[Short-term clinical efficacy observation of lesion removal, bone graft fusion, and external brace treatment for late-stage wrist tuberculosis].

OBJECTIVE: To observe the clinical efficacy of lesion removal, bone grafting, fusion, and external fixation in the treatment of late-stage wrist tuberculosis. METHODS: From October 2015 to May 2019, 25 patients with late-stage wrist tuberculosis were treated using lesion removal, bone grafting, fusion, and external fixation. Among these patients, there were 14 males and 11 females, aged from 40 to 74 years old, with an average age of (60.72±8.45) years old. The duration of the disease ranged from 5 to 24 months, with an average of (11.52±7.61) months. There were 11 cases of left wrist tuberculosis and 14 cases of right wrist tuberculosis, with 5 cases accompanied by sinus formation. Postoperative regular anti-tuberculosis treatment was continued. Visual analogue score (VAS), inflammatory indicators, Gartland-Werley wrist function score, and upper limb function score were observed before and after treatment. RESULTS: All 25 patients were followed up for ranging from 12 to 36 months with an average of (19.7±6.3) months. At the latest follow-up, all wounds were healed satisfactorily, and there was no recurrence of tuberculosis or infection. VAS at one week before operation and three months after operation were (5.16±1.14) score and (1.68±0.80) score respectively. One week before operation and three months after operation, erythrocyte sedimentation rate (ESR) was (44.20±20.56) mm·h-1 and (14.44±1.14) mm·h-1, and C-reactive protein (CRP) was (12.37±7.95) mg·L-1 and (4.3±3.37) mg·L-1. The differences in all three data sets were statistically significant (P<0.01). According to Gartland-Werley wrist function scoring, the scores at one week before operation and one year after operation were (21.32±3.44) and (14.96±1.37) respectively, showed a statistically significant difference (P<0.01). According to the upper limb function score (disabilities of the arm, shoulder, and hand, DASH), the score was (70.52±7.95) at one week before operation and(28.84±2.30) at one year after operation. The difference was statistically significant (P<0.01). At the latest follow-up, no patient had a recurrence of tuberculosis. CONCLUSION: The short-term clinical efficacy of treating wrist tuberculosis with lesion removal, bone grafting, fusion, and external fixation is satisfactory.

Inhibitory interaction of flavonoids with organic anion transporter 3 and their structure-activity relationships for predicting nephroprotective effects.

The organic anion transporter 3 (OAT3), an important renal uptake transporter, is associated with drug-induced acute kidney injury (AKI). Screening and identifying potent OAT3 inhibitors with little toxicity in natural products, especially flavonoids, in reducing OAT3-mediated AKI is of great value. The five strongest OAT3 inhibitors from the 97 flavonoids markedly decreased aristolochic acid I-induced cytotoxicity and alleviated methotrexate-induced nephrotoxicity. The pharmacophore model clarified hydrogen bond acceptors and hydrophobic groups are the critical pharmacophores. These findings would provide valuable information in predicting the potential risks of flavonoid-containing food/herb-drug interactions and optimizing flavonoid structure to alleviate OAT3-related AKI.

The effects of implicit emotion on the use of theory of mind among college students in China.

This research aims to study the impact of implicit emotion on the use of theory of mind and enrich the research on emotions and the use of theory of mind, thus allowing adults to apply theory of mind more effectively in the context of social interaction. This study includes 120 college students as participants. A two (level of theory of mind: high vs. low) * three (implicit emotional state: implicit positive emotion, implicit neutral emotion, or implicit negative emotion) * two (private knowledge: endowed vs. unendowed) between-subjects three-factor design was employed. This study obtained the following results: (1) The main effect of different implicit emotional states on college students' use of theory of mind is significant. College students with implicit positive emotions use theory of mind much less than those with implicit neutral and negative emotions. (2) In cases of implicit positive emotions, college students with a low level of theory of mind use theory of mind substantially less than students with a high level of theory of mind. In cases of implicit neutral and negative emotions, college students with the high and low theory of mind do not exhibit substantial differences in their use of theory of mind. This study concludes that different emotional states affect college students' use of theory of mind.

