Evaluation of Safety and Efficacy of Amniotic Mesenchymal Stem Cells for POI in Animals.

The efficacy of human amniotic mesenchymal stem cell (hAMSC) ovarian injection in improving ovarian function in primary ovarian insufficiency (POI) patients has been shown in some reports. However, the safety and efficacy of hAMSC vein injection remains unclear. In this study, we evaluated the safety and efficacy of hAMSC intravenous injection in cynomolgus macaques and SD rats and provided evidence for clinical trials. The hAMSCs were transplanted three times in SD rats at low, medium, and high doses. The animal behavior and biochemical and biophysical parameters were routinely monitored on a 2-month period posttransplantation, and histopathologic examinations were also performed. Experiments on the acute toxicity, allergy test, and hemolysis test showed that hAMSCs possess good biocompatibility. Our results showed that the maximum tolerated dose of hAMSCs in SD rats was 4.0 × 107 cells/kg. The maximum safe dose with three injections of hAMSCs in SD rats was 5.0 × 106 cells/kg. In addition, the results demonstrated that hAMSCs may restore POI rat ovarian function after two injections of 2.5 × 106 cells/kg or 5.0 × 106 cells/kg, which improved the disturbed estrous cycle, hormone levels, and ovarian lesions induced by pZP3. In conclusion, the preclinical results suggested that the transplantation of hAMSCs may be safe and efficacious for SD rats at doses of 5.0 × 106 cells/kg and lower.

Molecular characteristics of circulating B cells and kidney cells at the single-cell level in special types of primary membranous nephropathy.

Background: Although primary membranous nephropathy (pMN) associated with podocyte autoantibodies (POS) is becoming well-known, the molecular characteristics of the specific type of pMN that is negative for podocyte autoantibodies (NEG) is still unclear. Methods: We performed single-cell transcriptome sequencing and single-cell B cell receptor sequencing on circulating CD19+ cells and kidney cells of a NEG paediatric patient with pMN. The single-cell datasets of POS patients and healthy control individuals were included for integrative analysis. Results: The gene expression characteristics and clonal expansion of naïve and memory B cells in the NEG patient changed significantly. We found that a group of CD38+ naïve B cells expanded in the NEG patient, which had the functional characteristics of cell activation. In addition, the conversion between immunoglobulin M (IgM)/IgD and IgG1 in the NEG patient was increased. Parietal epithelial cells (PECs) and podocytes shared similar signature genes (WT1, CLIC5), and new candidate marker genes for PECs, such as NID2, CAV1 and THY1, might contribute to the definition of cell subsets. PECs might have undergone significant changes in the disease, mainly manifested by changes in the expression of CCN2, PLAAT4 and SEPTIN2. The scores of gene sets related to extracellular matrix, cell adhesion and calcium channel in podocytes of the NEG patient was significantly increased. The gene expression of sodium transporter in a group of proximal tubule cells in the disease was significantly increased, especially SLC5A12, which might be related to the oedema of patients. Conclusions: Our research demonstrated the cell type-specific molecular features in the circulation and kidney of the NEG pMN patient.

Efficacy of pharmacotherapies for bulimia nervosa: a systematic review and meta-analysis.

OBJECTIVE: The main purpose was to evaluate the efficacy and tolerability of different medications used to treat bulimia nervosa (BN). METHODS: Randomized controlled trials (RCTs) were identified from published sources through searches in PubMed, Cochrane Library, Web of Science, and Embase from inception to November 2022. Primary outcomes were changes in the frequency of binge eating episodes and vomiting episodes from baseline to endpoint. Secondary outcomes were differences in the improvement of scores in depressive symptoms, tolerability (dropout due to adverse events) and weight change. RESULTS: The literature search ultimately included 11 drugs, 33 studies and 6 types of drugs, 8 trials with TCAs (imipramine, desipramine), 14 with SSRIs (fluoxetine, citalopram and fluvoxamine), 6 with MAOIs (phenelzine, moclobemide and brofaromine), 3 with antiepileptic drugs (topiramate), 1 with mood stabilizers (lithium), and 1 with amphetamine-type appetite suppressant (fenfluramine). The reduction in binge eating episodes was more likely due to these drugs than the placebo, and the SMD was -0.4 (95% CI -0.61 ~ -0.19); the changes in the frequency of vomiting episodes (SMD = -0.16, 95% CI -0.3 ~ -0.03); weight (WMD = -3.05, 95% CI -5.97 ~ -0.13); and depressive symptoms (SMD = -0.32, 95% CI -0.51 ~ -0.13). However, no significant difference was found in dropout due to adverse events (RR = 1.66, 95% CI 1.14 ~ 2.41). CONCLUSIONS: This meta-analysis indicates that most pharmacotherapies decreased the frequency of binge-eating and vomiting episodes, body weight, and depressive symptoms in BN patients, but the efficacy was not significant. In each drug the efficacy is different, treating different aspects, different symptoms to improve the clinical performance of bulimia nervosa.

