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Over 50% of patients with hepatitis B virus‐associated hepatocellular carcinoma (HBV‐HCC) are diagnosed at an advanced stage, which is characterized by immune imbalance between CD8+ T cells and regulatory T (Treg) cells that accelerates disease progression. However, there is no imbalance indicator to predict clinical outcomes. Here, we show that the proportion of CD8+ T cells decreases and Treg cells increases in advanced HBV‐HCC patients. During this stage, CD8+ T cells and Treg cells expressed the coinhibitory molecule PD‐1 and the costimulatory molecule ICOS, respectively. Additionally, the ratio between PD‐1+CD8 and ICOS+Tregs showed significant changes. Patients were further divided into high‐ and low‐ratio groups: PD‐1+CD8 and ICOS+Tregs high‐ (PD‐1/ICOShi) and low‐ratio (PD‐1/ICOSlo) groups according to ratio median. Compared with PD‐1/ICOSlo patients, the PD‐1/ICOShi group had better clinical prognosis and weaker CD8+ T cells exhaustion, and the T cell‐killing and proliferation functions were more conservative. Surprisingly, the small sample analysis found that PD‐1/ICOShi patients exhibited a higher proportion of tissue‐resident memory T (TRM) cells and had more stable killing capacity and lower apoptosis capacity than PD‐1/ICOSlo advanced HBV‐HCC patients treated with immune checkpoint inhibitors (ICIs). In conclusion, the ratio between PD‐1+CD8 and ICOS+Tregs was associated with extreme immune imbalance and poor prognosis in advanced HBV‐HCC. These findings provide significant clinical implications for the prognosis of advanced HBV‐HCC and may serve as a theoretical basis for identifying new targets in immunotherapy. [ABSTRACT FROM AUTHOR]

Cold stimulation is the most common stressor in cold regions. Continuous cold stimulation can cause a series of pathophysiological changes in the body, such as aggregated neutrophils, macrophage activation, and increased inflammatory factors, which is also a risk factor for erectile function impairment. In addition, necroptosis is an important form of programmed cell death. However, the mechanisms of necroptosis in erectile function impairment due to cold stimulation have been very poorly studied. Therefore, we explored the mechanism of tumor necrosis factor-α (TNF-α)-mediated receptor interacting protein kinase 1 (RIP1)/receptor interacting protein kinase 3 (RIP3) necroptosis pathway on erectile function among cold-stressed rats. First, we established a cold-stressed rat model using cold stimulation and selected those rats that had developed erectile function impairment. Then, we used Necrostatin-1 (RIP1 specific inhibitor, Nec-1), Etanercept (TNF-α inhibitor, Ent), and Sildenafil (Sil) to intervene for 14 days and subsequently assessed their erectile function by apomorphine test and sexual behavioural test. Lastly, we performed various molecular studies and histopathological analyses of penile tissues collected from these rats after the experiments. We found that erectile function was impaired in cold-stressed rats, with increased penile tissue fibrosis and elevated levels of TNF-α and necroptosis. Contrastingly, intervention with Nec-1 and Ent restored erectile function, reduced penile tissue fibrosis, and decreased TNF-α and necroptosis levels, consistent with the results of intervention with Sil. Based on these results, we confirmed that the TNF-α-mediated RIP1/RIP3 necroptosis pathway was significantly altered in cold-stressed rats. In conclusion, inhibition of the TNF-α-mediated RIP1/RIP3 necroptosis pathway improved erectile function, suggesting that the specific downstream mechanisms need to be further explored. [ABSTRACT FROM AUTHOR]

The existing discrete cosine transform (DCT) differential quantization robust watermarking has poor robustness against JPEG compression, cropping, and combined attacks. To improve such issues, a pair of adjacent block coefficients are selected to reduce the offset and improve the robustness of the watermarking. Firstly, at adjacent positions of neighboring blocks, the differences of medium frequency coefficients are calculated, and then the differences are used to divide regions. Experimental results show that this method is more robust to various attacks than the existing DCT differential quantization robust watermarking. The accuracy of watermark extraction under a JPEG compression attack increased by 2%, while the error rates of watermark extraction under a cropping attack and a combination attack decreased by 4.4% and 9%. [ABSTRACT FROM AUTHOR]