Oat Peptides Alleviate Dextran Sulfate Sodium Salt-Induced Colitis by Maintaining the Intestinal Barrier and Modulating the Keap1-Nrf2 Axis.

The prevalence of inflammatory bowel disease (IBD) is progressively rising each year, emphasizing the significance of implementing rational dietary interventions for disease prevention. Oats, being a staple agricultural product, are abundant in protein content. This study aimed to investigate the protective effects and underlying mechanisms of oat peptides (OPs) in a mouse model of acute colitis induced by dextran sulfate sodium salt (DSS) and a Caco-2 cell model. The findings demonstrated that intervention with OPs effectively mitigated the symptoms associated with DSS-induced colitis. The physicochemical characterization analysis demonstrated that the molecular weight of the OPs was predominantly below 5 kDa, with a predominant composition of 266 peptides. This study provides further evidence of the regulatory impact of OPs on the Keap1-Nrf2 signaling axis and elucidates the potential role of WGVGVRAERDA as the primary bioactive peptide responsible for the functional effects of OPs. Ultimately, the results of this investigation demonstrate that OPs effectively mitigate DSS-induced colitis by preserving the integrity of the intestinal barrier and modulating the Keap1-Nrf2 axis. Consequently, these findings establish a theoretical foundation for the utilization of OPs as dietary supplements to prevent the onset of IBD.

Discovery, Optimization, and Evaluation of Novel N-(Benzimidazol-5-yl)-1,3,4-thiadiazol-2-amine Analogues as Potent STAT3 Inhibitors for Cancer Treatment.

Signal transducer and activator of transcription 3 (STAT3) is an attractive target for cancer therapy. However, identifying potent and selective STAT3 small-molecule inhibitors with drug-like properties remains challenging. Based on a scaffold combination strategy, compounds with a novel N-(benzimidazol-5-yl)-1,3,4-thiadiazol-2-amine scaffold were designed and their inhibition of the interleukin-6 (IL-6)/JAK/STAT3 pathway was tested in HEK-Blue IL-6 reporter cells. After optimization of lead compound 12, compound 40 was identified as a selective STAT3 inhibitor that directly binds the SH2 domain to inhibit STAT3 phosphorylation, translocation, and downstream gene transcription. Compound 40 exhibited antiproliferative activities against STAT3-overactivated DU145 (IC50 value = 2.97 µM) and MDA-MB-231 (IC50 value = 3.26 µM) cancer cells and induced cell cycle arrest and apoptosis. In the DU145 xenograft model, compound 40 showed in vivo antitumor efficacy following intraperitoneal administration, with a tumor growth inhibition rate of 65.3% at 50 mg/kg, indicating promise for further development.

Proximity ligation-transcription circuit-powered exponential amplifications for single-molecule monitoring of telomerase in human cells.

We develop a new strategy for single-molecule monitoring of telomerase based on proximity ligation-transcription circuit-powered exponential amplifications. This strategy exhibits high sensitivity with a detection limit of 0.1 aM for the synthetic telomerase product TPC4 in vitro and 1 HeLa cell in vivo. Moreover, it can screen potential inhibitors, discriminate telomerase from interferents, and distinguish cancer cells from normal cells.

Structure-Switchable Hairpin-Powered Exponential Replications for Sensing Attomolar microRNA-Related Single Nucleotide Polymorphisms in Human Cancer Tissues with Zero Background.

