Developmental Dopaminergic Signaling Modulates Neural Circuit Formation and Contributes to Autism Spectrum Disorder-Related Phenotypes.

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder with a complex etiology. Recent evidence suggests that dopamine plays a crucial role in neural development. However, whether and how disrupted dopaminergic signaling during development contributes to ASD remains unknown. In this study, human brain RNA sequencing transcriptome analysis revealed a significant correlation between changes in dopaminergic signaling pathways and neural developmental signaling in ASD patients. In the zebrafish model, disrupted developmental dopaminergic signaling led to neural circuit abnormalities and behavior reminiscent of autism. Dopaminergic signaling may impact neuronal specification by potentially modulating integrins. These findings shed light on the mechanisms underlying the link between disrupted developmental dopamine signaling and ASD, and they point to the possibility of targeting dopaminergic signaling in early development for ASD treatment.

SPATA2 regulates the activation of RIPK1 by modulating linear ubiquitination.

Stimulation of cells with TNFα leads to the formation of the TNF-R1 signaling complex (TNF-RSC) to mediate downstream cellular fate decision. Activation of the TNF-RSC is modulated by different types of ubiquitination and may lead to cell death, including apoptosis and necroptosis, in both RIPK1-dependent and RIPK1-independent manners. Spata2 (spermatogenesis-associated 2) is an adaptor protein recruited into the TNF-RSC to modulate the interaction between the linear ubiquitin chain assembly complex (LUBAC) and the deubiquitinase CYLD (cylindromatosis). However, the mechanism by which Spata2 regulates the activation of RIPK1 is unclear. Here, we report that Spata2-deficient cells show resistance to RIPK1-dependent apoptosis and necroptosis and are also partially protected against RIPK1-independent apoptosis. Spata2 deficiency promotes M1 ubiquitination of RIPK1 to inhibit RIPK1 kinase activity. Furthermore, we provide biochemical evidence for the USP domain of CYLD and the PUB domain of the SPATA2 complex preferentially deubiquitinating the M1 ubiquitin chain in vitro. Spata2 deficiency also promotes the activation of MKK4 and JNK and cytokine production independently of RIPK1 kinase activity. Spata2 deficiency sensitizes mice to systemic inflammatory response syndrome (SIRS) induced by TNFα, which can be suppressed by RIPK1 inhibitor Nec-1s. Thus, Spata2 can regulate inflammatory response and cell death in both RIPK1-dependent and RIPK1-independent manners.

ZNF692 drives malignant development of hepatocellular carcinoma cells by promoting ALDOA-dependent glycolysis.

Hepatocellular carcinoma (HCC) is one of the malignancies with the worst prognosis worldwide, in the occurrence and development of which glycolysis plays a central role. This study uncovered a mechanism by which ZNF692 regulates ALDOA-dependent glycolysis in HCC cells. RT-qPCR and western blotting were used to detect the expression of ZNF692, KAT5, and ALDOA in HCC cell lines and a normal liver cell line. The influences of transfection-induced alterations in the expression of ZNF692, KAT5, and ALDOA on the functions of HepG2 cells were detected by performing MTT, flow cytometry, Transwell, cell scratch, and colony formation assays, and the levels of glucose and lactate were determined using assay kits. ChIP and luciferase reporter assays were conducted to validate the binding of ZNF692 to the KAT5 promoter, and co-IP assays to detect the interaction between KAT5 and ALDOA and the acetylation of ALDOA. ZNF692, KAT5, and ALDOA were highly expressed in human HCC samples and cell lines, and their expression levels were positively correlated in HCC. ZNF692, ALDOA, or KAT5 knockdown inhibited glycolysis, proliferation, invasion, and migration and promoted apoptosis in HepG2 cells. ZNF692 bound to the KAT5 promoter and promoted its activity. ALDOA acetylation levels were elevated in HCC cell lines. KAT5 bound to ALDOA and catalyzed ALDOA acetylation. ALDOA or KAT5 overexpression in the same time of ZNF692 knockdown, compared to ZNF692 knockdown only, stimulated glycolysis, proliferation, invasion, and migration and reduced apoptosis in HepG2 cells. ZNF692 promotes the acetylation modification and protein expression of ALDOA by catalyzing KAT5 transcription, thereby accelerating glycolysis to drive HCC cell development.

RACK1 promotes the occurrence and progression of cervical carcinoma.

