Evaluating fit indices in a multilevel latent growth model with unbalanced design: a Monte Carlo study.

This study informed researchers about the performance of different level-specific and target-specific model fit indices in the Multilevel Latent Growth Model (MLGM) with unbalanced design. As the use of MLGMs is relatively new in applied research domain, this study helped researchers using specific model fit indices to evaluate MLGMs. Our simulation design factors included three levels of number of groups (50, 100, and 200) and three levels of unbalanced group sizes (5/15, 10/20, and 25/75), based on simulated datasets derived from a correctly specified MLGM. We evaluated the descriptive information of the model fit indices under various simulation conditions. We also conducted ANOVA to calculated the extent to which these fit indices could be influenced by different design factors. Based on the results, we made recommendations for practical and theoretical research about the fit indices. CFI- and TFI-related fit indices performed well in the MLGM and could be trustworthy to use to evaluate model fit under similar conditions found in applied settings. However, RMSEA-related fit indices, SRMR-related fit indices, and chi square-related fit indices varied by the factors included in this study and should be used with caution for evaluating model fit in the MLGM.

Widely Targeted Metabolomic Analysis Revealed the Diversity in Milk from Goats, Sheep, Cows, and Buffaloes and Its Association with Flavor Profiles.

The milk flavor can be attributed to the presence of numerous flavor molecules and precursors. In this study, we employed widely targeted metabolomic analysis techniques to analyze the metabolic profiles of various milk samples obtained from goats, sheep, dairy cows, and buffaloes. A total of 631 metabolites were identified in the milk samples, which were further categorized into 16 distinct classes. Principal component analysis (PCA) suggested that the metabolite profiles of samples from the same species exhibit clustering, while separated patterns of metabolite profiles are observed across goat, sheep, cow, and buffalo species. The differential metabolites between the groups of each species were screened based on fold change and variable importance in projection (VIP) values. Five core differential metabolites were subsequently identified, including 3-(3-hydroxyphenyl)-3-hydroxypropanoic acid, inosine 5'-triphosphate, methylcysteine, N-cinnamylglycine, and small peptide (L-tyrosine-L-aspartate). Through multiple comparisons, we also screened biomarkers of each type of milk. Our metabolomic data showed significant inter-species differences in the composition and concentration of some compounds, such as organic acids, amino acids, sugars, nucleotides, and their derivatives, which may affect the overall flavor properties of the milk sample. These findings provided insights into the molecular basis underlying inter-species variations in milk flavor.

Modification of myofibrillar protein structural characteristics: Effect of ultrasound-assisted first-stage thermal treatment on unwashed Silver Carp surimi gel.

The hardness properties of unwashed surimi gel are considered as the qualities of gelation defect. This research investigated the effect of ultrasound-assisted first-stage thermal treatment (UATT) on the physicochemical properties of unwashed Silver Carp surimi gel, and the enhancement mechanism. UATT could reduce protein particle size, which significantly reduced from 142.22 µm to 106.70 µm after 30 min of UATT compared with the nature protein. This phenomenon can promote the protein crosslinking, resulting in the hardness of surimi gel increased by 15.08 %. Partially unfolded structure of myofibrillar protein and exposures of tryptophan to water, lead to the increase in the zeta potential absolute value, driven by UATT. The reduced SH group level and the conformational conversion of proteins from random coiling to α-helix and ß-sheet, which was in support of intermolecular interaction and gel network construction. The results are valuable for processing protein gels and other food products.