MicroRNA (miRNA)-related single-nucleotide polymorphisms (miR-SNPs) are a novel class of genetic variations involved in multiple cellular functions, and they have emerged as promising biomarkers for cancer diagnostics and prognostics. Herein, we demonstrate for the first time the structure-switchable hairpin-powered exponential replications for sensing attomolar miR-SNPs in human cancer tissues with zero background. In the presence of target miR-196a2T, hairpin probes (i.e., HP1 and HP2) are splinted together to construct the dumbbell-shaped probe (DSP) with SplintR ligase catalysis. Once the DSP is formed, the self-primed polymerization extension and linear FIP/BIP-primed strand displacement DNA synthesis (SDS) are automatically repeated to activate self-circulated exponential amplification, producing large amounts of double-stranded DNAs (dsDNAs) which can be real-time monitored using SYBR Green I. This nanodevice can detect miR-196a2T with an ultralow detection limit of 2.46 aM; distinguish rare miR-196a2 SNP with a selectivity factor of 0.001%; and even profile miR-196a2T in human tissues for nonsmall cell lung cancer (NSCLC) diagnosis, risk assessment, and cancer type prediction. Notably, this nanodevice can be rapidly and homogeneously used in one tube in a real-time and label-free manner, providing a powerful point-of-care platform for noninvasive diagnostics and prognostics of miR-SNPs-related human cancers.

[Application of multimodal neuroelectrophysiological monitoring technology in surgical treatment of thoracic tuberculosis].

OBJECTIVE: To explore the value of multimodal neuroelectrophysiological monitoring technology in the evaluation of spinal cord and nerve root function for the treatment of thoracic tuberculosis with debridement and bone grafting and posterior internal fixation by transcostal transverse process approach. METHODS: The clinical data of 25 patients with thoracic tuberculosis underwent debridement and bone grafting and posterior vertebral arch internal fixation by transcostal transverse process approach from December 2018 to September 2019 was retrospectively analyzed. Among these 25 patients, including 14 males and 11 females;aged from 20 to 83 years old, with a mean of (63.45±9.65) years;there were 3 cases of single vertebral body destruction, 13 cases of 2 vertebral bodies destruction, and 9 cases of 3 or more vertebral bodies destruction. All surgical patients underwent intraoperative detection of somatosensory evoked potential(SEP) and transcranial electric stimulation-motor evoked potential(TES-MEP);and electromyography (EMG) was used to monitor the pedicle screw placement and lesion removal. The erythrocyte sedimentation rate(ESR) was used to evaluate the decline of inflammatory indexes, the visual analogue scale (VAS) was used to evaluate the thoracic spine pain, and the Cobb angle and Oswestry Disability Index(ODI) were used to evaluate the improvement of function. RESULTS: All 25 patients were successfully monitored. Five patients had abnormal SEP waveforms during operation, 3 cases were caused by intraoperative clearing of lesions and spinal cord compression during irrigation, timely replacement of instruments and gestures, and adjustment of irrigation water flow rate returned the waveform to normal; one case was caused by a decrease in systolic blood pressure, and the waveform returned to normal after timely treatment of increased blood pressure;after 1 case of SEP waveform abnormality, the operation was suspended for 10 minutes and recovered spontaneously, and the waveform abnormality did not reappear until the end of the operation. Seven patients had abnormal TES-MEP waveforms, 5 cases occurred when the pedicle screw was inserted, the nail path was adjusted in time, and the waveform recovered after nail repositioning;one case was caused by tilting the operation bed during operation, and the waveform gradually recovered after adjusting the tilt angle of operation bed; one case occurred during the correction of the pedicle screw and rod system, and the waveform gradually returned to normal after the contralateral screw and rod correction were completed during operation. In 5 cases, the EMG burst potential was detected at the same time when the TES-MEP waveform was abnormal. After adjustment, the EMG burst potential disappeared. There was no abnormality in the TES-MEP and SEP waveforms at the same time. Postoperative VAS, ESR, Cobb angle, and ODI were improved compared with preoperatively (P<0.05). CONCLUSION: In patients with thoracic tuberculosis, the use of debridement and bone grafting and posterior internal fixation by transcostal transverse process approach combined with intraoperative SEP, TES-MEP and EMG monitoring can timely reflect the spinal cord and nerve root function, avoid intraoperative injuries while achieving good fixation and lesion removal.