Dachshund homolog 1 (DACH1), a key cell-fate determinant, regulates transcription by DNA sequence-specific binding. We identified diminished Dach1 expression in a large-scale screen for mutations that convert injury-resistant podocytes into injury-susceptible podocytes. In diabetic kidney disease (DKD) patients, podocyte DACH1 expression levels are diminished, a condition that strongly correlates with poor clinical outcomes. Global Dach1 KO mice manifest renal hypoplasia and die perinatally. Podocyte-specific Dach1 KO mice, however, maintain normal glomerular architecture at baseline, but rapidly exhibit podocyte injury after diabetes onset. Furthermore, podocyte-specific augmentation of DACH1 expression in mice protects from DKD. Combined RNA sequencing and in silico promoter analysis reveal conversely overlapping glomerular transcriptomic signatures between podocyte-specific Dach1 and Pax transactivation-domain interacting protein (Ptip) KO mice, with upregulated genes possessing higher-than-expected numbers of promoter Dach7-binding sites. PTIP, an essential component of the activating histone H3 lysine 4 trimethylation (H3K4Me3) complex, interacts with DACH1 and is recruited by DACH1 to its promoter-binding sites. DACH1-PTIP recruitment represses transcription and reduces promoter H3K4Me3 levels. DACH1 knockdown in podocytes combined with hyperglycemia triggers target gene upregulation and increases promoter H3K4Me3. These findings reveal that in DKD, diminished DACH1 expression enhances podocyte injury vulnerability via epigenetic derepression of its target genes., Introduction Dachshund homolog 1 (DACH1) was originally identified as an essential member of the retinal determination gene network (RDGN), a fundamental signal that governs cell fate during development. That DACH1 [...]

Inflammation is a key contributor to diabetic kidney disease pathogenesis, including reactive oxidation stress (ROS)‐mediated nuclear factor‐κB (NF‐κB) signaling pathway. In this study, we examined the effect of Astragaloside IV (AS‐IV) on anti‐inflammatory and anti‐oxidative properties under high glucose (HG) condition and the potential mechanism in glomerular mesangial cells (GMCs). We showed that AS‐IV concentration‐dependently reduced GMCs proliferation, restrained ROS release and hydrogen peroxide content, and suppressed pro‐inflammatory cytokines as well as pro‐fibrotic factors expression, which were associated with the inhibition of NF‐κB and nuclear factor‐erythroid 2‐related factor 2 (Nrf2) signaling activation. Accordingly, both NF‐κB overexpression by using RNA plasmid and Nrf2 gene silencing by using RNA interference weakened the ability of AS‐IV to ameliorate HG‐induced oxidative stress, inflammation, and cell proliferation. Furthermore, phosphatidylinositide 3‐kinases (PI3K)/serine/threonine protein kinase (Akt) and extracellular regulated protein kinases (ERK) signaling pathway regulated the process of AS‐IV‐induced Nrf2 activation and antioxidant capacity, which evidenced by using PI3K inhibitor LY294002 or ERK inhibitor PD98059 that largely abolished the AS‐IV efficacy. Taken together, these results indicated that AS‐IV protected against HG‐induced GMCs damage by inhibiting ROS/NF‐kB‐induced increases of inflammatory cytokines, fibrosis biomarkers, and cell proliferation via up‐regulation of Nrf2‐dependent antioxidant enzyme expression, which were mediated by PI3K/Akt and ERK signaling pathway activation. [ABSTRACT FROM AUTHOR]