BACKGROUND: RACK1 has been identified as a multifunctional cytosolic protein, and plays a pivotal role in multiple biological responses involved in several kinds of tumors, while its effect in cervical cancer has not been well elucidated yet. The study aimed to investigate the role of RACK1 in cervical cancer occurrence and progression. METHODS: The expression of RACK1 in cervical specimens was measured by immunohistochemical staining and Western blot assay. Transgenic mice were used to detect the role of RACK1 in modulating tumorigenesis in vivo. Cervical carcinoma cell lines were used to explore the underlying mechanisms of RACK1 on the behaviors of tumor cells in vitro. RESULTS: We found that RACK1 expression was upregulated in cancer tissues compared with adjacent tissues, and its expression was gradually increased from cervictis, and cervical intraepithelial neoplasis (CIN) to carcinoma. Genetic overexpression of RACK1 facilitated tumor formation and growth in nude mice. Mechanism studies disclosed that RACK1 over-expression prolonged the G0 /G1 phase by up-regulating the expression of cyclinD1, down-regulating p21 and p27 probably by modulating the phosphorylation of AKT. CONCLUSIONS: Taken together, we concluded that RACK1 stimulates tumorigenesis and progression of cervical cancer via modulating the proliferation of tumor cells, implying that targeting RACK1 may serve as a promising method for cervical cancer therapy.

USP14 regulates autophagy by suppressing K63 ubiquitination of Beclin 1.

The ubiquitin-proteasome system (UPS) and autophagy are two major intracellular degradative mechanisms that mediate the turnover of complementary repertoires of intracellular proteomes. Simultaneously activating both UPS and autophagy might provide a powerful strategy for the clearance of misfolded proteins. However, it is not clear whether UPS and autophagy can be controlled by a common regulatory mechanism. K48 deubiquitination by USP14 is known to inhibit UPS. Here we show that USP14 regulates autophagy by negatively controlling K63 ubiquitination of Beclin 1. Furthermore, we show that activation of USP14 by Akt-mediated phosphorylation provides a mechanism for Akt to negatively regulate autophagy by promoting K63 deubiquitination. Our study suggests that Akt-regulated USP14 activity modulates both proteasomal degradation and autophagy through controlling K48 and K63 ubiquitination, respectively. Therefore, regulation of USP14 provides a mechanism for Akt to control both proteasomal and autophagic degradation. We propose that inhibition of USP14 may provide a strategy to promote both UPS and autophagy for developing novel therapeutics targeting neurodegenerative diseases.

Tripartite motif-containing protein 11 promotes hepatocellular carcinogenesis through ubiquitin-proteasome-mediated degradation of pleckstrin homology domain leucine-rich repeats protein phosphatase 1.

BACKGROUND AND AIMS: HCC is one of the main types of primary liver cancer, with high morbidity and mortality and poor treatment effect. Tripartite motif-containing protein 11 (TRIM11) has been shown to promote tumor formation in lung cancer, breast cancer, gastric cancer, and so on. However, the specific function and mechanism of TRIM11 in HCC remain open for study. APPROACH AND RESULTS: Through clinical analysis, we found that the expression of TRIM11 was up-regulated in HCC tissues and was associated with high tumor node metastasis (TNM) stages, advanced histological grade, and poor patient survival. Then, by gain- and loss-of-function investigations, we demonstrated that TRIM11 promoted cell proliferation, migration, and invasion in vitro and tumor growth in vivo. Mechanistically, RNA sequencing and mass spectrometry analysis showed that TRIM11 interacted with pleckstrin homology domain leucine-rich repeats protein phosphatase 1 (PHLPP1) and promoted K48-linked ubiquitination degradation of PHLPP1 and thus promoted activation of the protein kinase B (AKT) signaling pathway. Moreover, overexpression of PHLPP1 blocked the promotional effect of TRIM11 on HCC function. CONCLUSIONS: Our study confirmed that TRIM11 plays an oncogenic role in HCC through the PHLPP1/AKT signaling pathway, suggesting that targeting TRIM11 may be a promising target for the treatment of HCC.

Survival benefit of surgery with postoperative radiotherapy in locally advanced cervical adenocarcinoma: a population-based analysis.