Neutrophil-to-Lymphocyte Ratio and Treatment Failure in Peritoneal Dialysis-Associated Peritonitis.

Objective: We sought to explore if there is an association between neutrophil-to-lymphocyte ratio (NLR) and treatment failure in patients with peritoneal dialysis-associated peritonitis (PDAP). Methods: Our cohort involved 337 episodes of PDAP experienced by 202 patients who were undergoing continuous ambulatory peritoneal dialysis at a single center from 1 July 2013 to 30 June 2018. The exposures were log-transformed NLR and a categorical variable grouped by the tertiles of NLR levels (T1, <3.75; T2, 3.75-6.53; and T3, >6.53) at baseline. Generalized estimating equation (GEE) and restricted cubic spline (RCS) analyses were done to determine the association between NLR and treatment failure, defined as catheter removal or all-cause mortality during therapy. Results: After adjusting for other potential predictors, the log-transformed NLR exhibited an incremental relationship with the risk of treatment failure (odds ratio, 1.82; 95% confidence interval, 1.05-3.15). RCS analyses showed that the relationship was positively and linearly correlated (P for nonlinearity = 0.104). As a three-level categorical variable, in reference to T1, the T3 of NLR showed a 3.41-fold increased venture of treatment failure in fully adjusted model. Subgroup analyses suggested that the prognostic relevance of NLR in PDAP was particularly significant in gram-negative peritonitis. Conclusions: A greater level of NLR at baseline was remarkably associated with a higher incidence of treatment failure among PDAP episodes regardless of other potential risk factors.

Multi-modal Neuroelectrophysiological Monitoring in the Treatment of Thoracic Tuberculosis with Debridement and Bone Grafting and Posterior Pedicle Screw Fixation via Costal Transverse Process Approach.

OBJECTIVE: To explore the value of multi-mode neuroelectrophysiological monitoring (MIOM) in evaluating spinal cord and nerve root function in the treatment of thoracic tuberculosis via costal transverse process approach. METHODS: From December 2017 to September 2019, a retrospective study of thoracic tuberculosis patients in our hospital was conducted. This study included 25 patients (14 men and 11 women). The average age of patients at the time of surgery was 63.3 years (range, 20-83 years). All patients (three cases with the destruction of a single vertebral body, 13 cases with the destruction of two vertebral bodies, and nine cases with the destruction of three or more vertebral bodies) underwent costal transverse process approach with debridement and bone grafting and internal fixation combined with intraoperative multimodal neuroelectrophysiological monitoring. During the operation, somatosensory evoked potential (SEP), transcranial electrical stimulation motor evoked potential (TES-MEP), and spontaneous electromyography (EMG) were used to monitor progress. ESR, visual analogue scale (VAS), Cobb angle, and Oswestry disability index (ODI) were statistically analyzed to evaluate the treatment effects and patient satisfaction. RESULTS: All 25 patients were successfully monitored. The follow-up time ranged from 12 to 21 months, with an average of 15.3 months. SEP waveform abnormalities occurred in five patients during the operation, the incidence rate was 28%. Of these five patients, three patients changed their instruments and postures, and adjusted the flushing water flow in time; one patient received pressure therapy in time; the operation was suspended for 10 min for one patient. There were seven cases with abnormal TES-MEP waveform, the incidence rate was 28%. Among these seven cases, five cases adjusted the nail path during the operation and adjusted the nail position in time. One case adjusted the inclination angle of the operating table in time; one case completed the contralateral nail stick correction in time; five of them had abnormal TES-MEP waveforms, and EMG burst potential was also detected, the incidence rate was 20%. After prompt treatment, the abnormal waveforms of all patients returned to normal; no abnormal waveforms, recurrence of tuberculosis, loosening of internal fixation, nerve and spinal cord dysfunction, etc. The VAS score, erythrocyte sedimentation rate (ESR), Cobb angle, and ODI scores of the patients 1 year after operation were significantly improved compared with 1 week after operation (P < 0.05). CONCLUSION: Multi-mode intraoperative electrophysiological detection combined with costal transverse process approach for the treatment of thoracic tuberculosis could avoid intraoperative nerve and blood vessel damage, reduce surgical risk, improve surgical efficiency, and ensure curative effect.