NAD(P)H:quinone Oxidoreductase 1 Is Involved in AZ-1-induced Apoptotic Effects in Nasopharyngeal Carcinoma TW01 Cells.

BACKGROUND/AIM: Current NPC treatment methods have improved the 5-year survival rates of patients; however, some patients do not benefit from the treatments. Therefore, the existing treatment methods or new drugs must be developed to improve the patient's prognosis. NAD (P)H:quinone oxidoreductase 1 (NQO1), an electron reductase highly expressed in various cancers, can convert aziridinyl-substituted quinone-derived compound into an alkylating agent, resulting in cell apoptosis. Therefore, a di-aziridinyl-substituted quinone-derived compound, AZ-1, was designed previously. The present study investigated whether AZ-1 has anticancer activities in NPC cells and explored the underlying mechanism. MATERIALS AND METHODS: NPC-TW01 cells were used in the study, and 3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide, colony formation, terminal deoxynucleotidyl transferase dUTP nick end labeling, and immunoblotting assays were performed to assess the cell viability, cell survival, DNA fragmentation, and protein expression, respectively. RESULTS: The results show that AZ-1 significantly inhibited the viability and survival of NPC-TW01 cells. AZ-1 also induced the expression of cleaved PARP, cleaved caspase-8, cleaved caspase-9, and cleaved caspase-3, and triggered DNA fragmentation in NPC-TW01 cells. In addition, AZ-1 induced γH2AX expression, a DNA damage marker, in NPC-TW01 cells. Treatment with dicoumarol, an NQO1 activity inhibitor, not only reversed AZ-1-induced cell viability inhibition but also decreased AZ-1-induced expression of γH2AX, cleaved caspase-8, cleaved caspase-9, and cleaved caspase-3. CONCLUSION: NQO1 reverses AZ-1-triggered cell viability inhibition, DNA damage, and apoptosis. The findings of this study may provide a basis for the possible clinical application of AZ-1 in the treatment of NPC to improve the prognosis of patients with NPC.

Serum total bile acid levels assist in the prediction of acute intussusception with abdominal type Henoch-Schonlein purpura in children.

Background: The severe acute abdomen associated with Henoch-Schonlein purpura (HSP) is an acute intussusception (AI). There is no reliable specific marker for AI with abdominal-type HSP. The serum total bile acid (TBA) level is a new prognostic marker associated with the severity of intestinal inflammation. The purpose of this study was to identify the prognostic value of serum TBA levels for the diagnosis of AI in children with abdominal-type HSP. Methods: A retrospective study of 708 patients with abdominal-type HSP was conducted, with demographic data, clinical symptoms, hepatic function index, immune function markers, and clinical outcomes assessed. Patients were divided into two groups: HSP (613 patients) and HSP with AI (95 patients). The data were analysed using SPSS 22.0. Results: Of the 708 patients, the serum TBA levels were higher in the HSP with AI group than in the HSP group (P < 0.05). Logistic regression analysis showed that vomiting (OR = 396.492, 95% CI = 14.93-10,529.67, P < 0.001), haematochezia (OR = 87.436, 95% CI = 5.944-1,286.214, P = 0.001), TBA (OR = 16.287, 95% CI = 4.83-54.922, P < 0.001), and D-dimer (OR = 5.987, 95% CI = 1.892-15.834, P = 0.003) were independent risk factors for abdominal-type HSP with AI. Receiver operating characteristic (ROC) curve analysis showed that the optimal cut-off serum TBA value (sensitivity = 91.58%, specificity = 84.67%, AUC = 93.6524%) was >3 µmol/L for predicting AI in children with abdominal-type HSP. In this group of HSP patients with AI, a serum TBA level ≥6.98 µmol/L was significantly associated with an increased incidence of operative treatment (51.85% vs. 75.61%, P = 0.0181), intestinal necrosis (9.26% vs. 29.27%, P = 0.0117), and length of hospital stay [15.76 ± 5.31 vs. 10.98 ± 2.83 (days), P < 0.0001]. Conclusion: In children with HSP and AI, the serum TBA level was significantly higher. A novel but promising haematological indicator, the serum TBA level, helps identify HSP with and without AI and predicts intestinal necrosis in HSP with AI.

