Wogonin mitigates acetaminophen-induced liver injury in mice through inhibition of the PI3K/AKT signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Scutellaria baicalensis Georgi (SBG), a widely used traditional Chinese medicine, exhibits anti-inflammatory and antioxidant properties. Wogonin is one of the primary bioactive components of SBG. Acetaminophen (APAP)-induced liver injury (AILI) represents a prevalent form of drug-induced liver damage and is primarily driven by inflammatory responses and oxidative stress. AIM OF STUDY: To investigate the therapeutic effects of Wogonin on AILI and the underlying mechanisms. MATERIALS AND METHODS: C57BL/6 J mice were pre-treated with Wogonin (1, 2.5, and 5 mg/kg bodyweight) for 3 days, followed by treatment with APAP (300 mg/kg bodyweight). The serum and liver tissue samples were collected at 24 h post-APAP treatment. Bone marrow-derived macrophages and RAW264.7 cells were cultured and pre-treated with Wogonin (5, 10, and 20 µM) for 30 min, followed by stimulation with lipopolysaccharide (LPS; 100 ng/mL) for 3 h. To examine the role of the PI3K/AKT signaling pathway in the therapeutic effect of Wogonin on AILI, mice and cells were treated with LY294002 (a PI3K inhibitor) and MK2206 (an AKT inhibitor). RESULTS: Wogonin pre-treatment dose-dependently alleviated AILI in mice. Additionally, Wogonin suppressed oxidative stress and inflammatory responses. Liver transcriptome analysis indicated that Wogonin primarily regulates immune function and cytokines in AILI. Wogonin suppressed inflammatory responses of macrophages by inhibiting the PI3K/AKT signaling pathway. Consistently, Wogonin exerted therapeutic effects on AILI in mice through the PI3K/AKT signaling pathway. CONCLUSIONS: Wogonin alleviated AILI and APAP-induced hepatotoxicity in mice through the PI3K/AKT signaling pathway.

Differentiation between alcohol-associated cirrhosis and hepatitis B-associated cirrhosis based on hepatic complications and psychological symptoms.

Background: The prognosis of and occurrence of complications in patients with different clinical features of cirrhosis differ, and cirrhosis with different etiologies has varying clinical characteristics. The aim of this study was to describe the liver function markers, hepatic complications, and psychological features differentiating patients with hepatitis B virus (HBV) infection-related and alcohol-related cirrhosis. Materials and Methods: This was a retrospective and observational study that analyzed the medical data of inpatients with alcohol-related or HBV infection-related cirrhosis from May 2014 to May 2020. Markers of liver function, portal hypertension, and psychological symptoms were compared between the two groups. Results: Patients with alcohol-related cirrhosis showed higher Self-Rating Anxiety Scale scores and prevalence of hypoproteinemia, fatty liver, and depression than those with HBV infection-related cirrhosis (all P < 0.05). After adjustment for potential confounders, patients with alcohol-related cirrhosis also showed higher risks of increased total cholesterol (odds ratio [OR] =2.671, 95% confidence interval [CI]: 1.160-6.151, P = 0.021), increased high-density lipoprotein-cholesterol (OR = 2.714, 95% CI: 1.009-7.299, P = 0.048), and fatty liver (OR = 2.713, 95% CI: 1.002-7.215, P = 0.048); however, splenomegaly and splenectomy were significantly associated with HBV infection-related cirrhosis (OR = 2.320, 95% CI: 1.066-5.050, P = 0.034). Conclusion: Patients with alcohol-related cirrhosis were more likely to develop hyperlipidemia, fatty liver, and psychological symptoms, whereas those with HBV-related cirrhosis had a higher risk of splenomegaly.

Negative correlation between circulating integrin α4+ group 3 innate lymphoid cells and the severity of type 2 diabetes.