Identification of immune-related signature with prognosis in children with stage 4 and 4S neuroblastoma / Identificación de firma relacionada con el sistema inmunológico con pronóstico en niños con neuroblastoma en estadio 4 y 4S

Objective: Spontaneous regression of tumors is an attractive phenomenon that most commonly occurs in stage 4S neuroblastoma (NB). However, the mechanism underlying this phenomenon remains unclear. Methods: Datasets correlated with NB were downloaded from online public databases, the differentially expressed genes (DEGs) between stage 4 and 4S associated with immunity were identified, and functional enrichment analysis was utilized to explore the potential functions and signaling pathways of these DEGs. In addition, based on these DEGs, a prognostic signature was constructed and validated, and differences in immune cell infiltration were analyzed. Results: A total of 13 DEGs were finally identified, and functional enrichment analysis revealed that these DEGs were primarily enriched in the positive regulation of neuron differentiation and TGF-β signaling pathway. The signature successfully stratifies patients into two risk score groups and performs well in judging prognosis and predicting overall survival time. In addition, the prognostic value of the risk score calculated by the signature was independent of clinical factors. The results of immune cell infiltration showed that patients with a high infiltration of resting CD4 + memory T cells had a better prognosis, while plasma cells had a worse prognosis. Conclusion: The results of the functional enrichment analysis of these identified DEGs suggested that these DEGs may be related to spontaneous regression of NB. In addition, the prognostic signature has the potential to create new risk stratification in patients with NB.(AU)

Overexpression of miR-532-5p restrains oxidative stress response of chondrocytes in nontraumatic osteonecrosis of the femoral head by inhibiting ABL1.

This study is to probe into the meaning of serum miR-532-5p in nontraumatic osteonecrosis of the femoral head (ONFH), and a molecular mechanism of miR-532-5p in the development of nontraumatic ONFH. This study enrolled 96 patients diagnosed with nontraumatic ONFH and 96 patients with femoral neck fracture. The levels of miR-532-5p, ABL1, MMP-3, MMP-13, and cleaved-caspase3 were determined. Radiographic progression was assessed by ARCO staging system. Visual analog scale (VAS) and Harris hip score (HHS) were employed for evaluation of the symptomatic severity of nontraumatic ONFH. Cell viability and apoptosis in chondrocytes isolated from clinical samples were investigated with CCK-8 and flow cytometry. The levels of lactic dehydrogenase (LDH), superoxide dismutase (SOD), and malondialdehyde (MDA), mitochondrial membrane potential (ΔΨm), and reactive oxygen species (ROS) were determined. miR-532-5p was downregulated in tissues and serum of patients with nontraumatic ONFH, negatively related with ARCO staging and VAS, and positively correlated with HHS. Cell apoptosis, LDH, MDA, and ROS strengthened, while cell viability, ΔΨm, and SOD reduced in chondrocytes of nontraumatic ONFH patients. ABL1 was upregulated in cartilage tissues from nontraumatic ONFH patients. miR-532-5p targeted ABL1, and overexpressed miR-532-5p alleviated nontraumatic ONFH-induced oxidative stress damage of chondrocytes by restraining ABL1. miR-532-5p ameliorated oxidative stress injury in nontraumatic ONFH by inhibiting ABL1.

Ratiometric Near-Infrared Fluorescent Probe Monitors Ferroptosis in HCC Cells by Imaging HClO in Mitochondria.

Hypochlorous acid (HClO) is a typical endogenous ROS produced mainly in mitochondria, and it has strong oxidative properties. Abnormal HClO levels lead to mitochondrial dysfunction, strongly associated with various diseases. It has been shown that HClO shows traces of overexpression in cells of both ferroptosis and hepatocellular carcinoma (HCC). Therefore, visualization of HClO levels during ferroptosis of HCC is important to explore its physiological and pathological roles. So far, there has been no report on the visualization of HClO in ferroptosis of HCC. Thus, we present a ratiometric near-infrared (NIR) fluorescent probe Mito-Rh-S which visualized for the first time the fluctuation of HClO in mitochondria during ferroptosis of HCC. Mito-Rh-S has an ultrafast response rate (2 s) and large emission shift (115 nm). Mito-Rh-S was constructed based on the PET sensing mechanism and thus has a high signal-to-noise ratio. The cell experiments of Mito-Rh-S demonstrated that Fe2+- and erastin-induced ferroptosis in HepG2 cells resulted in elevated levels of mitochondrial HClO and that high concentration levels of Fe2+ and erastin cause severe mitochondrial damage and oxidative stress and had the potential to kill HepG2 cells. By regulating the erastin concentration, erastin induction time, and treatment of the ferroptosis model, Mito-Rh-S can accurately detect the fluctuation of mitochondrial HClO levels during ferroptosis in HCC.

