Quality of life in disease-free survived patients with early-stage extranodal nasal-type NK/T-cell lymphoma after definitive intensity-modulated radiotherapy: a cross-sectional study of 310 cases.

PURPOSE: Radiotherapy is a critical treatment for early-stage extranodal nasal-type NK/T-cell lymphoma (ENKTL) and has yielded favorable survival outcomes. However, their postradiotherapy quality of life (QOL) has not been investigated. Here, we conducted a cross-sectional study to assess the QOL of ENKTL patients with disease-free survival after definitive radiotherapy and to identify factors associated with QOL and treatment optimization. METHODS: This cross-sectional study included 310 patients with stage I-II ENKTL of the upper aerodigestive tract (UADT) who had received simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) with a consistent design and achieved disease-free survival. The median postradiotherapy time was 47.2 months (range, 3.1-115.7). The EORTC QLQ-H&N35 questionnaire was used to assess symptom-related QOL, and nine additional items were added to incorporate nasal, optical, and aural-related symptoms. The scores indicate the severity of the symptoms. RESULTS: The most common postradiotherapy symptoms among patients with ENKTL were nose problems (49.7%), dry mouth (44.8%), tooth problems (41.3%), sensory problems (32.6%), and less sexuality (25.8%). Tooth problems had the highest average score of 18.6, which is still acceptable. The severity of these symptoms decreased over time and reached a plateau in the second year after radiotherapy. Multivariable regression analysis showed that whole-neck irradiation was an independent predictive factor for xerostomia (P = 0.013, OR = 1.114), while age > 60 years was a predictive factor for lower sexuality (P < 0.001, OR = 1.32). CONCLUSION: The QOL of patients with early-stage ENKTL after radiotherapy was favorable, and most symptoms improved over time. Radiotherapy was correlated with specific symptoms, which may suggest a direction for further improvement in SIB-IMRT.

Proper phosphorylation of septin 12 regulates septin 4 and soluble adenylyl cyclase expression to induce sperm capacitation.

Septin-based ring complexes maintain the sperm annulus. Defective annular structures are observed in the sperm of Sept12- and Sept4-null mice. In addition, sperm capacitation, a process required for proper fertilization, is inhibited in Sept4-null mice, implying that the sperm annulus might play a role in controlling sperm capacitation. Hence, we analyzed sperm capacitation of sperm obtained from SEPT12 Ser196 phosphomimetic (S196E), phosphorylation-deficient (S196A), and SEPT4-depleted mutant mice. Capacitation was reduced in the sperm of both the Sept12 S196E- and Sept12 S196A-knock-in mice. The protein levels of septins, namely, SEPT4 and SEPT12, were upregulated, and these proteins were concentrated in the sperm annulus during capacitation. Importantly, the expression of soluble adenylyl cyclase (sAC), a key enzyme that initiates capacitation, was upregulated, and sAC was recruited to the sperm annulus following capacitation stimulation. We further found that SEPT12, SEPT4, and sAC formed a complex and colocalized to the sperm annulus. Additionally, sAC expression was reduced and disappeared in the annulus of the SEPT12 S196E- and S196A-mutant mouse sperm. In the sperm of the SEPT4-knockout mice, sAC did not localize to the annulus. Thus, our data demonstrate that SEPT12 phosphorylation status and SEPT4 activity jointly regulate sAC protein levels and annular localization to induce sperm capacitation.

A novel prognostic nomogram for adult acute lymphoblastic leukemia: a comprehensive analysis of 321 patients.

The cure rate of acute lymphoblastic leukemia (ALL) in adolescents and adults remains poor. This study aimed to establish a prognostic model for ≥14-year-old patients with ALL to guide treatment decisions. We retrospectively analyzed the data of 321 ALL patients between January 2017 and June 2020. Patients were randomly (2:1 ratio) divided into either the training or validation set. A nomogram was used to construct a prognostic model. Multivariate Cox analysis of the training set showed that age > 50 years, white blood cell count > 28.52×109/L, and MLL rearrangement were independent risk factors for overall survival (OS), while platelet count >37×109/L was an independent protective factor. The nomogram was established according to these independent prognostic factors in the training set, where patients were grouped into two categories: low-risk (≤13.15) and high-risk (>13.15). The survival analysis, for either total patients or sub-group patients, showed that both OS and progression-free survival (PFS) of low-risk patients was significantly better than that of high-risk patients. Moreover, treatment analysis showed that both OS and progression-free survival (PFS) of ALL with stem cell transplantation (SCT) were significantly better than that of ALL without SCT. Further stratified analysis showed that in low-risk patients, the OS and PFS of patients with SCT were significantly better than those of patients without SCT. In contrast, in high-risk patients, compared with non-SCT patients, receiving SCT can only significantly prolong the PFS, but it does not benefit the OS. We established a simple and effective prognostic model for ≥ 14-year-old patients with ALL that can provide accurate risk stratification and determine the clinical strategy.