Corrigendum: Clinical features and gene variation analysis of COQ8B nephropathy: Report of seven cases.

[This corrects the article DOI: 10.3389/fped.2022.1030191.].

Guanfacine for the Treatment of Attention-Deficit Hyperactivity Disorder: An Updated Systematic Review and Meta-Analysis.

Background: Non-stimulant guanfacine is a common second-line medication for attention-deficit hyperactivity disorder (ADHD). Numerous randomized controlled trials (RCTs) have explored the efficacy of guanfacine in ADHD treatment. This meta-analysis combined data from selected RCTs to analyze the efficacy and safety of guanfacine in treating ADHD. Methods: RCTs were identified from published sources through searches in PubMed, Cochrane Library, Web of Science, and Embase (up to February 2022), defining the Clinical Global Impression of Improvement (CGI-I) treatment response score of ≤2 as the primary outcome. Subgroup analysis was performed with a bound treatment duration of 10 weeks. Safety was defined by treatment-emergent adverse events (TEAEs). Results: Twelve out of 332 studies with 2653 participants were included. All studies compared guanfacine with placebos. Guanfacine was significantly more effective in treating ADHD (Risk Ratio [RR] 1.78, 95% CI: 1.59-2.01). In the <10 weeks subgroup, the efficacy in the guanfacine group compared with the placebo group was 58.5% versus 29.4%, respectively (RR 1.97, 95% CI: 1.71-2.26). In the >10 weeks subgroup, the efficacy in the guanfacine group compared with the placebo group was 63.6% versus 39.7%, respectively (RR 1.57, 95% CI: 1.37-1.79). Both subgroups lacked heterogeneity (I2 = 0), and a funnel plot showed a low publication bias risk. Around 80% of participants in the guanfacine group experienced at least one TEAE, compared with 66.5% in the placebo group (RR 1.23, 95% CI: 1.14-1.32), with low heterogeneity (I2 = 46, p = 0.05). The most common TEAEs in the guanfacine group were somnolence (38.6%), headaches (20.5%), and fatigue (15.2%). Conclusions: Guanfacine is safe and effective for treating ADHD, with no serious adverse events. Guanfacine should be considered as an effective treatment option where effectiveness or tolerability of the central nervous system stimulant is of concern. There is stronger evidence of efficacy for children; more clinical studies are needed for adults.

Microwave imaging of quasi-periodic pulsations at flare current sheet.

Quasi-periodic pulsations (QPPs) are frequently detected in solar and stellar flares, but the underlying physical mechanisms are still to be ascertained. Here, we show microwave QPPs during a solar flare originating from quasi-periodic magnetic reconnection at the flare current sheet. They appear as two vertically detached but closely related sources with the brighter ones located at flare loops and the weaker ones along the stretched current sheet. Although the brightness temperatures of the two microwave sources differ greatly, they vary in phase with periods of about 10-20 s and 30-60 s. The gyrosynchrotron-dominated microwave spectra also present a quasi-periodic soft-hard-soft evolution. These results suggest that relevant high-energy electrons are accelerated by quasi-periodic reconnection, likely arising from the modulation of magnetic islands within the current sheet as validated by a 2.5-dimensional magnetohydrodynamic simulation.

PTC124 Rescues Nonsense Mutation of Two Tumor Suppressor Genes NOTCH1 and FAT1 to Repress HNSCC Cell Proliferation.