BACKGROUND: Impaired intestinal barrier and immune dysfunction promote the development of type 2 diabetes (T2D). Group 3 innate lymphoid cells (ILC3s), which are enriched in the intestinal lamina propria, are key for intestinal barrier integrity. However, there is a paucity of data on circulating ILC3s in patients with T2D. PURPOSE: To examine the characteristics of ILC3s in patients with T2D and identify the relationship between ILC3s and clinical indicators of T2D. METHODS: Fifty-nine patients with T2D and thirty controls were enrolled in this retrospective study. Peripheral blood mononuclear cells were isolated and analyzed by flow cytometry and plasma cytokine levels were measured by enzyme-linked immunosorbent assays. RESULTS: The proportion of circulating ILC3s in the T2D group was significantly lower than that in controls and showed a negative correlation with fasting glucose and glycated hemoglobin and a positive correlation with granulocyte-macrophage colony-stimulating factor (GM-CSF). Similarly, the proportion of circulating integrin α4+ ILC3s was also significantly lower in the T2D group and showed a negative correlation with fasting glucose and glycated hemoglobin and a positive correlation with GM-CSF. Moreover, the level of circulating integrin α4+ ILC3s showed a positive correlation with the proportion of circulating dendritic cells (DCs), which was also decreased in patients with T2D and positively associated with GM-CSF. CONCLUSION: ILC3s, especially integrin α4+ ILC3s, were decreased in patients with T2D and showed a negative correlation with disease severity. These cell subsets may delay the progression of T2D by promoting DC differentiation via the secretion of GM-CSF.

Reduced type 3 innate lymphoid cells related to worsening kidney function in renal dysfunction.

Intestinal mucosa barrier injury and immunity imbalance contribute to chronic kidney disease (CKD) progression. Type 3 innate lymphoid cells (ILC3s) are essential for normal intestinal homeostasis. Nevertheless, the relationship between ILC3s and CKD remains largely unknown. The aim of this study was to investigate the relationship linking ILC3s to clinical indicators among patients with renal dysfunction. The levels of circulating ILC3s and dendritic cells, as well as their subsets, in patients with renal dysfunction and healthy controls were determined through flow cytometry. The levels of human plasma granulocyte-macrophage colony-stimulating factor (GM-CSF) were measured using enzyme-linked immunosorbent assay. Renal function was evaluated by measuring the estimated glomerular filtration rate (eGFR), as well as the levels of serum creatinine, blood urea nitrogen (BUN), and uric acid. The results revealed that the proportion of peripheral ILC3s was significantly decreased in patients with renal dysfunction. This reduction was positively associated with the levels of eGFR, and inversely associated with the levels of BUN and uric acid. Similarly, the percentage of circulating C-C motif chemokine receptor 6-positive (CCR6 +) ILC3s was also obviously reduced, and demonstrated positive and negative associations with the levels of eGFR and BUN, respectively. Furthermore, the levels of CCR6 + ILC3s correlated positively with those of GM-CSF, as well as type 1 conventional dendritic cells (cDC1s), which also decreased in parallel with kidney function. Thus, the reduction of ILC3s, particularly CCR6 + ILC3s, was related to worsening kidney function in patients with renal dysfunction. This effect may delay renal function impairment by regulating cDC1s via the secretion of GM-CSF, indicating that CCR6 + ILC3s may serve as efficient biomarkers for evaluating kidney function.

A likely pathogenic POLD1 variant associated with mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome in a Chinese patient.

BACKGROUND: Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL; OMIM# 615381) is a rare autosomal dominant disorder, with only a few reported cases worldwide. Herein, we describe the clinical features and underlying molecular etiology of MDPL syndrome in an 8-year-old Chinese patient. METHODS: We performed otological, endocrine, ultrasound, and radiological examinations, as well as genetic testing. Additionally, the literature concerning MDPL was reviewed to do a retrospective analysis of the pathogenesis, genotype-phenotype correlation, and clinical management. RESULTS: The proband was diagnosed with MDPL, presenting with mandibular hypoplasia, a characteristic facial appearance, lipodystrophy, and sensorineural hearing loss (SNHL). Whole-exome sequencing and bioinformatics analysis revealed a de novo missense variant in the POLD1 gene, NM_002691.4:c.3185A>G (NP_002682.2:p.(Gln1062Arg)). The retrospective analysis showed wide variation in the MDPL phenotype, but the most frequent features included mandibular hypoplasia, characteristic facial appearance, lipodystrophy, and SNHL. CONCLUSIONS: This study supplements the mutational spectrum of POLD1. The genetic analysis contributes to the diagnosis of syndromic deafness, and it has a vital role in clinical management and future genetic consultation.

Beneficial Effects of Repeated Washed Microbiota Transplantation in Children With Autism.