Detecting Genetic Ancestry and Adaptation in the Taiwanese Han People.

The Taiwanese people are composed of diverse indigenous populations and the Taiwanese Han. About 95% of the Taiwanese identify themselves as Taiwanese Han, but this may not be a homogeneous population because they migrated to the island from various regions of continental East Asia over a period of 400 years. Little is known about the underlying patterns of genetic ancestry, population admixture, and evolutionary adaptation in the Taiwanese Han people. Here, we analyzed the whole-genome single-nucleotide polymorphism genotyping data from 14,401 individuals of Taiwanese Han collected by the Taiwan Biobank and the whole-genome sequencing data for a subset of 772 people. We detected four major genetic ancestries with distinct geographic distributions (i.e., Northern, Southeastern, Japonic, and Island Southeast Asian ancestries) and signatures of population mixture contributing to the genomes of Taiwanese Han. We further scanned for signatures of positive natural selection that caused unusually long-range haplotypes and elevations of hitchhiked variants. As a result, we identified 16 candidate loci in which selection signals can be unambiguously localized at five single genes: CTNNA2, LRP1B, CSNK1G3, ASTN2, and NEO1. Statistical associations were examined in 16 metabolic-related traits to further elucidate the functional effects of each candidate gene. All five genes appear to have pleiotropic connections to various types of disease susceptibility and significant associations with at least one metabolic-related trait. Together, our results provide critical insights for understanding the evolutionary history and adaption of the Taiwanese Han population.

Cyclin-Dependent Kinase 9 Inhibition as a Potential Treatment for Hepatocellular Carcinoma.

PURPOSE: Composite cyclin-dependent kinase (CDK) inhibition has shown potential as a treatment for hepatocellular carcinoma (HCC) in preclinical studies. We tested whether the specific inhibition of CDK9 was effective against HCC. METHODS: The effects of two specific CDK9 inhibitors, BAY1143572 and AZD4573, in HCC cell lines were examined. We tested the in vivo efficacy of CDK9 inhibition in mouse xenograft models of HuH7 human HCC cells and in an orthotopic model of BNL mouse HCC cells. Overexpression and knockdown of CDK9 were performed to confirm the efficacy of CDK9 inhibition. RESULTS: CDK9 inhibitors exhibited potent antiproliferative activities in HCC cells regardless of the levels of c-myc expression while inhibiting the downstream signals of CDK9, such as the phosphorylation of RNA polymerase II. These 2 CDK9 inhibitors induced apoptosis in HCC cells and reduced the expression of antiapoptotic proteins such as myeloid cell leukemia-1 and survivin. In the xenograft studies, mice receiving either CDK9 inhibitor exhibited significantly slower tumor growth than did the mice receiving vehicles. In the orthotopic model, the HCC growth in mice receiving a CDK9 inhibitor also tended to be slower than that in the control group. Overexpression of CDK9 in HuH7 cells reduced the efficacy of both CDK9 inhibitors. Knockdown of CDK9 expression reduced the proliferative activities of HCC cells. CONCLUSION: We demonstrated the in vitro and in vivo activity of CDK9 inhibition on multiple HCC cell lines. Our data support further clinical development of CDK9 inhibitors as a treatment for HCC.

Harnessing Natural Products by a Pharmacophore-Oriented Semisynthesis Approach for the Discovery of Potential Anti-SARS-CoV-2 Agents.

Natural products possessing unique scaffolds may have antiviral activity but their complex structures hinder facile synthesis. A pharmacophore-oriented semisynthesis approach was applied to (-)-maoelactone A (1) and oridonin (2) for the discovery of anti-SARS-CoV-2 agents. The Wolff rearrangement/lactonization cascade (WRLC) reaction was developed to construct the unprecedented maoelactone-type scaffold during semisynthesis of 1. Further mechanistic study suggested a concerted mechanism for Wolff rearrangement and a water-assisted stepwise process for lactonization. The WRLC reaction then enabled the creation of a novel family by assembly of the maoelactone-type scaffold and the pharmacophore of 2, whereby one derivative inhibited SARS-CoV-2 replication in HPA EpiC cells with a low EC50 value (19±1 nM) and a high TI value (>1000), both values better than those of remdesivir.