Prevalence and risk factors of relapse in patients with ANCA-associated vasculitis receiving cyclophosphamide induction: a systematic review and meta-analysis of large observational studies.

BACKGROUND: Clinical relapses are common in patients with ANCA-associated vasculitis (AAV). The aim of this systematic review was to estimate time-point prevalence and risk factors of relapse. METHODS: We searched PubMed, Embase, and Cochrane Library databases from their inception to March 30, 2020. Cohorts and post-hoc studies were included for the estimation of summary cumulative relapse rates (CRRs) and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs). Sensitivity and meta-regression analyses were also performed. RESULTS: Of the 42 eligible studies, 24 studies with 6236 participants were used for the pooled analyses of CRRs. The summary 1-year, 3-year, and 5-year CRRs were 0.12 (95% CI, 0.10-0.14), 0.33 (0.29-0.38), and 0.47 (0.42-0.52), respectively. In meta-regressions, the baseline age was positively associated with 1-year CRR. The proportion of granulomatosis with polyangiitis was positively associated with 5-year CRR. Twenty-eight studies with 5390 participants were used for the meta-analysis of risk factors for relapse, including a lower level of baseline serum creatine, proteinase 3 (PR3)-ANCA positivity at diagnosis, an ANCA rise, extrarenal organ involvement (including lung, cardiovascular, upper respiratory, and gastrointestinal involvement), intravenous (vs oral) cyclophosphamide induction, a shorter course of immunosuppressant maintenance, and maintenance with mycophenolate mofetil (vs azathioprine). CONCLUSIONS: Our systematic review demonstrated that the 1-year, 3-year, and 5-year cumulative probabilities of relapse were ∼12%, 33%, and 47% in AAV patients receiving cyclophosphamide induction, respectively. Early identification of risk factors for relapse is helpful to the risk stratification of patients so as to achieve personalized treatment.

Hdc-expressing myeloid-derived suppressor cells promote basal-like transition and metastasis of breast cancer.

Metastases are the greatest contributors to death from breast cancer. Here, we identified a distinct subpopulation of luminal breast cancer characterized by cytokeratin 14 (CK14) expression in secondary colonies rather than primary tumors. This entity possessed a poorer prognosis compared to their CK14- counterparts. Immunohistochemical analysis showed that myeloid-derived suppressor cells (MDSCs) were recruited into the tumor microenvironment and exhibited a close spatial relationship with CK14+ cancer cells. We demonstrated that histidine decarboxylase (Hdc) is capable of labeling myeloid-biased hematopoietic stem cell/progenitor cell (HSC/HSPC) and immature myeloid cells infiltrating in tumor tissues. FACS data obtained from Hdc-CreERT2; eGFP; MMTV-PyVT female mice revealed an increased percentage of Hdc+ PMN-MDSCs in metastatic masses. Hdc+ PMN-MDSCs expressed high levels of canonical Wnts, including Wnt2, Wnt4, Wnt5a, and Wnt7b, to aberrantly activate Wnt/ß-catenin signaling in CK14+ malignant cells. ß-catenin translocated from the membrane into the cytoplasm and nucleus. Targeted ablation of Hdc+ PMN-MDSCs-derived Wnts through porcupineflox/flox and iDTR transgenic models hampered the metastatic cascade, making Hdc+ immature myeloid cells an attractive candidate for tailed immunotherapies.