(1) Background: PTC124 (Ataluren) is an investigational drug for the treatment of nonsense mutation-mediated genetic diseases. With the exception of the TP53 tumor suppressor gene, there has been little research on cancers with nonsense mutation. By conducting a database search, we found that another two tumor suppressor genes, NOTCH1 and FAT1, have a high nonsense mutation rate in head and neck squamous cell carcinoma (HNSCC). PTC124 may re-express the functional NOTCH1 or FAT1 in nonsense mutation NOTCH1 or FAT1 in HSNCC (2) Methods: DOK (with NOTCH1 Y550X) or HO-1-u-1 (with FAT1 E378X) HNSCC cells were treated with PTC124, and the NOTCH1 or FAT1 expression, cell viability, and NOTCH1- or FAT1-related downstream gene profiles were assayed. (3) Results: PTC124 was able to induce NOTCH1 or FAT1 expression in DOK and HO-1-u-1 cells. PTC124 was able to upregulate NOTCH downstream genes HES5, AJUBA, and ADAM10 in DOK cells. PTC124 enhanced DDIT4, which is under the control of the FAT1-YAP1 pathway, in HO-1-u-1 cells. FLI-06 (a NOTCH signaling inhibitor) reversed PTC124-mediated cell growth inhibition in DOK cells. PTC124 could reverse TT-10 (a YAP signaling activator)-mediated HO-1-u-1 cell proliferation. (4) Conclusions: PTC124 can rescue nonsense mutation of NOTCH1 and FAT1 to repress HNSCC cell proliferation.

Polyguanine alleviated autoimmune hepatitis through regulation of macrophage receptor with collagenous structure and TLR4-TRIF-NF-κB signalling.

Autoimmune hepatitis (AIH) is a progressive and chronic inflammatory disease in the liver. MARCO is a surface receptor of macrophage involving in tissue inflammation and immune disorders. Moreover, polyguanine (PolyG) is considered to bind to macrophage receptor with collagenous structure (MARCO). However, the role of MARCO and PolyG in the development and treatment of AIH still remains unclear. Therefore, this study explores the expression of MARCO and therapeutic activity of PolyG in both S100-induced AIH in mouse and Lipopolysaccharide (LPS)-treated macrophage (RAW264.7 cells). Moreover, there were significant increases in inflammatory factors and MARCO, as well as decrease in I-kappa-B-alpha (Ik-B) in the liver of AIH mice and LPS-induced cells. However, PolyG treatment significantly reversed the elevation of inflammatory cytokins, MARCO and reduction of Ik-B. In addition, PolyG treatment could downregulate the expression of Toll-like receptor 4 (TLR4) and TIR-domain-containing adaptor inducing interferon-ß (TRIF), decrease macrophage M1 polarization and increase macrophage M2 polarization. When hepatocytes were co-cultured with different treatment of macrophages, similar expression profile of inflammatory cytokines was observed in hepatocytes. The research revealed that MARCO expression was elevated in AIH mice. PolyG treatment and inhibition of MARCO significantly reduced inflammatory cytokines expression in the liver as well as hepatocytes and macrophages. Therefore, MARCO could be a target for the treatment of AIH.

New insights into the role of ribonuclease P protein subunit p30 from tumor to internal reference.

Ribonuclease P protein subunit p30 (RPP30) is a highly conserved housekeeping gene that exists in many species and tissues throughout the three life kingdoms (archaea, bacteria, and eukaryotes). RPP30 is closely related to a few types of tumors in human diseases but has a very stable transcription level in most cases. Based on this feature, increasing number of studies have used RPP30 as an internal reference gene. Here, the structure and basic functions of RPP30 are summarized and the likely relationship between RPP30 and various diseases in plants and human is outlined. Finally, the current application of RPP30 as an internal reference gene and its advantages over traditional internal reference genes are reviewed. RPP30 characteristics suggest that it has a good prospect of being selected as an internal reference; more work is needed to develop this research avenue.

Whole-exome sequencing of a multicenter cohort identifies genetic changes associated with clinical phenotypes in pediatric nephrotic syndrome.

Understanding the association between the genetic and clinical phenotypes in children with nephrotic syndrome (NS) of different etiologies is critical for early clinical guidance. We employed whole-exome sequencing (WES) to detect monogenic causes of NS in a multicenter cohort of 637 patients. In this study, a genetic cause was identified in 30.0% of the idiopathic steroid-resistant nephrotic syndrome (SRNS) patients. Other than congenital nephrotic syndrome (CNS), there were no significant differences in the incidence of monogenic diseases based on the age at manifestation. Causative mutations were detected in 39.5% of patients with focal segmental glomerulosclerosis (FSGS) and 9.2% of those with minimal change disease (MCD). In terms of the patterns in patients with different types of steroid resistance, a single gene mutation was identified in 34.8% of patients with primary resistance, 2.9% with secondary resistance, and 71.4% of children with multidrug resistance. Among the various intensified immunosuppressive therapies, tacrolimus (TAC) showed the highest response rate, with 49.7% of idiopathic SRNS patients achieving complete remission. Idiopathic SRNS patients with monogenic disease showed a similar multidrug resistance pattern, and only 31.4% of patients with monogenic disease achieved a partial remission on TAC. During an average 4.1-year follow-up, 21.4% of idiopathic SRNS patients with monogenic disease progressed to end-stage renal disease (ESRD). Collectively, this study provides evidence that genetic testing is necessary for presumed steroid-resistant and idiopathic SRNS patients, especially those with primary and/or multidrug resistance.