The association between BMI, smoking, drinking and thyroid disease: a cross-sectional study in Wuhan, China.

BACKGROUND: There is no clear conclusion on the relationship between thyroid disease and obesity and lifestyle factors such as smoking and drinking. In this study, we analysed the association of body mass index (BMI), smoking and drinking with subclinical hypothyroidism (SHO) and thyroid nodules (TNs) with the results of a cross-sectional survey of urban residents in central China and discussed the potential mechanism linking these predictive factors and the two diseases. METHODS: This study included 1279 participants who were recruited from a Chinese community in 2011 and 2012. A questionnaire, laboratory examination and ultrasound diagnosis were conducted on these participants. Binary logistic regression analysis was used to analyse these factors. RESULTS: Overweight (BMI ≥ 25 kg/m2) was closely related to SHO and TNs in univariate and multivariate logistic regression analyses. Smoking had a protective effect on SHO and TNs, while drinking had a protective effect on TNs in univariate logistic regression and multivariate logistic regression with some covariates, but there was no significant difference between smoking and drinking and the two kinds of thyroid diseases in multivariate logistic regression analysis with all the covariates. In subgroup analysis, BMI ≥ 25 kg/m2 was significantly associated with SHO in people with positive thyroid antibodies (odds ratio (OR) = 2.221, 95 % confidence interval (CI): 1.168-4.184, P = 0.015) and smokers (OR = 2.179, 95 % CI: 1.041-4.561, P = 0.039). BMI ≥ 25 kg/m2 was significantly associated with TNs in people over 60 years old (OR = 2.069, 95 % CI: 1.149-3.724, P = 0.015) and drinkers (OR = 3.065, 95 % CI: 1.413-6.648, P = 0.005). Drinking alcohol had a protective effect on TNs in smokers (OR = 0.456, 95 % CI: 0.240-0.865, P = 0.016) and people with BMI ≥ 25 kg/m2 (OR = 0.467, 95 % CI: 0.236-0.925, P = 0.029). No significant association was found between smoking and the two thyroid diseases in different subgroups. CONCLUSIONS: Obesity is a risk factor for both TNs and SHO, especially in elderly individuals and people with positive thyroid autoantibodies. Obesity and metabolic syndrome may be more associated with TNs than SHO. Smoking may have a protective effect on thyroid disease, while drinking may have a protective effect only on TNs.

The SEPT12 complex is required for the establishment of a functional sperm head-tail junction.

The connecting pieces of the sperm neck link the flagellum and the sperm head, and they are important for initiating flagellar beating. The connecting pieces are important building blocks for the sperm neck; however, the mechanism of connecting piece assembly is poorly understood. In the present study, we explored the role of septins in sperm motility and found that Sept12D197N knock-in (KI) mice produce acephalic and immotile spermatozoa. Electron microscopy analysis showed defective connecting pieces in sperm from KI mice, indicating that SEPT12 is required for the establishment of connecting pieces. We also found that SEPT12 formed a complex with SEPT1, SEPT2, SEPT10 and SEPT11 at the sperm neck and that the D197N mutation disrupted the complex, suggesting that the SEPT12 complex is involved in the assembly of connecting pieces. Additionally, we found that SEPT12 interacted and colocalized with γ-tubulin in elongating spermatids, implying that SEPT12 and pericentriolar materials jointly contribute to the formation of connecting pieces. Collectively, our findings suggest that SEPT12 is required for the formation of striated columns, and the capitulum and for maintaining the stability of the sperm head-tail junction.

Clinical characteristics and outcomes of COVID-19 patients with gastrointestinal symptoms admitted to Jianghan Fangcang Shelter Hospital in Wuhan, China.