Coexistence of pulmonary arterial hypertension and straight back syndrome in a patient with a novel BMPR2 variant affecting cytoplasmic tail domain.

BACKGROUND: Pathologic variants in the bone morphogenetic protein receptor-2 (BMPR2) gene cause a pulmonary arterial hypertension phenotype in an autosomal-dominant pattern with incomplete penetrance. Straight back syndrome is one of the causes of pseudo-heart diseases. To date, no cases of idiopathic or heritable pulmonary arterial hypertension with straight back syndrome have been reported. CASE PRESENTATION: A 30-year-old female was diagnosed with pulmonary arterial hypertension by right heart catheterization. Computed tomography revealed a decreased anteroposterior thoracic space with heart compression, indicating a straight back syndrome. Genetic analysis by whole exome sequencing identified a novel c.2423_2424delGT (p.G808Gfs*4) germline frameshift variant within BMPR2 affecting the cytoplasmic tail domain. CONCLUSIONS: This is the first report of different straight back characteristics in heritable pulmonary arterial hypertension with a novel germline BMPR2 variant. This finding may provide a new perspective on the variable penetrance of the pulmonary arterial hypertension phenotype.

APLN promotes the proliferation, migration, and glycolysis of cervical cancer through the PI3K/AKT/mTOR pathway.

Apelin (APLN) is an endogenous ligand of the G protein-coupled receptor APJ (APLNR). APLN has been implicated in the development of multiple tumours. Herein, we determined the effect of APLN on the biological behaviour and underlying mechanisms of cervical cancer. The expression and survival curves of APLN were determined using Gene Expression Profiling Interactive Analysis. The cellular functions of APLN were detected using CCK-8, clone formation, EdU, Transwell assays, flow cytometry, and seahorse metabolic analysis. The underlying mechanisms were elucidated using gene set enrichment analysis and Western blotting. APLN was upregulated in the samples of patients with cervical cancer and is associated with poor prognosis. APLN knockdown decreased the proliferation, migration, and glycolysis of cervical cancer cells. The opposite results were observed when APLN was overexpressed. Mechanistically, we determined that APLN was critical for activating the PI3K/AKT/mTOR pathway via APLNR. APLN receptor inhibitor ML221 reversed the effect of APLN overexpression on cervical cancer cells. Treatment with LY294002, the PI3K inhibitor, drastically reversed the oncological behaviour of APLN-overexpressing C-33A cells. APLN promoted the proliferation, migration, and glycolysis of cervical cancer cells via the PI3K/AKT/mTOR pathway.

Basic magnesium sulfate@TiO2 composite for efficient adsorption and photocatalytic degradation of 4-dodecylmorpholine in brine.

More than 70% of the potash fertilizer globally is produced by the froth flotation process, in which 4-dodecylmorpholine (DMP) serves as a reverse flotation agent. As the potash fertilizer production rapidly rises, the increased DMP levels in discharged brine pose a threat to the production of high-value chemicals. In this paper, composite particles of basic magnesium sulfate@TiO2 (BMS@TiO2) were prepared using a simple and mild loading method. These particles were utilized for the adsorption and photocatalytic degradation of DMP in brine. Compared with normal powdered materials, the granular BMS@TiO2 in this study can be easily separated from liquid, and the degradation intermediates will not enter the brine without causing secondary pollution. BMS@TiO2 consists of 5·1·7 phase (5Mg(OH)2·MgSO4·7H2O) whisker clusters embedding 2.3% TiO2. The adsorption equilibrium of DMP on BMS@TiO2 particles was achieved through hydrogen bonding and pore interception with the adsorption capacity of approximately 5 mg g-1 after 6 h. The photodegradation efficiency of DMP adsorbed on BMS@TiO2 reached about 92% within 16 h, which is compared with that of pure TiO2 nanoparticles. Additionally, excellent stability and recyclability of BMS@TiO2 were also observed in five cycle tests of adsorption and photocatalytic degradation of DMP, and the possible photocatalytic degradation pathways and mechanism of DMP are proposed following molecular electrostatic potential analysis. This work provides a sustainable and environmentally friendly approach for eliminating organic micropollutants from water environments.