P63 and P73 Activation in Cancers with p53 Mutation.

The members of the p53 family comprise p53, p63, and p73, and full-length isoforms of the p53 family have a tumor suppressor function. However, p53, but not p63 or p73, has a high mutation rate in cancers causing it to lose its tumor suppressor function. The top and second-most prevalent p53 mutations are missense and nonsense mutations, respectively. In this review, we discuss possible drug therapies for nonsense mutation and a missense mutation in p53. p63 and p73 activators may be able to replace mutant p53 and act as anti-cancer drugs. Herein, these p63 and p73 activators are summarized and how to improve these activator responses, particularly focusing on p53 gain-of-function mutants, is discussed.

Solar flare accelerates nearly all electrons in a large coronal volume.

Solar flares, driven by prompt release of free magnetic energy in the solar corona1,2, are known to accelerate a substantial portion (ten per cent or more)3,4 of available electrons to high energies. Hard X-rays, produced by high-energy electrons accelerated in the flare5, require a high ambient density for their detection. This restricts the observed volume to denser regions that do not necessarily sample the entire volume of accelerated electrons6. Here we report evolving spatially resolved distributions of thermal and non-thermal electrons in a solar flare derived from microwave observations that show the true extent of the acceleration region. These distributions show a volume filled with only (or almost only) non-thermal electrons while being depleted of the thermal plasma, implying that all electrons have experienced a prominent acceleration there. This volume is isolated from a surrounding, more typical flare plasma of mainly thermal particles with a smaller proportion of non-thermal electrons. This highly efficient acceleration happens in the same volume in which the free magnetic energy is being released2.

NAMPT Inhibitor and P73 Activator Represses P53 R175H Mutated HNSCC Cell Proliferation in a Synergistic Manner.

The p53 family has the following three members: p53, p63 and p73. p53 is a tumor suppressor gene that frequently exhibits mutation in head and neck cancer. Most p53 mutants are loss-of-function (LoF) mutants, but some acquire some oncogenic function, such as gain of function (GoF). It is known that the aggregation of mutant p53 can induce p53 GoF. The p73 activators RETRA and NSC59984 have an anti-cancer effect in p53 mutation cells, but we found that p73 activators were not effective in all head and neck squamous cell carcinoma (HNSCC) cell lines, with different p53 mutants. A comparison of the gene expression profiles of several regulator(s) in mutant HNSCC cells with or without aggregation of p53 revealed that nicotinamide phosphoribosyltransferase (NAMPT) is a key regulator of mutant p53 aggregation. An NAMPT inhibitor, to reduce abnormal aggregation of mutant p53, used in combination with a p73 activator, was able to effectively repress growth in HNSCC cells with p53 GoF mutants. This study, therefore, suggests a potential combination therapy approach for HNSCC with a p53 GoF mutation.

Enabling Anionic Redox Stability of P2-Na5/6 Li1/4 Mn3/4 O2 by Mg Substitution.

Oxygen-based anionic redox reactions have recently emerged as a lever to increase the capacity of Mn-rich layered oxide cathodes in addition to the charge compensation based on cationic redox reactions for sodium-ion batteries. Unfortunately, the irreversibility of anionic redox often aggravates irreversible structure change and poor cycling performance. Here, a stable anionic redox is achieved through substituting Na ions by Mg ions in P2-type Na0.83 Li0.25 Mn0.75 O2 . Density functional theory (DFT) calculations reveal that Mg substitution effectively decreases the oxygen chemical potential, causing an improvement in lattice oxygen stability. Moreover, at a highly desodiated state, Mg ions that remain in the lattice and interact with O 2p orbitals can decrease the undercoordinated oxygen and the nonbonded, electron-deficient O 2p states, facilitating the reversibility of oxygen redox. When cycled in the voltage range of 2.6-4.5 V where only anionic redox occurs for charge compensation, Na0.773 Mg0.03 Li0.25 Mn0.75 O2 presents a much better reversibility, giving a 4 times better cycle stability than that of Na0.83 Li0.25 Mn0.75 O2 . Experimentally, Na0.773 Mg0.03 Li0.25 Mn0.75 O2 exhibits a ≈1.1% volume expansion during sodium insertion/extraction, suggestive of a "zero-strain" cathode. Overall, the work opens a new avenue for enhancing anionic reversibility of oxygen-related Mn-rich cathodes.