Coronavirus disease 2019 (COVID-19) is a health emergency worldwide, and gastrointestinal (GI) symptoms are increasingly reported in COVID-19 patients. However, sample size was small and the incidence of GI symptoms in patients was variable across studies, and the correlation between these symptoms and clinical outcomes remains incompletely understood. The objective of this study is to compare clinical characteristics and outcomes between patients with and without GI symptoms admitted to Jianghan Fangcang Shelter Hospital in Wuhan. This retrospective study recruited 1320 COVID-19 patients admitted to hospital from 5 February 2020 to 9 March 2020. On the basis of the presence of GI symptoms, the sample was divided into a GI group (n = 192) and a non-GI group (n = 1128). The three most common GI symptoms were diarrhea (8.1%), anorexia (4.7%), and nausea and vomiting (4.3%). The rate of clinical deterioration was significantly higher in the GI group than in the non-GI group (15.6% vs. 10.1%, P = .032). GI symptoms (P = .045), male gender P < .001), and increased C-reactive protein (P = .008) were independent risk factors for clinical worsening. This study demonstrated that the rate of clinical deterioration was significantly higher in the GI group. Furthermore, potential risk factors for developing GI symptoms, male gender, and increased C-reactive protein can help clinicians predict clinical outcomes in COVID-19 patients.

SEPT12 phosphorylation results in loss of the septin ring/sperm annulus, defective sperm motility and poor male fertility.

Septins are critical for numerous cellular processes through the formation of heteromeric filaments and rings indicating the importance of structural regulators in septin assembly. Several posttranslational modifications (PTMs) mediate the dynamics of septin filaments in yeast. However, little is known about the role of PTMs in regulating mammalian septin assembly, and the in vivo significance of PTMs on mammalian septin assembly and function remains unknown. Here, we showed that SEPT12 was phosphorylated on Ser198 using mass spectrometry, and we generated SEPT12 phosphomimetic knock-in (KI) mice to study its biological significance. The homozygous KI mice displayed poor male fertility due to deformed sperm with defective motility and loss of annulus, a septin-based ring structure. Immunohistochemistry of KI testicular sections suggested that SEPT12 phosphorylation inhibits septin ring assembly during annulus biogenesis. We also observed that SEPT12 was phosphorylated via PKA, and its phosphorylation interfered with SEPT12 polymerization into complexes and filaments. Collectively, our data indicate that SEPT12 phosphorylation inhibits SEPT12 filament formation, leading to loss of the sperm annulus/septin ring and poor male fertility. Thus, we provide the first in vivo genetic evidence characterizing importance of septin phosphorylation in the assembly, cellular function and physiological significance of septins.

Sinusoidal Single-Pixel Imaging Based on Fourier Positive-Negative Intensity Correlation.

Single-pixel imaging techniques extend the time dimension to reconstruct a target scene in the spatial domain based on single-pixel detectors. Structured light illumination modulates the target scene by utilizing multi-pattern projection, and the reflected or transmitted light is measured by a single-pixel detector as total intensity. To reduce the imaging time and capture high-quality images with a single-pixel imaging technique, orthogonal patterns have been used instead of random patterns in recent years. The most representative among them are Hadamard patterns and Fourier sinusoidal patterns. Here, we present an alternative Fourier single-pixel imaging technique that can reconstruct high-quality images with an intensity correlation algorithm using acquired Fourier positive-negative images. We use the Fourier matrix to generate sinusoidal and phase-shifting sinusoid-modulated structural illumination patterns, which correspond to Fourier negative imaging and positive imaging, respectively. The proposed technique can obtain two centrosymmetric images in the intermediate imaging course. A high-quality image is reconstructed by applying intensity correlation to the negative and positive images for phase compensation. We performed simulations and experiments, which obtained high-quality images, demonstrating the feasibility of the methods. The proposed technique has the potential to image under sub-sampling conditions.

Epigenetic inactivation of HOXD10 is associated with human colon cancer via inhibiting the RHOC/AKT/MAPK signaling pathway.