DCDC2 inhibits hepatic stellate cell activation and ameliorates CCl4-induced liver fibrosis by suppressing Wnt/ß-catenin signaling.

Liver fibrosis, as a consequence of chronic liver disease, involves the activation of hepatic stellate cell (HSC) caused by various chronic liver injuries. Emerging evidence suggests that activation of HSC during an inflammatory state can lead to abnormal accumulation of extracellular matrix (ECM). Investigating novel strategies to inhibit HSC activation and proliferation holds significant importance for the treatment of liver fibrosis. As a member of the doublecortin domain-containing family, doublecortin domain containing 2 (DCDC2) mutations can lead to neonatal sclerosing cholangitis, but its involvement in liver fibrosis remains unclear. Therefore, this study aims to elucidate the role of DCDC2 in liver fibrosis. Our findings revealed a reduction in DCDC2 expression in both human fibrotic liver tissues and carbon tetrachloride (CCl4)-induced mouse liver fibrotic tissues. Furthermore, exposure to transforming growth factor beta-1(TGF-ß1) stimulation resulted in a dose- and time-dependent decrease in DCDC2 expression. The overexpression of DCDC2 inhibited the expression of α-smooth muscle actin (α-SMA) and type I collagen alpha 1 (Col1α1), and reduced the activation of HSC stimulated with TGF-ß1. Additionally, we provided evidence that the Wnt/ß-catenin signaling pathway was involved in this process, wherein DCDC2 was observed to inhibit ß-catenin activation, thereby preventing its nuclear translocation. Furthermore, our findings demonstrated that DCDC2 could attenuate the proliferation and epithelial-mesenchymal transition (EMT)-like processes of HSC. In vivo, exogenous DCDC2 could ameliorate CCl4-induced liver fibrosis. In summary, DCDC2 was remarkably downregulated in liver fibrotic tissues of both humans and mice, as well as in TGF-ß1-activated HSC. DCDC2 inhibited the activation of HSC induced by TGF-ß1 in vitro and fibrogenic changes in vivo, suggesting that it is a promising therapeutic target for liver fibrosis and warrants further investigation in clinical practice.

Comparative transcriptome and metabolome reveal the role of acidic electrolyzed oxidizing water in improving postharvest disease resistance of longan fruit.

Acidic electrolyzed oxidizing water (AEOW) was applied to suppress disease development and maintain good quality of fresh fruit. However, the involvement of AEOW in improving disease resistance of fresh longan remains unknown. Here, transcriptomic and metabolic analyses were performed to compare non-treated and AEOW-treated longan during storage. The transcriptome analysis showed AEOW-induced genes associated with phenylpropanoid and flavonoid biosynthesis. The metabolome analysis found the contents of coumarin, phenolic acid, and tannin maintained higher levels in AEOW-treated longan than non-treated longan. Moreover, the weighted correlation network analysis (WGCNA) was performed to identify hub genes, and a gene-metabolite correlation network associated with AEOW-improved disease resistance in longan was constructed by the co-analysis of transcriptomics and metabolomics. These findings identified a series of important genes and metabolites involving in AEOW-induced disease resistance of longan fruit, expanding our knowledges on fruit disease resistance and quality maintenance at the transcript and metabolic levels.