BACKGROUND: The incidence of cervical adenocarcinoma (AC) has experienced a considerable increase in recent decades. Despite this, our understanding of the optimal management of locally advanced cervical AC remains limited. The present study sought to compare the clinical outcomes of radical hysterectomy with postoperative radiotherapy (PORT) and primary radiotherapy (RT) in patients with locally advanced cervical AC using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: The data were extracted from the SEER database utilizing the SEER ∗ STAT software (version 8.4.0.1). The study included patients diagnosed with locally advanced cervical AC between 2004 and 2017 with adequate information available for analysis. Patients were assigned to either the Surgery + PORT or Primary RT group based on treatment modality, and their clinical characteristics were compared. Propensity score matching (PSM) was utilized to adjust for differences in baseline characteristics between groups. The primary endpoints of the study were overall survival (OS) and cancer-specific survival (CSS). RESULTS: Of the 1363 patients who met the inclusion criteria, 302 (22.16%) underwent Surgery + PORT, while 1061 patients received Primary RT. The two groups differed significantly in terms of age, year of diagnosis, tumor size, grade, stage, T/N stage, and chemotherapy. PSM was performed to balance the baseline characteristics between the two groups, resulting in 594 patients being analyzed. After PSM, the Surgery + PORT group exhibited significantly improved survival rates. The 5-year OS rates were 69.7% (95% CI: 63.3%-76.9%) for the Surgery + PORT group and 60.9% (95% CI: 56.0%-66.3%) for the group receiving Primary RT (p = 0.002). The 5-year CSS rates for the two groups were 70.7% (95% CI: 64.3%-77.8%) and 66.2% (95% CI: 61.3%-71.5%), respectively (p = 0.049). Multivariate analysis revealed that Surgery + PORT was an independent favorable prognostic factor for OS (HR = 0.60, p = 0.001) and CSS (HR = 0.69, p = 0.022). Although the combined approach of surgery and PORT resulted in a favorable impact on OS in patients aged 65 years or older (HR = 0.57, p = 0.048), it did not result in a statistically significant improvement in CSS in the same age group (HR = 0.56, p = 0.087). Similarly, the combined treatment did not yield a statistically significant increase in either OS (HR = 0.78, p = 0.344) or CSS (HR = 0.89, p = 0.668) in patients with tumors larger than 60 mm. CONCLUSION: The present study demonstrated that Surgery + PORT was associated with improved OS and CSS in patients with locally advanced cervical AC when compared to Primary RT. As such, Surgery + PORT may be a preferable therapeutic option for carefully selected patients with cervical AC. These findings offer valuable insight into the management of locally advanced cervical AC and may assist in personalized treatment decisions.

Chaperone-mediated autophagy is involved in the execution of ferroptosis.

Necroptosis and ferroptosis are two distinct necrotic cell death modalities with no known common molecular mechanisms. Necroptosis is activated by ligands of death receptors such as tumor necrosis factor-α (TNF-α) under caspase-deficient conditions, whereas ferroptosis is mediated by the accumulation of lipid peroxides upon the depletion/or inhibition of glutathione peroxidase 4 (GPX4). The molecular mechanism that mediates the execution of ferroptosis remains unclear. In this study, we identified 2-amino-5-chloro-N,3-dimethylbenzamide (CDDO), a compound known to inhibit heat shock protein 90 (HSP90), as an inhibitor of necroptosis that could also inhibit ferroptosis. We found that HSP90 defined a common regulatory nodal between necroptosis and ferroptosis. We showed that inhibition of HSP90 by CDDO blocked necroptosis by inhibiting the activation of RIPK1 kinase. Furthermore, we showed that the activation of ferroptosis by erastin increased the levels of lysosome-associated membrane protein 2a to promote chaperone-mediated autophagy (CMA), which, in turn, promoted the degradation of GPX4. Importantly, inhibition of CMA stabilized GPX4 and reduced ferroptosis. Our results suggest that activation of CMA is involved in the execution of ferroptosis.

Immunomodulatory effects of fentanyl and morphine on DSS- and TNBS-induced colitis.