Significance of Neutrophil Gelatinase-Associated Lipocalin as a Biomarker for the Diagnosis of Diabetic Kidney Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is a promising marker for the diagnosis of diabetic kidney disease (DKD), but its utility is currently debated. This meta-analysis aims to evaluate the diagnostic value of NGAL for DKD. METHOD: MEDLINE, Embase, -Cochrane Library, CNKI, and CBM databases were searched up to April 13, 2019. In bivariate random-effect models, the diagnostic performance of NGAL for DKD was assessed using pooled estimates of sensitivity, specificity, likelihood ratio, diagnostic odds ratio, and hierarchical summary receiver-operating characteristic analysis. RESULTS: Nineteen studies were eligible for the meta-analysis. Serum NGAL had a pooled sensitivity and specificity of 0.79 (95% confidence intervals [CI] 0.60-0.91) and 0.87 (0.75-0.93) (7 studies, 1,238 patients). The pooled positive likelihood ratio (LR+) and negative likelihood ratio (LR-) were 5.97 (3.03-11.76) and 0.24 (0.11-0.51). For urine NGAL, the pooled sensitivity, specificity, LR+, and LR- were 0.85 (0.74-0.91), 0.74 (0.57-0.86), 3.26 (1.87-5.67), and 0.21 (0.12-0.35), respectively (10 studies, 1,369 patients). The pooled sensitivity and specificity for kidney disease in normoalbuminuric patients with diabetes was 0.90 (0.82-0.95) and 0.97 (0.90-0.99) for both serum NGAL and 0.94 (0.87-0.98) and 0.90 (0.81-0.96) for urine NGAL (4 studies, 221 patients). NGAL appeared to perform similarly in subgroup analysis. CONCLUSION: The meta-analysis has shown that NGAL may be useful for DKD classification and also has a potential diagnostic value for normoalbuminuric kidney disease. Large-scale prospective studies are required to clarify its role in the diagnosis and risk stratification of patients with DKD.

Red blood cell distribution width and peritoneal dialysis-associated peritonitis prognosis.

Objective: Red blood cell distribution width (RDW) is a parameter of the heterogeneity of circulating erythrocyte size. Recent researches have pointed out a link among RDW, chronic kidney disease, and inflammation. We sought to investigate the prognostic value of baseline RDW in patients with peritoneal dialysis-associated peritonitis (PDAP).Methods: Our study included 337 peritonitis episodes experienced by 202 patients who were undergoing continuous ambulatory peritoneal dialysis (CAPD) at a single center from 2013 to 2018. Episodes were categorized according to the tertiles of baseline RDW levels (T1, <13.2%; T2, 13.2-14.3%; T3, >14.3%). Routine logistic regression and generalized estimating equation (GEE) were used to estimate the association between RDW and treatment failure, which was defined as relapse/recurrent episodes, catheter removal, or death during therapy.Results: After adjusting for other potential predictors, RDW exhibited an incremental relationship with the risk of treatment failure. The baseline RDW of T3 indicated a 43% and 52% increased venture of treatment failure in logistic and GEE analyses, respectively, compared with T1. As a continuous variable, the fitting curve based on restricted cubic spiline showed that the relationship was nonlinearly but positively correlated. The multivariate model A (combined RDW with baseline age, albumin, serum ferritin, and duration on CAPD) showed an area under the curve of 0.671 (95% confidence interval, 0.5920.749) for the prediction of treatment failure.Conclusions: A Higher baseline level of RDW was significantly associated with a greater rate of treatment failure among PDAP episodes independent of other potential predictors.

Roles of differential expression of miR-543-5p in GH regulation in rat anterior pituitary cells and GH3 cells.

Growth hormone (GH) is an important hormone released by the pituitary gland that plays a key role in the growth and development of organisms. In our study, TargetScan analysis and the dual luciferase reporter assays were used to predict and screen for miRNAs that might act on the rat Gh1 gene, and we identified miR-543-5p. Then, the GH3 cell line and the primary rat pituitary cells were transfected with miRNA mimic, inhibitor, and siRNA. We detected the Gh1 gene expression and the GH secretion by real-time PCR and ELISAs, respectively, to verify the regulatory effect of miR-543-5p on GH secretion. The results showed that miR-543-5p can inhibit Gh1 mRNA expression and reduce GH secretion. MiR-543-5p inhibitor upregulated Gh1 mRNA expression and increased GH secretion compared with the negative control. In summary, miR-543-5p downregulates Gh1 expression, resulting in a decrease in GH synthesis and secretion, which demonstrates the important role of miRNAs in regulating GH and animal growth and development.