Clinical features and gene variation analysis of COQ8B nephropathy: Report of seven cases.

Objective: COQ8B nephropathy is a relatively rare autosomal recessive kidney disease characterized by proteinuria and a progressive deterioration of renal function, eventually leading to end-stage renal disease (ESRD). The objective is to study the characteristics and correlation between the genotype and the clinical phenotype of COQ8B nephropathy. Methods: This is a retrospective study focusing on the clinical characteristics of seven COQ8B nephropathy patients diagnosed by gene sequencing. Basic clinical information, clinical manifestations, examinations, imaging, genomes, pathology, treatments, and prognosis of the patients were reviewed. Results: Of the seven patients, two were male children and five were female children. The median age at the disease onset was 5 years and 3 months. The initial main clinical manifestations were proteinuria and renal insufficiency. Four patients had severe proteinuria, four had focal segmental glomerulosclerosis (FSGS) diagnosed by a renal biopsy, and two had nephrocalcinosis after an ultrasound was performed on them. There were no other clinical manifestations such as neuropathy, muscle atrophy, and so on in all of them. Their gene mutations were all exon variants, which were classified as heterozygous or homozygous variants by performing family verification analysis. Compound heterozygous variants were predominant in all, and all gene variants were inherited from their parents. One novel mutation, c.1465c>t, was found in this study. This gene mutation resulted from changes in the amino acid sequence, thus leading to an abnormal protein structure. Two patients with early diagnosis of COQ8B nephropathy presented with no renal insufficiency and were treated with oral coenzyme Q10 (CoQ10), and they maintained normal renal function. For the remaining five who were treated with CoQ10 following renal insufficiency, the deterioration of renal function could not be reversed, and they progressed to ESRD within a short time (median time: 7 months). A follow-up of these patients showed normal renal function with a CoQ10 supplement. Conclusion: For unexplained proteinuria, renal insufficiency, or steroid-resistant nephrotic syndrome, gene sequencing should be considered, in addition to renal biopsy, as early as possible. Timely diagnosis of COQ8B nephropathy and early supplementation of sufficient CoQ10 can help control the progression of the disease and significantly improve the prognosis.

Clinical manifestations, prognosis, and treat-to-target assessment of pediatric lupus nephritis.

BACKGROUND: Pediatric lupus nephritis (pLN) is one of the most refractory secondary kidney diseases in childhood. The treat-to-target (T2T) strategy has become the standard treatment for systemic lupus erythematosus (SLE). This study reviewed clinical features, overall remission status, and factors affecting prognosis, to guide pLN management according to T2T strategy. METHODS: This single-center retrospective study studied 220 children diagnosed with LN from January 2012 to December 2018, with > 6-month follow-up data on 173 and complete data on 137 patients. Primary outcome was treatment failure (deterioration or no response) at the latest follow-up. RESULTS: The most common pLN manifestation was proteinuria (81.36%). Females presented more often with rash (P<0.001) and alopecia (P=0.026) than males. Class IV LN (33.33%) was the most common grade on kidney biopsy. Median follow-up was 27.20 months (IQR, 15.78-44.45 months). One-, 3-, and 5-year cumulative overall survival rates were 93.5%, 87.8%, and 86.5%, respectively. The 5-year cumulative kidney survival rate was 97.1%. Regarding initial therapy, efficacy of corticosteroids combined with immunosuppressive agents was significantly better than corticosteroids alone (P=0.010). Factors with P<0.05 in univariate analysis, including hypoalbuminemia, higher SCr at diagnosis, lower eGFR at diagnosis, anti-dsDNA positivity, heavy proteinuria, hypertension, nervous-system involvement, treatment non-compliance, and SLEDAI-2K score, were used for logistic regression analysis. Logistic regression analysis showed hypertension (OR=0.845, P=0.011), nervous-system involvement (OR=4.240, P=0.005), treatment non-compliance (OR=6.433, P=0.001), and lower estimated glomerular filtration rate at diagnosis (OR=1.020, P=0.021) affected prognosis. At end of follow-up, 34.31% achieved varying levels of remission, and 8.76% were in low disease activity state (LDAS). CONCLUSIONS: pLN usually presented with proteinuria, and class IV LN was the dominant pathology. Hypertension, nervous-system involvement, treatment non-compliance, and lower eGFR at diagnosis were independent risk factors for poor prognosis of kidney outcomes. Compared with renal remission rate and cumulative overall survival rate, the proportion of targets achieved was not ideal, suggesting T2T strategy should be used to guide pLN management. A higher resolution version of the Graphical abstract is available as Supplementary information.