Santacruzamate A Alleviates Pain and Pain-Related Adverse Emotions through the Inhibition of Microglial Activation in the Anterior Cingulate Cortex.

Chronic pain is a complex disease. It seriously affects patients' quality of life and imposes a significant economic burden on society. Santacruzamate A (SCA) is a natural product isolated from marine cyanobacteria in Panama. In this study, we first demonstrated that SCA could alleviate chronic inflammatory pain, pain-related anxiety, and depression emotions induced by complete Freund's adjuvant in mice while inhibiting microglial activation in the anterior cingulate cortex. Moreover, SCA treatment attenuated lipopolysaccharide (LPS)-induced inflammatory response by downregulating interleukin 1ß and 6 (IL-1ß and IL-6) and tumor necrosis factor-α (TNF-α) levels in BV2 cells. Furthermore, we found that SCA could bind to soluble epoxide hydrolase (sEH) through molecular docking technology, and the thermal stability of sEH was enhanced after binding of SCA to the sEH protein. Meanwhile, we identified that SCA could reduce the sEH enzyme activity and inhibit sEH protein overexpression in the LPS stimulation model. The results indicated that SCA could alleviate the development of inflammation by inhibiting the enzyme activity and expression of sEH to further reduce chronic inflammatory pain. Our study suggested that SCA could be a potential drug for treating chronic inflammatory pain.

NSC689857, an inhibitor of Skp2, produces antidepressant-like effects in mice.

We have previously reported that two inhibitors of an E3 ligase S-phase kinase-associated protein 2 (Skp2), SMIP004 and C1, have an antidepressant-like effect in non-stressed and chronically stressed mice. This prompted us to ask whether other Skp2 inhibitors could also have an antidepressant effect. Here, we used NSC689857, another Skp2 inhibitor, to investigate this hypothesis. The results showed that administration of NSC689857 (5 mg/kg) produced an antidepressant-like effect in a time-dependent manner in non-stressed male mice, which started 8 days after drug administration. Dose-dependent analysis showed that administration of 5 and 10 mg/kg, but not 1 mg/kg, of NSC689857 produced antidepressant-like effects in both non-stressed male and female mice. Administration of NSC689857 (5 mg/kg) also induced antidepressant-like effects in non-stressed male mice when administered three times within 24 h (24, 5, and 1 h before testing) but not when administered acutely (1 h before testing). In addition, NSC689857 and fluoxetine coadministration produced additive antidepressant-like effects in non-stressed male mice. These effects of NSC689857 were not associated with the changes in locomotor activity. Administration of NSC689857 (5 mg/kg) also attenuated depression-like behaviors in male mice induced by chronic social defeat stress, suggesting therapeutic potential of NSC689857 in depression. Overall, these results suggest that NSC689857 is capable of exerting antidepressant-like effects in both non-stressed and chronically stressed mice.

Functional differentiation of olive PLP_deC genes: insights into metabolite biosynthesis and genetic improvement at the whole-genome level.

KEY MESSAGE: This study identified 16 pyridoxal phosphate-dependent decarboxylases in olive at the whole-genome level, conducted analyses on their physicochemical properties, evolutionary relationships and characterized their activity. Group II pyridoxal phosphate-dependent decarboxylases (PLP_deC II) mediate the biosynthesis of characteristic olive metabolites, such as oleuropein and hydroxytyrosol. However, there have been no report on the functional differentiation of this gene family at the whole-genome level. This study conducted an exploration of the family members of PLP_deC II at the whole-genome level, identified 16 PLP_deC II genes, and analyzed their gene structure, physicochemical properties, cis-acting elements, phylogenetic evolution, and gene expression patterns. Prokaryotic expression and enzyme activity assays revealed that OeAAD2 and OeAAD4 could catalyze the decarboxylation reaction of tyrosine and dopa, resulting in the formation of their respective amine compounds, but it did not catalyze phenylalanine and tryptophan. Which is an important step in the synthetic pathway of hydroxytyrosol and oleuropein. This finding established the foundational data at the molecular level for studying the functional aspects of the olive PLP_deC II gene family and provided essential gene information for genetic improvement of olive.