The involvement of blood cells in the phosphorylation of the selective sphingosine-1-phosphate receptor 1 agonist SYL-927.

SYL-927 is a selective sphingosine-1-phosphate receptor 1 (S1P1) agonist for autoimmune diseases. It undergoes phosphorylation to the active SYL-927-P in vivo, which activates S1P1 on lymphocytes, causing lymphopenia by retention of lymphocytes in the lymph nodes. The aim of this study was to identify the involvement of blood cells in the phosphorylation of SYL-927. In addition, pharmacokinetics of SYL-927 and SYL-927-P in blood and plasma were compared in rats. The results demonstrated that SYL-927 can be converted to SYL-927-P in rat blood, but not in rat plasma. However, both rat blood and plasma are capable of dephosphorylating SYL-927-P to SYL-927. SYL-927-P generation and release were observed after incubating SYL-927 with rat and human erythrocytes and platelets. The addition of sphingosine kinases (SPHKs) inhibitors N,N-dimethylsphingosine (DMS) and FTY720 significantly inhibited SYL-927-P generation, indicating the involvement of SPHKs. In addition, SYL-927 and SYL-927-P levels in blood were significantly higher than those in plasma after oral administration of SYL-927 in rats, suggesting the blood cells for the production of SYL-927-P. In summary, the blood cells such as erythrocytes and platelets contribute to the generation and release of SYL-927-P, which is important for maintaining plasma active phosphate levels for prolonged effects.

Cutaneous transcriptome analysis in NIH hairless mice.

Mice with spontaneous coat mutations are ideal animal models for studying skin development and tumorigenesis. In this study, skin hair growth cycle abnormalities were examined in NIH hairless mice 42 days after birth (P42) by using hematoxylin-eosin (H&E) staining. To examine the gene expression patterns in the skin of mutant mice, the dorsal skin of P42 female NIH mice and NIH hairless mice was sequenced by RNA-Seq, and 5,068 differentially expressed genes (DEGs) were identified (false discovery rate [FDR] ≥ 2, P < 0.05). A pathway analysis showed that basal cell carcinoma, the cell cycle and the Hippo, Hedgehog and Wnt signaling pathways were up-regulated in NIH hairless mice. Previous studies have shown that these pathways are closely associated with cell proliferation, cell cycle, organ size and cancer development. In contrast, signal transduction, bacterial and parasitic infection, and receptor-mediated pathways, including calcium signaling, were down-regulated in NIH hairless mice. A gene interaction network analysis was performed to identify genes related to hair follicle development. To verify the reliability of the RNA-Seq results, we used q-PCR to analyze 12 key genes identified from the gene interaction network analysis, including eight down-regulated and four up-regulated genes, and the results confirmed the reliability of the RNA-Seq results. Finally, we constructed the differential gene expression profiles of mutant mice by RNA-Seq. NIH hairless mice exhibited abnormalities in hair development and immune-related pathways. Pik3r1 and Pik3r3 were identified as key genes, laying the foundation for additional in-depth studies of hairless mice.

Analyzing the innate immunity of NIH hairless mice and the impact of gut microbial polymorphisms on Listeria monocytogenes infection.