BACKGROUND: To examine the influence of HOXD10 on the metabolism and growth of colon carcinoma cells by suppressing the RHOC/AKT/MAPK pathway. METHODS: Thirty-seven paired colon cancer and its adjacent samples from The Cancer Genome Atlas (TCGA) were analyzed. Chip Analysis Methylation Pipeline (ChAMP) analysis was employed for differential methylated points (DMPs) and the differential methylation regions (DMRs) screening. The HOXD10 mRNA expression and DNA methylation levels were detected by RT-PCR. The Cell proliferation, migration, invasion and apoptosis were respectively measured by MTT assay, transwell assay, wound healing assay and flow cytometry assay in carcinoma cell lines after treated with 5-aza-2'-deoxycytidine (5-Aza-dC) or transfected with HOXD10-expressing plasmid. The expression of HOXD10 and RHOC was revealed by immunohistochemistry in disparate differentiation colon carcinoma tissues, and the dephosphorylation of AKT and MAPK pathways were detected by RT-PCR and western blot. RESULTS: The bioinformatics analysis demonstrated that HOXD10 was hypermethylated and low-expressed in colorectal cancer tissues. The detection of RT-PCR indicated the similar results in colorectal cancer cell lines and tissues. The induction of demethylation was recovered by treatment with 5-Aza-dC and the HOXD10 in colorectal cancer cell lines was re-expressed by transfection with a HOXD10 expression vector. The demethylation or overexpression of HOXD10 suppressed proliferation, migration, invasion and promoted apoptosis in colorectal cancer cells. HXOD10 suppressed the tumor growth and detected an opposite trend of protein RHOC. AKT and MAPK pathways were notably inactivated after the dephosphorylation due to the overexpression of HOXD10. CONCLUSIONS: HOXD10 was suppressed in colon adenocarcinoma cells, which down-regulated RHOC/AKT/MAPK pathway to enhance colon cancer cells apoptosis and constrain the proliferation, migration and invasion.

Occurrence of Plasmid- and Chromosome-Carried mcr-1 in Waterborne Enterobacteriaceae in China.

The aim of this study was to investigate the prevalence of the polymyxin resistance gene mcr-1 in Enterobacteriaceae from environmental water sources in Hangzhou, China. Colistin-resistant bacteria were isolated from environmental water samples using an enrichment broth culture method, were screened for mcr-1, and then were analyzed for the location and transferability of mcr-1 Isolates positive for mcr-1 were further examined to determine their susceptibility profiles and were screened for the presence of additional resistance genes. Twenty-three mcr-1-positive isolates (16 Escherichia coli, two Citrobacter freundii, two Klebsiella oxytoca, two Citrobacter braakii, and one Enterobacter cloacae) were isolated from 7/9 sampling locations; of those, eight mcr-1-positive isolates also contained ß-lactamase-resistance genes, eight contained qnrS, and 10 contained oqx No mcr-2-positive isolates were identified. The majority of isolates demonstrated a low to moderate level of colistin resistance. Transconjugation was successfully conducted from 14 of the 23 mcr-1-positive isolates, and mcr-1 was identified on plasmids ranging from 60 to 220 kb in these isolates. Conjugation and hybridization experiments revealed that mcr-1 was chromosome-borne in only three isolates. Pulsed-field gel electrophoresis showed that the majority of E. coli isolates belonged to different clonal lineages. Multilocus sequence typing analysis revealed that sequence type 10 (ST10) was the most prevalent, followed by ST181 and ST206. This study demonstrates the utility of enrichment broth culture for identifying environmental mcr-1-positive isolates. Furthermore, it highlights the importance of responsible agriculture and clinical use of polymyxins to prevent further widespread dissemination of polymyxin-resistant pathogens.

YLL056C from Saccharomyces cerevisiae encodes a novel protein with aldehyde reductase activity.

The short-chain dehydrogenase/reductase (SDR) family, the largest family in dehydrogenase/reductase superfamily, is divided into "classical," "extended," "intermediate," "divergent," "complex," and "atypical" groups. Recently, several open reading frames (ORFs) were characterized as intermediate SDR aldehyde reductase genes in Saccharomyces cerevisiae. However, no functional protein in the atypical group has been characterized in S. cerevisiae till now. Herein, we report that an uncharacterized ORF YLL056C from S. cerevisiae was significantly upregulated under high furfural (2-furaldehyde) or 5-(hydroxymethyl)-2-furaldehyde concentrations, and transcription factors Yap1p, Hsf1p, Pdr1/3p, Yrr1p, and Stb5p likely controlled its upregulated transcription. This ORF indeed encoded a protein (Yll056cp), which was grouped into the atypical subgroup 7 in the SDR family and localized to the cytoplasm. Enzyme activity assays showed that Yll056cp is not a quinone or ketone reductase but an NADH-dependent aldehyde reductase, which can reduce at least seven aldehyde compounds. This enzyme showed the best Vmax, Kcat, and Kcat/Km to glycolaldehyde, but the highest affinity (Km) to formaldehyde. The optimum pH and temperature of this enzyme was pH 6.5 for reduction of glycolaldehyde, furfural, formaldehyde, butyraldehyde, and propylaldehyde, and 30 °C for reduction of formaldehyde or 35 °C for reduction of glycolaldehyde, furfural, butyraldehyde, and propylaldehyde. Temperature and pH affected stability of this enzyme and this influence varied with aldehyde substrate. Metal ions, salts, and chemical protective additives, especially at high concentrations, had different influence on enzyme activities for reduction of different aldehydes. This research provided guidelines for study of more uncharacterized atypical SDR enzymes from S. cerevisiae and other organisms.