Osteoporosis and depression in perimenopausal women: From clinical association to genetic causality.

BACKGROUND: Osteoporosis and major depressive disorder (MDD) represent two significant health challenges globally, particularly among perimenopausal women. This study utilizes NHANES data and Mendelian randomization (MR) analysis to explore the link between them, aiming to provide a basis for intervention strategies for this group. METHODS: The study analyzed NHANES 2007-2018 data using weighted logistic regression in R software to evaluate the link between MDD and osteoporosis risk. Then, a two-sample MR analysis with GWAS summary statistics was performed, mainly using the IVW method. Additional validation included MR Egger, Weighted Median, Mode, and MR-PRESSO methods. RESULTS: The research analysis indicated a significant link between MDD and the risk of osteopenia/osteoporosis. Our analysis revealed a significant positive relationship between MDD and both femoral neck osteoporosis (OR = 6.942 [95 % CI, 1.692-28.485]) and trochanteric osteoporosis (OR = 4.140 [95 % CI, 1.699-10.089]). In analyses related to osteopenia, a significant positive correlation was observed between MDD and both total femoral osteopenia (OR = 3.309 [95 % CI, 1.577-6.942]) and trochanteric osteopenia (OR = 2.467 [95 % CI, 1.004-6.062]). Furthermore, in the MR analysis, genetically predicted MDD was causally associated with an increased risk of osteoporosis via the IVW method (P = 0.013). LIMITATIONS: Our study was limited by potential selection bias due to excluding subjects with missing data, and its applicability was primarily to European and American populations. CONCLUSION: Integrating NHANES and MR analyses, a robust correlation between MDD and osteoporosis was identified, emphasizing the significance of addressing this comorbidity within clinical practice and meriting further investigation.

Ginseng in white and red processed forms: Ginsenosides and cardiac side effects.

Ginseng (Panax ginseng Meyer) has long been consumed as a medicinal or functional food in East Asia. It is available as dried white ginseng (WG) and steamed red ginseng (RG), which might differ in ginsenoside profiles. We compared ginsenoside types of RG and WG using UPLC-MS/MS and evaluated how they biologically affected heart of healthy rats by recording electrocardiography, measuring biochemical indicators, analyzing cardiac tissue slides, and Ca2+ signaling pathways. About 25 and 29 ginsenosides were detected in WG and RG, respectively, and the total ginsenoside content of RG contained was nearly 1.8 times higher than that of WG. Among them, ginsenoside Rg4, ginsenoside Rg6, ginsenoside Rh4, ginsenoside Rk1, ginsenoside Rg5, and protopanaxadiol were detected only in RG, while 20(R)-ginsenoside Rg2 was detected only in WG. Male SD rats treated by intraperitoneal injection of WG or RG extracts were similar to the control in terms of electrocardiography and heart histology, indicating that both may not significantly affect the rats' myocardial function. However, WG and RG may induce mild cardiac injury resulting in increased cardiac collagen and creatine kinase levels. In addition, upregulated p-CaMKII and PPARδ and downregulated SERCA2a for WG and RG treatments were further associated with increased cardiac contractility. In general, RG had less effect on the heart of healthy rats than WG, which may be due to RG having a high proportion of low-polar ginsenosides.

Establishment and methodological evaluation of a chemiluminescence assay for detection of anti-envelope protein (E1, E2) antibodies in the serum of hepatitis C virus-infected patients.