BACKGROUND: Opioid prescription for inflammatory bowel disease (IBD)-related pain is on the rise. However, the use of strong opioids can result in severe complications, and even death, in IBD patients. This study aimed to define the role of fentanyl and morphine, two representative strong opioids, in the pathogenesis of dextran sodium sulfate (DSS)- and 2,4,6-trinitrobenzenesulfonic acid solution (TNBS)-induced colitis. METHOD: DSS and TNBS models were induced in C57BL/6J and Balb/c mice, respectively. Disease activity index (DAI), histopathology, enzyme-linked immunosorbent assay (ELISA), multiplex ELISA, and flow cytometry were performed to evaluate the effects of fentanyl and morphine. RESULT: Fentanyl exacerbated DSS- and TNBS-induced colitis, while morphine exhibited no significant immunomodulatory effect. Fentanyl and morphine had no obvious effects on the serum levels of adrenocorticotropic hormone (ACTH), glucocorticoid (GC), and prostaglandin E2 (PGE-2) in DSS and TNBS models. Fentanyl elevated the proportions of Th1 cells, µ-opioid receptor (MOR) + Th1 cells, and MOR + macrophages in the colonic mucosa of DSS-treated mice, and enhanced the proportions of Th1 cells, macrophages, MOR + Th1 cells, and MOR + macrophages in the colonic mucosa of TNBS-treated mice. We found that fentanyl upregulated the levels of inflammatory cytokines/chemokines in MOR + macrophages of the colonic lamina propria mononuclear cells (LPMCs) from DSS-treated mice, whereas it had no effect on the expression of most inflammatory cytokines/chemokines in MOR + macrophages in the colonic LPMCs from TNBS-treated mice. CONCLUSION: Our findings suggest that fentanyl exacerbates murine colitis via Th1 cell- and macrophage-mediated mechanisms, while morphine exhibits no significant immunomodulatory effect.

Gut mucosal virome alterations in ulcerative colitis.

OBJECTIVE: The pathogenesis of UC relates to gut microbiota dysbiosis. We postulate that alterations in the viral community populating the intestinal mucosa play an important role in UC pathogenesis. This study aims to characterise the mucosal virome and their functions in health and UC. DESIGN: Deep metagenomics sequencing of virus-like particle preparations and bacterial 16S rRNA sequencing were performed on the rectal mucosa of 167 subjects from three different geographical regions in China (UC=91; healthy controls=76). Virome and bacteriome alterations in UC mucosa were assessed and correlated with patient metadata. We applied partition around medoids clustering algorithm and classified mucosa viral communities into two clusters, referred to as mucosal virome metacommunities 1 and 2. RESULTS: In UC, there was an expansion of mucosa viruses, particularly Caudovirales bacteriophages, and a decrease in mucosa Caudovirales diversity, richness and evenness compared with healthy controls. Altered mucosal virome correlated with intestinal inflammation. Interindividual dissimilarity between mucosal viromes was higher in UC than controls. Escherichia phage and Enterobacteria phage were more abundant in the mucosa of UC than controls. Compared with metacommunity 1, metacommunity 2 was predominated by UC subjects and displayed a significant loss of various viral species. Patients with UC showed substantial abrogation of diverse viral functions, whereas multiple viral functions, particularly functions of bacteriophages associated with host bacteria fitness and pathogenicity, were markedly enriched in UC mucosa. Intensive transkingdom correlations between mucosa viruses and bacteria were significantly depleted in UC. CONCLUSION: We demonstrated for the first time that UC is characterised by substantial alterations of the mucosa virobiota with functional distortion. Enrichment of Caudovirales bacteriophages, increased phage/bacteria virulence functions and loss of viral-bacterial correlations in the UC mucosa highlight that mucosal virome may play an important role in UC pathogenesis.

AK000953 silencing can enhance the killing effect of danazol on uterine fibroids.

PURPOSE: Our aim was to study the role of AK000953 silencing for the killing effect of danazol on uterine fibroids. METHODS: Quantitative PCR was applied to identify differential expression of AK000953 in uterine fibroid tissue and normal uterine tissue. Then we isolated and cultured uterine fibroid cells, designed the siRNA of AK000953 to silence its expression in uterine fibroid cells, and detected the treatment effect of danazol and AK000953 siRNA on cell proliferation, cell apoptosis, and cell invasion. Finally, guinea pig model of uterine fibroids was constructed to verify the effect of AK000953 silencing on uterine fibroid treatment with danazol in vivo. RESULTS: Quantitative PCR showed that the AK000953 gene was highly expressed in uterine fibroid tissue compared with normal uterine tissue (2.1 ± 0.15 vs. 0.8 ± 0.05, p < 0.01). After AK000953 silencing in uterine fibroid cells, we discovered that the inhibition rate in danazol-siRNA group was 56 ± 5 %, the cell apoptosis rate of danazol-siRNA group was 43 ± 2.3 %, and the invasion rate of uterine fibroid cells was 12 ± 1 %, which all showed significant differences with the control group or danazol group. Guinea pig model confirmed that the treatment of danazol and AK000953 siRNA effectively inhibited the development of fibroids in vivo. CONCLUSION: AK000953 silencing could effectively enhance the killing effect of danazol on uterine fibroid cells.