Research Advancements in the Interplay between T3 and Macrophages.

3,3',5-Triiodo-L-thyronine (T3) is a key endocrine hormone in the human body that plays crucial roles in growth, development, metabolism, and immune function. Macrophages, the key regulatory cells within the immune system, exhibit marked "heterogeneity" and "plasticity", with their phenotype and function subject to modulation by local environmental signals. The interplay between the endocrine and immune systems is well documented. Numerous studies have shown that T3 significantly target macrophages, highlighting them as key cellular components in this interaction. Through the regulation of macrophage function and phenotype, T3 influences immune function and tissue repair in the body. This review comprehensively summarizes the regulatory actions and mechanisms of T3 on macrophages, offering valuable insights into further research of the immunoregulatory effects of T3.

Trillium tschonoskii rhizome saponin improves spatial learning and memory by enhancing neurovascular restorative in ischemic rats.

BACKGROUND: Trillium tschonoskii rhizome saponins (TSTT) has been significantly effective in treating traumatic injury, neurasthenia, cancer and inflammatory diseases as a folk medicine. However, the mechanism regarding to TSTT induced the neurovascular restorative after ischemia is without fully elucidated. PURPOSE: This research was constructed to study the value of TSTT in promoting endogenous repair of neurovascular and augmenting the ability of spatial study and memory retention in ischaemic rats. STUDY DESIGN: The improvement of TSTT on cerebral infraction and perfusion was observed by magnetic resonance imaging (MRI) experiments and the molecular mechanisms were further explored. METHODS: First, rats were ligated the middle cerebral artery to construct a permanent ischaemia model, subsequently intragastric injection administrated with TSTT (120, 60, 30 mg kg-1) at 6 h after operation, then once a day during next 30 days. Morris water maze was applied to observe the neurobehavioral changes. Multimodal MRI sequences were performed to monitoring brain injuries as well as cerebral blood flow. Histopathological staining was employed to evaluate the morphological changes of neurons. Transmission electron microscopy (TEM) was employed to detect the neurons, vascular structure, and synapse. Immunofluorescent staining was utilized to evaluate the endogenous repair progress. The axonal growth-inhibitors and axonal guidance cues were analyzed using western blotting. RESULTS: Contrast to the model group, TSTT declined the infarction and elevated the parenchymal volume. Notably, treated with TSTT significantly decreased the ADC (ipsilateral/contralateral). In histopathologic examination, TSTT prominently boosted amounts of cortical and striatal nerve cells and protected ultrastructure of neurovascular unit. According with results of nuclear magnetic imaging, TSTT enhanced endogenous repair progress. Especially, TSTT treatments obviously inhibited protein levels of NogoA/NgR/RhoA/ROCK2, accompanied by increased expression of Netrin/DCC and Slit2/Robo1. CONCLUSION: To sum up, our data illustrated that TSTT promoted cerebral reestablishment. The above result was in line with improving cerebral blood flow, elevated integrity of neurovascular structure, accelerating endogenous restoration and impairing the axonal growth inhibitors NogoA/NgR/RhoA/ROCK2 signaling, thereby improving poststroke learning and memory.

Cyclin dependent kinase 9 inhibition reduced programmed death-ligand 1 expression and improved treatment efficacy in hepatocellular carcinoma.

The anti-programmed death-ligand 1 (PD-L1) antibody is a standard therapy for advanced hepatocellular carcinoma (HCC). Tumor expression of PD-L1 can be induced upon stimulus. Because cyclin-dependent kinase 9 (CDK9) inhibition reduces the expression of inducible proteins, we explored the influence of CDK9 inhibition on PD-L1 expression in HCC cells. We found that PD-L1 expression was low in HCC cells; however, IFN-γ treatment increased this expression. CDK9 inhibitors AZD4573 and atuveciclib reduced the IFN-γ induced PD-L1 expression in a dose-dependent manner. CDK9 knockdown yielded similar results, but CDK9 overexpression reversed the influence of the CDK9 inhibitors. In the orthotopic mouse model, mice treated with a CDK9 inhibitor and an anti-PD-L1 antibody had significantly smaller tumors and exhibited longer survival than mice treated with either agent. In conclusion, CDK9 inhibition could reduce the expression of PD-L1 in HCC cells. Using both CDK9 inhibitors and anti-PD-L1 antibodies is more effective than using either agent alone.