Objective: While fecal microbiota transplantation is demonstrated to improve symptoms of autism spectrum disorder (ASD), it remains unclear whether additional treatment courses yield better results. This study sought to evaluate the efficacy of repeated washed microbiota transplantation (WMT) in children with ASD. Methods: Retrospective data from children who were serially treated with WMT, including ASD symptoms, sleep disorders, gastrointestinal (GI) symptoms, and white blood cell (WBC) and globulin levels were obtained. The effect of WMT on children with ASD and whether additional WMT courses led to a further improvement in symptoms were assessed. Results: Aberrant Behavior Checklist (ABC), Childhood Autism Rating Scale, and Sleep Disturbance Scale for Children (SDSC) scores, the proportion of children with constipation and abnormal fecal forms, and WBC and globulin levels were all significantly lower in ASD children after WMT. More WMT treatment courses led to significantly lower scores on the ABC and SDSC. Conclusion: WMT significantly improved ASD and GI symptoms and sleep disorders in children with ASD, and reduced systemic inflammation. Additional WMT courses led to more obvious improvements in ASD symptoms within three treatment courses.

Effects of Washed Fecal Bacteria Transplantation in Sleep Quality, Stool Features and Autism Symptomatology: A Chinese Preliminary Observational Study.

Purpose: Autism spectrum disorder is a highly complex neurological and psychosocial disorder characterized by social dysfunction, severe reduction in speech, and a single stereotyped behavior. The treatment methods are currently limited, and children with autism generally suffer from constipation and sleep disorders. It is urgent to find an alternative psychotropic drug, given the drug dependence and adverse reactions that may occur with long-term medication. Patients and Methods: This retrospective study included 49 children with autism at the first affiliated Hospital of Guangdong Pharmaceutical University, who received washed fecal microbiota transplantation (WMT) treatment between June 2019 and July 2021 and compared the sleep disorder scores between the constipation group, control group and blank group. Results: Second WMT could significantly improve the sleep disorder scores in the constipation group (p=0.026) and the decrease in sleep disturbance scale for children (SDSC) score was synchronized with the increase in Bristol stool form scale (BSFS) score. However, there was no significant difference between patients without constipation (p=0.54), and the behavior of autism improved in both groups. Conclusion: WMT could relieve constipation and improve sleep disorders in children with autism, with no deterioration in stool morphology and sleep disorders in other children. Moreover, there were no obvious serious adverse clinical events after WMT.

Differences in complications between hepatitis B-related cirrhosis and alcohol-related cirrhosis.

OBJECTIVES: This study aimed to investigate the differences in complications between hepatitis B virus (HBV)-related and alcohol-related cirrhoses. METHODS: Medical records of patients with HBV-related and alcohol-related cirrhoses treated from January 2014 to January 2021 were, retrospectively, reviewed. The unadjusted rate and adjusted risk of cirrhotic complications between the two groups were assessed. RESULTS: The rates of hepatocellular carcinoma (HCC) and hypersplenism were higher in HBV-related cirrhosis (both P < 0.05), whereas the rates of hepatic encephalopathy (HE) and acute-on-chronic liver failure (ACLF) were higher in alcohol-related cirrhosis (both P < 0.05). After adjusting for potential confounders, HBV-related cirrhotic patients had higher risks of HCC (odds ratio [OR] = 34.06, 95% confidence interval [CI]: 4.61-251.77, P = 0.001) and hypersplenism (OR = 2.29, 95% CI: 1.18-4.42, P = 0.014), whereas alcohol-related cirrhotic patients had higher risks of HE (OR = 0.22, 95% CI: 0.06-0.73, P = 0.013) and ACLF (OR = 0.30, 95% CI: 0.14-0.73, P = 0.020). CONCLUSION: Cirrhotic patients with different etiologies had different types of complications: HBV-related cirrhotic patients exhibited increased risks of HCC and hypersplenism and alcohol-related cirrhotic patients more readily developing HE and ACLF.

Treacher Collins syndrome: Clinical report and retrospective analysis of Chinese patients.