High-Performance Flat-Panel Perovskite X-ray Detectors Enabled by Defect Passivation in Ruddlesden-Popper Perovskites.

Halide perovskites have emerged as promising candidates in X-ray detection due to their strong X-ray absorption and excellent optoelectronic properties. The development of sensitive and stable flat-panel X-ray detectors with high resolution is crucial for practical applications. In this paper, we introduce a novel flat-panel X-ray detector that integrates quasi-two-dimensional (2D) Ruddlesden-Popper (RP) perovskite with a pixeled thin film transistor (TFT) backplane. We incorporate 2,5-dibromopyrimidine (DBPM) as an additive to passivate the Lewis acid defects in the quasi-2D RP perovskite. This modification results in suppressed ion migration, improved optoelectronic performance, and enhanced operational stability of the device. Impressively, the activation energy of the RP perovskite increases from 0.96 to 1.35 eV with the DBPM additive. As a result, X-ray detectors exhibit a high sensitivity of ∼13,600 µC Gyair-1 cm-2, a low detection limit of 6.56 nGyair s-1, and excellent operational stability. Moreover, the flat-panel detectors demonstrate a high spatial resolution of 3.7 line pairs per millimeter and excellent X-ray imaging properties under a remarkably low X-ray dose of ∼50 µGyair, which is just half of the X-ray dose typically used in commercial equipment. This study opens new avenues for the development of flat-panel perovskite X-ray detectors with significant potential for various applications.

Platelet-to-lymphocyte and neutrophil-to-lymphocyte ratios are associated with the efficacy of immunotherapy in stage III/IV non-small cell lung cancer.

Peripheral serological indicators are novel markers associated with prognosis in multiple malignant tumors. In the present study, platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) were selected to construct a model that predicts long-term survival of patients with stage IIIB-IV non-small cell lung cancer (NSCLC) who received treatment with an anti-programmed cell death protein-1 (PD-1) monoclonal antibody. A total of 133 patients were eligible for the present retrospective study (January 2019-February 2021). The area under the receiver operating characteristic curve was used to compare the diagnostic value of PLR and NLR, and combined PLR and NLR. The objective response rate and disease control rate of each group were obtained and the differences were compared using the χ2 test. The prognostic value of these indicators was assessed using the Kaplan-Meier method. Cox regression analysis was used to evaluate risk factors associated with long-term survival. Statistically significant parameters were included in the nomogram. Based on the median PLR and NLR values, the patients were divided into high PLR (H-PLR) (PLR >200.00, 67 patients) and low PLR (L-PLR) (PLR ≤200.00, 66 patients), and high NLR (H-NLR) (NLR >3.56, 65 patients) and low NLR (L-NLR) (NLR ≤3.56, 68 patients) groups. Immune-related adverse events (irAEs) occurred in 22 patients (16.5%) during the observation period, including 18 grade 2-3 irAEs and 4 grade 4 cases. H-NLR and H-PLR were associated with poor progression-free (PFS) and overall survival (OS) in the present study. NLR was an independent prognostic factor for PFS [hazard ratio (HR): 0.201, 95% confidence interval (CI): 0.060-0.670; P=0.009) and OS (HR: 0.413, 95% CI: 0.226-0.754; P=0.004) in this patient group. Therefore, NLR may be used in the prognostication of patients with stage IIIB-IV NSCLC treated with PD-1 inhibitors. These serological markers may be used in combination with established immunomarkers to help predict outcomes.

Built environment impact on the per capita cycling frequency of family--Based on two-level hierarchical linear model.