Schisandrin A alleviates renal fibrosis by inhibiting PKCß and oxidative stress.

BACKGROUND: Renal fibrosis is a common pathway that drives the advancement of numerous kidney maladies towards end-stage kidney disease (ESKD). Suppressing renal fibrosis holds paramount clinical importance in forestalling or retarding the transition of chronic kidney diseases (CKD) to renal failure. Schisandrin A (Sch A) possesses renoprotective effect in acute kidney injury (AKI), but its effects on renal fibrosis and underlying mechanism(s) have not been studied. STUDY DESIGN: Serum biochemical analysis, histological staining, and expression levels of related proteins were used to assess the effect of PKCß knockdown on renal fibrosis progression. Untargeted metabolomics was used to assess the effect of PKCß knockdown on serum metabolites. Unilateral Ureteral Obstruction (UUO) model and TGF-ß induced HK-2 cells and NIH-3T3 cells were used to evaluate the effect of Schisandrin A (Sch A) on renal fibrosis. PKCß overexpressed NIH-3T3 cells were used to verify the possible mechanism of Sch A. RESULTS: PKCß was upregulated in the UUO model. Knockdown of PKCß mitigated the progression of renal fibrosis by ameliorating perturbations in serum metabolites and curbing oxidative stress. Sch A alleviated renal fibrosis by downregulating the expression of PKCß in kidney. Treatment with Sch A significantly attenuated the upregulated proteins levels of FN, COL-I, PKCß, Vimentin and α-SMA in UUO mice. Moreover, Sch A exhibited a beneficial impact on markers associated with oxidative stress, including MDA, SOD, and GSH-Px. Overexpression of PKCß was found to counteract the renoprotective efficacy of Sch A in vitro. CONCLUSION: Sch A alleviates renal fibrosis by inhibiting PKCß and attenuating oxidative stress.

Astragaloside IV promotes cerebral tissue restoration through activating AMPK- mediated microglia polarization in ischemic stroke rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Astragaloside IV (AS), a key active ingredient obtained from Chinese herb Astragalus mongholicus Bunge, exerts potent neuroprotective and anti-inflammatory effects for treating neurodegenerative diseases. However, mechanisms of AS on improvement of ischemic brain tissue repair remain unclear. AIM OF THE STUDY: This research aims at using magnetic resonance imaging (MRI) to noninvasively determine whether AS facilitates brain tissue repair, and investigating whether AS exerts brain remodeling through adenosine monophosphate-activated protein kinase (AMPK) metabolic signaling regulating key glycolytic enzymes and energy transporters, thereby impacting microglia polarization. MATERIALS AND METHODS: Ischemic stroke model in male Sprague-Dawley rats were induced through permanent occlusion of the middle cerebral artery (MCAO). Infarct volume, the alterations of brain microstructure and nerve fibers reorganization were examined by multi-parametric MRI. The pathological damages of myelinated axons and microglia polarization surrounding infarct tissue were detected using pathological techniques. Furthermore, M1/M2 microglia polarization associated protein, glycolytic rate-limiting enzymes, energy transporters and AMPK/mammalian target of rapamycin (mTOR)/hypoxia inducible factor-1α (HIF-1α) signal were examined both in ischemic stroke rats and BV2 microglia treated with lipopolysaccharide (LPS) + interferon-γ (IFN-γ) by western blotting. RESULTS: MRI revealed that AS obviously decreased infarct volume, relieved brain microstructure damage and improved nerve fibers reorganization in ischemic stroke rats. Histological tests supported MRI findings. Notably, AS promoted microglia M2 and reduced M1 polarization, induced the AMPK activation accompanied with decreased levels of phosphorylated mTOR and HIF-1α. Moreover, AS suppressed the expression of glycolytic rate-limiting enzymes and energy transporters in ischemic stroke rats and BV2 microglia. In contrast, these beneficial effects were greatly blocked by AMPK inhibitor compound C. CONCLUSION: Overall, these results collectively suggested that AS facilitated tissue remodeling that may be partially through modulating polarization of microglia in AMPK- dependent metabolic pathways after ischemic stroke.