BACKGROUND: Treacher Collins syndrome-1 (TCS1; OMIM# 154500) is a rare autosomal dominant disease that is defined by congenital craniofacial dysplasia. Here, we report four sporadic and one familial case of TCS1 in Chinese patients with clinical features presenting as hypoplasia of the zygomatic complex and mandible, downslanting palpebral fissures, coloboma of the lower eyelids, and conductive hearing loss. MATERIALS AND METHODS: Audiological, radiological, and physical examinations were performed. Targeted next-generation sequencing (NGS) was performed to examine the genetics of this disease in five probands, and Sanger sequencing was used to confirm the identified variants. A literature review discusses the pathogenesis, treatment, and prevention of TCS1. RESULTS: We identified a novel insertion of c.939_940insA (p.Gly314Argfs*35; NM_001135243.1), a novel deletion of c.1766delC (p.Pro589Leufs*7), two previously reported insertions of c.1999_2000insC (p.Arg667Profs*31) and c.4218_4219insG (p.Ser1407Valfs*23), and one previously reported deletion of c.4369_4373delAAGAA (p.Lys1457Glufs*12) in the TCOF1 gene. All five cases exhibited a degree of interfamilial and intrafamilial phenotypic variability. A review of the literature revealed no clear evidence of a genotype-phenotype correlation in TCS1. CONCLUSION: Our results expand the variant spectrum of TCOF1 and highlight that NGS is essential for the diagnosis of TCS and that genetic counseling is beneficial for guiding prevention.

Perrault syndrome: Clinical report and retrospective analysis.

BACKGROUND: Perrault syndrome (PRLTS4; OMIM# 615300) is a rare autosomal recessive disorder and only a few cases have been reported worldwide. We report a Chinese female characterized by sensorineural hearing loss and premature ovarian insufficiency. METHODS: We evaluated audiological, endocrine, and ultrasound examinations and examined the genetic causes using whole-exome sequencing. We reviewed the literature to discuss the pathogenesis, genotype-phenotype correlation, treatment, and prevention of PRLTS4. RESULTS: Bioinformatic analysis revealed compound heterozygous mutations in the LARS2 gene, c.880G>A (p.Glu294Lys), and c.2108T>C (p.Ile703Thr) which is a novel missense mutation, co-segregated in this family. Taken together, the patient was clinically diagnosed as PRLTS4. The literature review showed that the phenotype for PRLTS4 varies widely, but the sensorineural hearing loss, increased gonadotropin levels, and amenorrhea occurred frequently. All reported mutations are highly conserved in mammals based on conservation analysis, and there is a mutation hotspot for PRLTS4. CONCLUSION: This study expanded the mutation spectrum of LARS2 and is the first report of PRLTS4 in a Chinese family. Genetic testing plays an important role in early diagnosis of syndromic deafness and clinical genetic evaluation is essential to guide prevention.

Multiple synostoses syndrome: Clinical report and retrospective analysis.

Multiple synostoses syndrome (SYNS1; OMIM# 186500) is a rare autosomal dominant disorder reported in a few cases worldwide. We report a Chinese pedigree characterized by proximal symphalangism, conductive hearing loss, and distinctive facies. We examined the genetic cause and reviewed the literature to discuss the pathogeny, treatment, and prevention of SYNS1. Audiological, ophthalmological, and radiological examinations were evaluated. Whole-exome sequencing (WES) was performed to identify mutations in the proband and her parents. Sanger sequencing was used to verify the results for the proband, parents, and grandmother. The literature on the genotype-phenotype correlation was reviewed. The patient was diagnosed with multiple synostoses syndrome clinically. WES and bioinformatic analysis revealed a novel missense mutation in the NOG gene, c.554C>G (p.Ser185Cys), cosegregated in this family. The literature review showed that the phenotype varies widely, but the typical facies, conductive hearing loss, and proximal symphalangism occurred frequently. All reported mutations are highly conserved in mammals based on conservation analysis, and there are regional hot spots for these mutations. However, no distinct genotype-phenotype correlations have been identified for mutations in NOG in different races. Regular systematic examinations and hearing aids are beneficial for this syndrome. However, the outcomes of otomicrosurgery are not encouraging owing to the regrowth of bone. This study expanded the mutation spectrum of NOG and is the first report of SYNS1 in a Chinese family. Genetic testing is recommended as part of the diagnosis of syndromic deafness. A clinical genetic evaluation is essential to guide prevention, such as preimplantation genetic diagnosis.

Occurrence of polybrominated diphenyl ethers in soil from the central Loess Plateau, China: role of regional range atmospheric transport.