Nimbolide attenuated the inflammation in the liver of autoimmune hepatitis's mice through regulation of HDAC3.

A chronic liver disease named autoimmune hepatitis (AIH) will carry elevated levels of inflammatory cytokines, but there is currently no effective treatment to cure it. Histone deacetylase 3 (HDAC3) takes an important position in regulating the expression of inflammatory genes. Nimbolide (NIB) is a limonoid extracted from the neem tree (Azadirachta indica) that has been found to be effective against many diseases, including cancer, scleroderma, and acute respiratory distress syndrome. Here, we investigated the protective effect of nimbolide on AIH liver. Mice and AML12 cells were employed to establish AIH model with liver antigen S100 and cell injury model of LPS, and then treated with different concentrations of nimbolide. After the successful establishment of the animal model and cell model, inflammatory cytokines of IL-1ß, IL-6 and TNF-α as well as cellular signaling related to inflammation such as STAT3, IκB-α and NF-κB were examined. We observed for the first time about nimbolide can effectively inhibit inflammation in AIH mice's liver and AML12 cells by inhibiting HDAC3 expression. HDAC3 knocked down by siRNA in cells can also effectively alleviate the inflammation in AML12 cells, further confirming that HDAC3 plays an important role in the inflammation of liver cells. These results suggest nimbolide could be a potential new treatment for autoimmune hepatitis, and HDAC3 may become a new target for autoimmune hepatitis.

GPX4-Regulated Ferroptosis Mediates S100-Induced Experimental Autoimmune Hepatitis Associated with the Nrf2/HO-1 Signaling Pathway.

Autoimmune hepatitis (AIH) is an inflammatory autoimmune disease of the liver. Oxidative stress triggered by reactive oxygen radicals is a common pathophysiological basis for the pathogenesis of many liver diseases, and ferroptosis is associated with the toxic accumulation of reactive oxygen species. The signaling transduction pathways responsible for iron processing and lipid-peroxidation mechanisms are believed to drive ferroptosis. However, the specific mechanisms regulating ferroptosis remain unclear. The aims of this investigation were to identify the possible effector functions of ferroptosis, based on glutathione peroxidase 4 (GPX4) regulation in an S100-induced autoimmune hepatitis mouse model and hepatocyte injury models. The S100 liver antigen-induced AIH mouse model was used to detect ferroptotic biomarkers using western blotting. Upregulated levels of cyclooxygenase2 (COX2) and Acyl-Coenzyme A synthase long-chain family member 4 (ACSL4) were observed in the S100-induced AIH model group, while levels of GPX4 and ferritin heavy chain 1 (FTH1) were downregulated (P < 0.05). The expression profiles of COX2, ACSL4, GPX4, and FTH1 were restored following the administration of ferrostatin-1. In addition, Nrf2 and HO-1 levels in the S100-induced AIH model mice after treatment with ferrostatin-1 were downregulated compared to the nonferrostatin-1-treated S100-induced AIH model mice (P < 0.05). Moreover, COX2 and ACSL4 levels were significantly upregulated, with significant FTH1 downregulation, in the AIH model mice when liver-specific GPX4 was silenced using AAV8 constructs. These data indicate that inhibition of ferroptosis significantly ameliorated the influence of AIH on the Nuclear factor E2-related factor 2 (Nrf2)/Heme oxygenase-1 (HO-1) signaling pathway, and that ferroptosis may act as an initiator or intermediate mediator leading to AIH.