BACKGROUND: To establish a chemiluminescence method for detecting anti-E1 and anti-E2 antibodies in the serum of patients with hepatitis C virus (HCV) infection. METHODS: The microplate was coated with recombinant envelope proteins E1 and E2 by indirect method, respectively, and the kits for detecting anti-E1 and anti-E2 antibodies were prepared. The methodological indexes were evaluated. RESULTS: The methodological indexes of the kits were as follows: precision test (the variation coefficient of anti-E1 antibody 6.71%-8.95% for within run and 9.91%-12.16% for between run, the variation coefficient of anti-E2 antibody 6.06%-8.44% for within run and 10.77%-13.98% for between run, respectively). The blank limit and detection limit were 1.18 RLIR and 3.16 RLIR for the anti-E1 antibody, and 1.26 RLIR and 3.32 RLIR for the anti-E2 antibody, respectively. The correlation coefficients (r) of anti-E1 and anti-E2 were 0.9963 and 0.9828, the analysis and measurement ranges (AMR) were 1.66-41.28 RLIR and 1.55-19.46 RLIR, and the average recovery was 96.4% and 93.7%, respectively. The rheumatoid factor and other positive serum samples had no interference or cross-reaction to the test, and the kits were stable within 15 months. The positive rates of anti-E1 and anti-E2 antibodies in 45 patients with HCV infection were 35.6% (16/45) and 44.4% (20/45), respectively. CONCLUSIONS: The kits for detecting anti-E1 and anti-E2 meet the requirements of methodology, and can be used in screening diagnosis, disease monitoring, prognosis evaluation, disease mechanism, and epidemiological studies of HCV infection. The HCV envelope proteins E1 and E2 have an immune response in HCV-infected patients.

Berberine alleviates concanavalin A-induced autoimmune hepatitis in mice by modulating the gut microbiota.

BACKGROUND: Autoimmune hepatitis (AIH) is an immune-mediated liver disease of unknown etiology accompanied by intestinal dysbiosis and a damaged intestinal barrier. Berberine (BBR) is a traditional antibacterial medicine that has a variety of pharmacological properties. It has been reported that BBR alleviates AIH, but relevant mechanisms remain to be fully explored. METHODS: BBR was orally administered at doses of 100 mg⋅kg-1⋅d-1 for 7 days to mice before concanavalin A-induced AIH model establishment. Histopathological, immunohistochemical, immunofluorescence, western blotting, ELISA, 16S rRNA analysis, flow cytometry, real-time quantitative PCR, and fecal microbiota transplantation studies were performed to ascertain BBR effects and mechanisms in AIH mice. RESULTS: We found that liver necrosis and apoptosis were decreased upon BBR administration; the levels of serum transaminase, serum lipopolysaccharide, liver proinflammatory factors TNF-α, interferon-γ, IL-1ß, and IL-17A, and the proportion of Th17 cells in spleen cells were all reduced, while the anti-inflammatory factor IL-10 and regulatory T cell proportions were increased. Moreover, BBR treatment increased beneficial and reduced harmful bacteria in the gut. BBR also strengthened ileal barrier function by increasing the expression of the tight junction proteins zonula occludens-1 and occludin, thereby blocking lipopolysaccharide translocation, preventing lipopolysaccharide/toll-like receptor 4 (TLR4)/ NF-κB pathway activation, and inhibiting inflammatory factor production in the liver. Fecal microbiota transplantation from BBR to model mice also showed that BBR potentially alleviated AIH by altering the gut microbiota. CONCLUSIONS: BBR alleviated concanavalin A-induced AIH by modulating the gut microbiota and related immune regulation. These results shed more light on potential BBR therapeutic strategies for AIH.

Pharmacological effects and target analysis of Guipi wan in the treatment of cerebral ischemia-reperfusion injury.

