozygous mutation in the PKHD1 gene and their family members were collected. High-throughput sequencing was used to detect pathogenic mutations in the proband, and PCR amplification and Sanger sequencing were used to verify the pathogenic mutations in the family. AlphaFold software was applied to predict changes in protein structure in the present or absent mutations, and the pathogenicity of mutations was analyzed. Results:The patient was a young male who underwent splenectomy due to liver cirrhosis and hypersplenism at age 7. He developed end-stage renal disease at age 22, requiring maintenance peritoneal dialysis, and died of severe pneumonia and septic shock at age 24. Genetic testing revealed three compound heterozygous mutations in the PKHD1 gene inherited from his parents: a missense mutation (c.5935G>A) inherited from the father and a missense mutation (c.1187G>A) and a novel splice mutation (c.6332+1_6332+2insG) from the mother. The single missense mutation allele likely contributed to the prolonged survival. c. 6332+1_ 6332+2insG is a novel splicing mutation that has not been reported in the past, which can lead to early termination of protein translation. This discovery expands the PKHD1 gene mutation database. c. 1187G>A (p.S396N) and c.5935G>A (p.G1979R) occur in the PA14 and G8 domains of the protein, respectively, and are associated with early and severe liver phenotypes in patients. Conclusions:The mutation types and amino acid localization of the PKHD1 gene are associated with the heterogeneity of clinical phenotypes in ARPKD patients. Analyzing structural changes in proteins before and after mutations can help understand the pathogenicity at a molecular level, establishing genotype-phenotype correlations and providing valuable insights for assessing prognosis and identifying high-risk ARPKD patients early.

The effect of anti-programmed cell death 1 (anti-PD-1) immunotherapy is limited in patients with hepatocellular carcinoma (HCC). Yes-associated protein 1 (YAP1) expression increased in liver tumor cells in early HCC, and Akkermansia muciniphila abundance decreased in the colon. The response to anti-PD-1 treatment is associated with A. muciniphila abundance in many tumors. However, the interaction between A. muciniphila abundance and YAP1 expression remains unclear in HCC. Here, anti-PD-1 treatment decreased A. muciniphila abundance in the colon, but increased YAP1 expression in the tumor cells by mice with liver tumors in situ. Mechanistically, hepatocyte-specific Yap1 knockout (Yap1^LKO) maintained bile acid homeostasis in the liver, resulting in an increased abundance of A. muciniphila in the colon. Yap1 knockout enhanced anti-PD-1 efficacy. Therefore, YAP1 inhibition is a potential target for increasing A. muciniphila abundance to promote anti-PD-1 efficacy in liver tumors. Dihydroartemisinin (DHA), acting as YAP1 inhibitor, increased A. muciniphila abundance to sensitize anti-PD-1 therapy. A. muciniphila by gavage increased the number and activation of CD8⁺ T cells in liver tumor niches during DHA treatment or combination with anti-PD-1. Our findings suggested that the combination anti-PD-1 with DHA is an effective strategy for liver tumor treatment.

Vascular malformationss (VMs) are resulted from localized vascular developmental defects. Most sporadic cases are associated with genetically heterozygous mutations, whereas some stem from autosomal dominant disorders caused by germline mutations. VMs often exhibit dinstinct gene mutations with diverse phenotypes for the same genes. Conversely, similar phenotypes may be resulted from mutations in different genes, making the differential diagnosis of VMs challenging. This article provide a comprehensive review of recent addition to the new International Society for Study of Vascular Anomalies classification, including causative genes for vasculogenic lesions. There are four primary signaling pathways involved in specific mutations, namely, PIK3CA/mTOR, RAS/MAPK, G-protein-coupled receptor signaling pathway, and transforming growth factor-β. The author also explore the factors affecting the genotype-phenotype correlations, including the time of mutation occurrence, cell types, mutation types, allele variants frequency and epigenetic abnormalities. Furthermore, it discusses the diagnostic method for VMs, encompassing clinical screening, diagnostic imaging, and genetic diagnosis, with a focus on facilitaing clinical application of targeted drug therapy.

Vascular malformationss (VMs) are resulted from localized vascular developmental defects. Most sporadic cases are associated with genetically heterozygous mutations, whereas some stem from autosomal dominant disorders caused by germline mutations. VMs often exhibit dinstinct gene mutations with diverse phenotypes for the same genes. Conversely, similar phenotypes may be resulted from mutations in different genes, making the differential diagnosis of VMs challenging. This article provide a comprehensive review of recent addition to the new International Society for Study of Vascular Anomalies classification, including causative genes for vasculogenic lesions. There are four primary signaling pathways involved in specific mutations, namely, PIK3CA/mTOR, RAS/MAPK, G-protein-coupled receptor signaling pathway, and transforming growth factor-β. The author also explore the factors affecting the genotype-phenotype correlations, including the time of mutation occurrence, cell types, mutation types, allele variants frequency and epigenetic abnormalities. Furthermore, it discusses the diagnostic method for VMs, encompassing clinical screening, diagnostic imaging, and genetic diagnosis, with a focus on facilitaing clinical application of targeted drug therapy.

Objective:To compare the efficacy and side effects of multi-fraction stereotactic radiotherapy (SRT) and single-fraction stereotactic radiosurgery (SRS) in the treatment of brain metastases from colorectal cancer.Methods:A total of 98 patients with brain metastases from colorectal cancer searched from the database of Professional Committee of Brain Metastasis of Shanghai Anticancer Association were recruited in this study. Among them, 46 patients weretreated with SRT and 52 patients with SRS. Clinical characteristics of all patients were analyzed between two groups and the local tumor control rate, median survival time and the incidence of radiation-induced brain injury were compared between two groups.Results:The objective remission rates (ORR) in the SRT and SRS groups were 76.1% and 67.3%, respectively. The 12-month local tumor control rates were 88.3% and 83.9% between two groups, with no statistical difference ( P=0.689). The median overall survival time of all patients was 11.6 months, 10.8 months in the SRT group and 12.7 months in the SRS group. There was no statistical difference between two groups ( P=0.129). Multivariate analysis showed that the main factors leading to poor prognosis included the number of tumors of >3( P=0.026), low GPA score ( P=0.035), and lack of systematic treatment mode and bevacizumab ( P=0.001). There was no statistical difference in the incidence of acute and late radiation-induced brain injury between two groups. Conclusions:Both SRT and SRS are effective therapies for brain metastases from colorectal cancer. The synergistic application of systematic treatment mode may be one of the main reasons affecting the survival time of the patients.