At present, there is less attention paid to the relationship between the frequency of travel and built environment, especially in households. In this paper, some of the determining factors in the frequency of daily cycling per household were explored based on the data from 2018 Daily Trip Survey in Xianyang, China. Then a two-level linear model was construct to identify the determining factors in the frequency of per capita daily cycling of household. According to the research results, 22.8% of the differences in the per capita cycling frequency of household are due to the differences between communities. In terms of community factors, the densities of road networks and educational facilities delivered a significantly positive impact on the per capita daily cycling frequency of family; on the contrary, the densities of medical facilities, intersections and POI delivered a significantly negative impact. Per capita cycling frequency varies considerably between households. For instance, the number of bicycles owned and the number of school-age children have a significantly positive impact on the per capita daily cycling frequency of family. However, car ownership, household income and occupation composition impose a significantly negative impact. The findings of this study would benefit the transportation engineers and planners who are keen to boost the use of active means of transportation for residents.

Combretastatin A4-loaded Poly (Lactic-co-glycolic Acid)/Soybean Lecithin Nanoparticles with Enhanced Drug Dissolution Rate and Antiproliferation Activity.

OBJECTIVE: This study aimed to prepare combretastatin A4 (CA4)-loaded nanoparticles (CA4 NPs) using poly(lactic-co-glycolic acid) (PLGA) and soybean lecithin (Lipoid S100) as carriers, and further evaluate the physicochemical properties and cytotoxicities of CA4 NPs against cancer cells. METHODS: CA4 NPs were prepared using a solvent evaporation technique. The effects of formulations on CA4 NPs were investigated in terms of particle size, zeta potential, encapsulation efficacy, and drug loading. The physicochemical properties of CA4 NPs were characterized using transmission electron microscopy, X-ray powder diffraction, differential scanning calorimetry, and Fourier transform infrared spectra. The drug release from CA4NPs was performed using a dialysis method. In addition, the cytotoxicity of CA4NPs against human alveolar basal epithelial (A549) cells was also evaluated. RESULTS: CA4 NPs prepared with a low organic/water phase ratio (1:20) and high drug/PLGA mass ratio (1:2.5) exhibited a uniform hydrodynamic particle size of 142 nm, the zeta potential of -1.66 mV, and encapsulation efficacy and drug loading of 92.1% and 28.3%, respectively. CA4 NPs showed a significantly higher release rate than pure CA4 in pH 7.4 phosphate-buffered solution with 0.5% Tween 80. It was found that the drug molecules could change from the crystal state to an amorphous form when loaded into the PLGA/Lipoid S100 matrix, and some molecular interactions could also occur between the drug and PLGA. Importantly, CA4 NPs showed a remarkably higher antiproliferation activity against A549 cancer cells compared to pure CA4. CONCLUSION: These results suggested the promising potential of PLGA/Lipoid S100 nanoparticles as the drug delivery system of CA4 for effective cancer therapy.

PP6 negatively modulates LUBAC-mediated M1-ubiquitination of RIPK1 and c-FLIPL to promote TNFα-mediated cell death.

Activation of TNFR1 by TNFα induces the formation of a membrane-associated, intracellular complex termed complex I. Complex I orchestrates a complex pattern of modifications on key regulators of TNF signaling that collectively determines the cell fate by activating pro-survival or executing cell death programs. However, the regulatory mechanism of complex I in cell-fate decision is not fully understood. Here we identify protein phosphatase-6 (PP6) as a previously unidentified component of complex I. Loss of PP6 protects cells from TNFα-mediated cell death. The role of PP6 in regulating cell death requires its phosphatase activity and regulatory subunits. Further mechanistic studies show that PP6 modulates LUBAC-mediated M1-ubiquitination of RIPK1 and c-FLIPL to promote RIPK1 activation and c-FLIPL degradation. We also show that melanoma-associated PP6 inactivating mutants offer resistance to cell death due to the loss of sensitivity to TNFα. Thus, our study provides a potential mechanism by which melanoma-related PP6 inactivating mutations promote cancer progression.

Indirubin combined with umbilical cord mesenchymal stem cells to relieve psoriasis-like skin lesions in BALB/c mice.