Very few studies were conducted in highland and depositional areas in studying the transport and behavior of polybrominated diphenyl ethers (PBDEs). In this study, surface soils were collected from Huan County to investigate the level, profile, and potential influence of PBDEs via regional range atmospheric transport in the central part of the Loess Plateau (CLP) of China, one of the most extensive areas of loess deposition in the world. PBDEs were ubiquitous and log-normally distributed in soils from the CLP with mean concentrations of 0.91 and 0.54 ng g(-1) for ΣPBDEs (sum of PBDE congeners except for BDE-209) and BDE-209, respectively. BDE-209 was predominated congener (43.5%), followed by BDE-47 (15.7%), 99 (10.7%), and 153 (7.5%). Further principal component analysis on congener profiles showed that PBDEs in the CLP originated from similar source(s). Additionally, significant differences in the ratios of BDE-47 to 99 and BDE-153 to 154 were found between soil samples and commercial products, indicating that they have undergone fractionation during the process of regional range atmospheric transport. The deposition of PBDEs in the CLP could be influenced by the sources from surrounding regions. For example, Xi'an may have potential influence to the CLP based on geographical analysis and concentrations comparison of PBDEs in gaseous. Therefore, more studies are needed to clarify the atmospheric transport and fate of PBDEs in this region.

Occurrence, sources, and inventory of hexabromocyclododecanes (HBCDs) in soils from Chongming Island, the Yangtze River Delta (YRD).

Hexabromocyclododecanes (HBCDs) is a concern due to their large usage combining with physico-chemical properties and toxicity to wildlife and human. However, very limited data were reported on HBCDs in soils, especially from rural area. In this study, 22 soil samples were collected from Chongming Island at estuary of the Yangtze River Delta, to investigate the level, diasteroisomer profile, potential sources, and mass inventory of HBCDs. The total concentrations ranged from not detected to 93.8pgg(-1) dry weight (dw) with a mean of 23.3pgg(-1)dw, which was at the low end of the global levels. The wide distribution of HBCDs in soils suggested that the local emissions of HBCD-containing materials and/or the inputs via atmospheric transport from other regions were two possible sources. Variation of HBCDs levels was observed in different types of soils. Woodland, tideland and road soils contained slightly higher HBCDs than those of farmland and grassland. Overall, γ-HBCD was the dominant diasteroisomer in soils, followed by α-HBCD and ß-HBCD. Significant but weak correlations were only found between α-HBCD and ß-HBCD versus TOC content in soils. Currently, the mass inventory of HBCDs in soils of Chongming Island was 5.3kg. Based on these data, we gave perspective on human intake of HBCDs via soil ingestion by age. Local resident's intakes ranged from 15.5 to 97.8fgkg body weight(-1)d(-1), in which children are exposed more than adults.

Polybrominated diphenyl ethers in background surface soils from the Yangtze River Delta (YRD), China: occurrence, sources, and inventory.

PURPOSES: Very few data for polybrominated diphenyl ethers (PBDEs) were available in the Yangtze River Delta (YRD), one of the most developed and urbanized region in China. In this study, Chongming Island, located at the estuary of the Yangtze River, was selected as background area to investigate the occurrence, sources, and inventory of PBDEs. METHODS: Forty-two PBDE congeners were determined in surface soils from farmland, woodland, grassland, tideland, and road collected in Chongming Island. RESULTS: The mean concentrations of Sigma26PBDE (not including BDE-209) and BDE-209 in soils were 0.76 and 12 ng/g dry weight, respectively. BDE-209 contributed more than 90% of the total of 27 frequently detected BDE congeners, followed by BDE-99 and BDE-47. Weak correlations were found between total organic carbon content and PBDE congeners concentrations in surface soils. PBDE levels varied with land use. Farmland and woodland soils contained higher Sigma26PBDE concentrations. BDE-209 levels were the highest in road soils. The mass inventories of PBDEs in soils of Chongming Island were estimated at 3.1 and 310 kg for Sigma26PBDEs and BDE-209, respectively. CONCLUSIONS: The PBDE levels in Chongming Island were similar to those in European background soils, suggesting minimum influence of pollutants from the YRD via air, and wastewater inputs or few PBDE products were used herein. From the standpoint of eco-inland, more studies are needed to explore the reasons of PBDE difference by land use and to assess people intake PBDEs via agriculture products consumption in this region.