Spontaneous mutant hairless (HL) mice are often used to study hair growth and hair follicle development, and they often exhibit immune dysfunctions. Listeria monocytogenes, an important food-borne bacterium, has been used in animal models to study immune responses to infection. Herein, we analyzed the innate immunity of HL mice and the impact of gut microbial polymorphisms on L. monocytogenes infection. Compared to NIH mice, NIH HL mice were more susceptible to L. monocytogenes, as weight losses, mortality, bacterial load, and histopathological lesions were more severe; the decrease in monocytes may be an important underlying reason. The degree of spleen damage was reduced after co-housing, indicating that the host guides the gut microbiota to alleviate infection. High-throughput pyrosequencing of 16S rRNA demonstrated that gut microbiota composition differed between NIH HL and NIH mice. Infection with L. monocytogenes induced an increase in the number of bacteria belonging to the Rikenellaceae family and Gammaproteobacteria class, and decreased bacteria belonging to the Clostridiales class and Lachnospiraceae family. A substantial reduction in Clostridiales bacteria in infected HL mice may cause a serious infection. The Mycoplasma genus was present only in NIH HL mice and was, thus, considered a biomarker. The results of this study improve our understanding of the use of NIH HL mice as a good animal model of innate immune dysfunction.

Analysis of epithelial-mesenchymal transition markers in the histogenesis of hepatic progenitor cell in HBV-related liver diseases.

BACKGROUND: The origin and heterogeneity of hepatic progenitor cells (HPCs) remain unclear. This study aimed to investigate the involvement of epithelial-mesenchymal transition (EMT) in the histogenesis of HPCs. METHODS: Surgical liver specimens from patients with HBV-related hepatitis and cirrhosis were investigated with double immunofluorescence labeling to detect antigens associated with HPCs and EMT. Ductular reactions were subjected to quantitative reverse transcription PCR following isolation by laser capture microdissection. Electron microscopic examination was performed to find an ultrastructural evidence of EMT. RESULTS: The number of EpCAM-positive HPCs was proportional to the disease severity. The S100A4 expression of HPCs was firstly observed in mild hepatitis and increased significantly in moderate hepatitis, but decreased in severe hepatitis and cirrhosis. The levels of MMP-2, Twist, and Snail increased in direct proportion to the number of HPCs. Some hepatocytes adjacent to portal tracts in cirrhosis showed positivity for MMP-2. Although CK7 and E-cadherin levels decreased in mild and moderate hepatitis, HPCs re-expressed both of them in severe hepatitis and cirrhosis. However, HPCs expressed neither vimentin nor αSMA. The relative mRNA expression levels of EpCAM and EMT-associated markers supported immunohistochemical results. Electron microscopic examination demonstrated the existence of intercellular junctions among HPCs, cholangiocytes, and intermediate hepatocyte-like cells. CONCLUSION: We provided preliminary evidence for the involvement of EMT in the histogenesis of HPCs from cholangiocytes in HBV-related liver diseases. HPCs may re-transdifferentiate into hepatocytes, and the differentiation direction depends, at least in part, on interactions between HPCs and the surrounding microenvironment, especially the non-resolving inflammation caused by HBV infection.

A Novel Parkinson's Disease Drug Candidate with Potent Anti-neuroinflammatory Effects through the Src Signaling Pathway.

Numerous drug treatments are available for Parkinson's disease (PD), an age-related neurodegenerative disease, but most cause serious side effects. Therefore, novel therapeutic strategies that halt disease progression and allow for long-term administration are urgently needed. Neuroinflammation critically contributes to the pathogenesis of PD. Here, we report the discovery and optimization of phloroglucinol derivatives, a novel class of anti-neuroinflammatory compounds. Structural modifications of the hit compound 3-methyl-1-(2,4,6-trihydroxyphenyl)butan-1-one produced 43 derivatives, including a preclinical candidate (compound 21), that exhibited potent in vitro anti-neuroinflammatory effects, good blood-brain barrier penetration, and desirable safety margins in mice at a median lethal dose (LD50) >5000 mg/kg. Its in vivo efficacy was demonstrated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- and MPTP/probenecid (prob)-induced subacute and chronic PD models, respectively, and α-synuclein transgenic mice. Mechanistic studies revealed neuroinflammation inhibition by targeting Src/phosphatase and tensin homologue deleted on chromosome 10 (PTEN)/Akt signaling might be promising. We highlighted the potential usefulness of phloroglucinol derivatives in PD treatment.