Objective: To investigate the efficacy of indirubin combined with human umbilical cord mesenchymal stem cells (hUC-MSCs) in the treatment of psoriatic lesions in BALB/c mice and to explore the related mechanism of indirubin in the treatment of psoriasis. Methods: A BALB/c mouse psoriasis model induced by imiquimod was established and randomly divided into the control group, model group, indirubin group, hUC-MSCs group, and indirubin combined with hUC-MSCs group. Psoriasis area and severity index (PASI) score was used to observe skin lesion changes in the psoriasis-like mouse model. The epidermal scale, the degree of keratinization, and the infiltration of inflammatory cells were observed by hematoxylin eosin (HE) staining. The concentrations of TNF-α, IFN-γ, IL-17A, and IL-23 in serum of mice were measured using enzyme-linked immunosorbent assay (ELISA). Results: The PASI integral trend chart indicates that hUC-MSCs and indirubin and the combination of drugs could relieve the appearance of skin lesions and accelerate the recovery of skin lesions. The indirubin group had the best effect in improving the scale of skin lesions. HE staining showed that the number of parakeratosis cells in the three treatment groups was significantly reduced, the degree of erythrocyte extravasation dermis hyperplasia and inflammatory cell infiltration was significantly lower than that in the model group, and the skin thickness and spleen index of the combined treatment group exhibited the most noticeable improvement. ELISA showed that the concentrations of TNF-α, IFN-γ, IL-17A, and IL-23 in serum of mice in the hUC-MSCs treatment group, indirubin group, and combined administration group were all decreased compared with those in the model group, and the concentrations of IFN-γ, IL-17A, and IL-23 could be decreased significantly in the indirubin group. Conclusions: Both hUC-MSCs and indirubin can effectively reduce psoriasis-like lesions in BALB/c mice, and the combined administration of these drugs has the best effect.

Gut microbiota in the early stage of Crohn's disease has unique characteristics.

BACKGROUND: Emerging evidence suggests that gut microbiota plays a predominant role in Crohn's disease (CD). However, the microbiome alterations in the early stage of CD patients still remain unclear. The present study aimed to identify dysbacteriosis in patients with early CD and explore specific gut bacteria related to the progression of CD. METHODS: This study was nested within a longitudinal prospective Chinese CD cohort, and it included 18 early CD patients, 22 advanced CD patients and 30 healthy controls. The microbiota communities were investigated using high-throughput Illumina HiSeq sequencing targeting the V3-V4 region of 16S ribosomal DNA (rDNA) gene. The relationship between the gut microbiota and clinical characteristics of CD was analyzed. RESULTS: Differential microbiota compositions were observed in CD samples (including early and advanced CD samples) and healthy controls samples. Notably, Lachnospiracea_incertae_sedis and Parabacteroides were enriched in the early CD patients, Escherichia/Shigella, Enterococcus and Proteus were enriched in the advanced CD patients, and Roseburia, Gemmiger, Coprococcus, Ruminococcus 2, Butyricicoccus, Dorea, Fusicatenibacter, Anaerostipes, Clostridium IV were enriched in the healthy controls [LDA score (log10) > 2]. Furthermore, Kruskal-Wallis Rank sum test results showed that Blautia, Clostridium IV, Coprococcus, Dorea, Fusicatenibacter continued to significantly decrease in early and advanced CD patients, and Escherichia/Shigella and Proteus continued to significantly increase compared with healthy controls (P < 0.05). The PICRUSt analysis identified 16 remarkably different metabolic pathways [LDA score (log10) > 2]. Some genera were significantly correlated with various clinical parameters, such as fecal calprotectin, erythrocyte sedimentation rate, C-reactive protein, gland reduce, goblet cells decreased, clinical symptoms (P < 0.05). CONCLUSIONS: Dysbacteriosis occurs in the early stage of CD and is associated with the progression of CD. This data provides a foundation that furthers the understanding of the role of gut microbiota in CD's pathogenesis.

HBV Reactivation During the Treatment of Non-Hodgkin Lymphoma and Management Strategies.

Hepatitis B virus reactivation (HBV-R), which can lead to HBV-related morbidity and mortality, is a common and well-known complication that occurs during the treatment of non-Hodgkin lymphoma (NHL) patients with current or past exposure to HBV infection. HBV-R is thought to be closely associated with chemotherapeutic or immunosuppressive therapies. However, immunosuppressive agents such as anti-CD20 antibodies (e.g., rituximab and ofatumumab), glucocorticoids, and hematopoietic stem cell transplantation (HSCT) administered to NHL patients during treatment can cause deep immunodepression and place them at high risk of HBV-R. In this review, we explore the current evidence, the guidelines of several national and international organizations, and the recommendations of expert panels relating to the definition, risk factors, screening and monitoring strategies, whether to use prophylaxis or pre-emptive therapy, and the optimal antiviral agent and duration of antiviral therapy for HBV-R.