Guipi wan (GPW) is a traditional Chinese medicine commonly used in clinical practice, typically to treat neurological diseases such as neurasthenia and traumatic brain injury. It may have positive effects on cerebral ischemia‒reperfusion injury (cI/R). This study aimed to assess the effects of GPW in a mouse model of cI/R and find its possible targets. C57BL/6J mice were used to establish the cI/R model, and the laser speckle doppler was used to determine the success of the model. GPW was administered intragastrically for 7 days, brain tissue sections were stained with TTC, HE, and TUNEL, Western blot assay was performed to detect the effect of apoptosis-related proteins. Furthermore, we screened active ingredients from the TCM Database and constructed a compound‒target network using the Cytoscape 3.8.0 software. Moreover, we employed protein‒protein interaction and component‒target‒pathway network analyses to determine the potential components of GPW and its target genes, the key target was verified through molecular docking. Finally, we detected the influence of the downstream signaling pathway of the target through Western blot. The results showed that GPW decreased the cerebral infarction area, neurological function scores, and neuronal apoptosis in mice by regulating PI3K/AKT signaling pathway. Network analysis indicated that gamma-aminobutyric acid B receptor 1 (GABBR1) might be a potential target for the treatment of cI/R. Molecular docking indicated that 9 active components in GPW could bind to GABBR1 with desirable binding energy. This study represented the demonstratable effect of GPW in the treatment of cI/R injury and suggested GABBR1 as a potential target using network analysis.

The efficacy and safety of PD-1 inhibitor combined with TACE in the first-line treatment of unresectable hepatocellular carcinoma.

The application of immune checkpoint inhibitors (ICIs) has changed the treatment of advanced hepatocellular carcinoma. Transcatheter arterial chemoembolization (TACE) is a first-line treatment for intermediate hepatocellular carcinoma. Serving as a local treatment modality that can induce immunogenic cell death, the efficacy and safety of combined use with ICI have not been evaluated. Although there have been prospective studies aimed at evaluating the efficacy and safety of ICI combined with TACE in BCLC stage B HCC patients, there are few reports on the evaluation of BCLC stage C patients with distant metastasis or portal vein cancer thrombus. Data of unresectable hepatocellular carcinoma patients received PD-1 inhibitor and TACE were collected in Xijing Hospital from June 2019 to December 2022. The tumor response was evaluated according to the Solid Tumor Modified Response Evaluation Standard (mRECIST), including complete response (CR), partial response (PR), disease stability (SD), disease progression (PD), objective response rate (ORR), and disease control rate (DCR). The progression-free survival (PFS) and overall survival (OS) were used to estimate therapy efficacy. The treatment-related adverse events were evaluated based on National Cancer Institute Common Adverse Event Evaluation Criteria (CTCAE) version 5.0. A total of 42 patients with unresectable hepatocellular carcinoma were included in this study, including 34 males (80.5%) and 8 females (19.5%). The average age is 54.5 years, ranging from 34 to 72. The median follow-up time was 12.3 months, with an ORR of 42.9% and a DCR of 90.5% as of the follow-up time. The median PFS is 7.5 months (95% CI: 5.76-9.23), and the median OS has not yet been reached; 6-month PFS was 62.2%. Safety analysis showed that 41 (97.6%) patients experienced treatment-related adverse reactions, mainly including elevated AST and ALT, fever, elevated bilirubin, hypothyroidism, nausea, abdominal pain, and rash. 40 patients had grade 1/2 adverse reactions, and only one patient had grade 3 adverse reactions, manifested as intolerable rash, nausea, and vomiting. Treatment is terminated when symptomatic treatment and drug suspension cannot be alleviated. In this study, thre patients with unresectable hepatocellular carcinoma were treated with PD-1 inhibitor combined with TACE to achieve good tumor reduction effect and underwent liver cancer resection surgery. For patients with unresectable hepatocellular carcinoma, whether in BCLC stage B or stage C, effective systemic therapy (PD-1 inhibitor) combined with local therapy (TACE) can achieve a high rate of tumor regression and objective response. Some patients may even pursue surgical treatment opportunities, and the treatment-related adverse reactions are controllable, which is expected to provide new options for extending the survival of unresectable hepatocellular carcinoma patients.