Background Inflammation is a key risk factor for heart disease and has also been linked to erectile dysfunction (ED). Sildenafil is a phosphodiesterase type 5 inhibitor with a strong antioxidant effect. Interleukin (IL)-18 is a proinflammatory factor. Excessive production and release of IL-18 disrupt the balance between IL-18 and IL-18 binding proteins in certain inflammatory diseases, leading to the occurrence of pathological inflammation. Aim We evaluated the effects of sildenafil on erectile function in a rat model of high-fat diet–induced ED. Methods Male Sprague Dawley rats (6 weeks old) were divided into 5 groups: control, ED, sildenafil, IL-18, and IL-18 + sildenafil. Subsequently, intracavernous pressure and mean arterial pressure were used to assess the erectile function of these rats. The expression of endothelial nitric oxide synthase, pyroptosis factors, and the ratio of smooth muscle cells and collagen fibers were evaluated in the serum and corpora tissue. Outcomes Exploring the role and mechanism of sildenafil in ED through NLRP3-mediated pyroptosis pathway. Results In comparison to the ED and IL-18 groups, there were statistically significant increases in the ratio of intracavernous pressure to mean arterial pressure, endothelial nitric oxide synthase expression, and the ratio of smooth muscle cells to collagen fibers following sildenafil intervention (P <.05). The sildenafil group and IL-18 + sildenafil group also showed statistically significant decreases the expression of NLRP3, caspase-1, and gasdermin D (P <.05). Clinical Implications Sildenafil can improve erectile dysfunction by inhibiting inflammation. Strengths and Limitations Strengths are that the relationship between pyroptosis and ED has been verified through in vitro and in vivo experiments. The limitation is that the conclusions drawn from animal and cells experiments need to be confirmed in clinical research. Conclusion Sildenafil may reduce the effect of IL-18–induced inflammation in high-fat diet–induced ED rats through NLRP3/caspase-1 pyroptosis pathway. [ABSTRACT FROM AUTHOR]

Improved encryption devices place higher demands on the randomness and security of encrypted images. Existing image encryption optimization methods based on single- or multi-objectives concentrate on selecting keys and parameters, resulting in relatively fixed parameters and keys that are susceptible to leakage and cracking. Despite the possibility of increasing security, the DNA coding encryption method does not fully take into account the large capacity of image data and the difference between pixels, resulting in a limited level of randomness. To overcome the problems above, this paper proposes a method for generating complex texture features in images using random variation of pixels. With an annealing algorithm that can find an optimal solution in a large search space, the image is optimally optimized in terms of information entropy, pixel correlation, and value of x2. Each iteration involves selecting one of 25632 combinations of DNA coding and operation. In comparison with current encryption algorithms based on optimization algorithms and DNA coding, this method is more secure and unbreakable. [ABSTRACT FROM AUTHOR]

There are growing concerns that the coronavirus disease of 2019 (COVID-19) pandemic may change antibiotic use patterns and accelerate antibiotic resistance, but evidence from the community level is lacking. This study aims to estimate the impact of the COVID-19 outbreak on the antibiotic use patterns among a community population in Eastern China. A self-administered medicine diary was used to collect information on antibiotic use from July 2019 to June 2021 among a rural community in Eastern China. We analyzed the changes in antibiotic use patterns over five months from August to December 2019 and the corresponding months in 2020. The risk of antibiotic use and its changes were measured with the incidence rate (IR) and relative risk (RR). In total, 1111 participants were eligible for the final analysis (440 in 2019 and 671 in 2020). After the COVID-19 outbreak, antibiotic use increased by 137% (5.43 per 100 person months in the 2019 vs. 12.89 per 100 person months in the 2020), and after the adjustment of covariates, the adjusted RR was 1.72 (95% CI: 1.10~2.34). It was higher among those who were women (RR = 2.62), aged 35–59 years old (RR = 2.72), non-farmers (RR = 2.75), had less than six years of education (RR = 2.61), had an annual household income over CNY 100,000 (USD 14,940) (RR = 2.60), and had no history of chronic diseases (RR = 2.61) (all p < 0.05). The proportion of cephalosporins consumed increased from 54.29% in 2019 to 64.92% in 2020 (p = 0.011). Among those aged 35 years and older, the proportion of antibiotics obtained from medical facilities increased, while the proportion obtained from retail pharmacies, homes, and other sources decreased (all p < 0.05). The COVID-19 outbreak changed antibiotic use patterns in this study population (Eastern China) significantly. More efforts to monitor and enhance antibiotic stewardship activities at the community level are needed in future. [ABSTRACT FROM AUTHOR]

Podocyte damage is vital for the etiopathogenesis of diabetic nephropathy (DN). Klotho (KL), a multifunctional protein, has been demonstrated to have renoprotective effects; nevertheless, the mechanism for protective effect has not been completely elucidated. Transient receptor potential cation channel subfamily C, member 6 (TRPC6), a potential target of KL, is implicated in glomerular pathophysiology. Here, we sought to determine whether KL could protect against podocyte injury through inhibiting TRPC6 in DN. We found that high glucose (HG) triggered podocyte injury as manifested by actin cytoskeleton damage along with the downregulation of KL and Synaptopodin and the upregulation of TRPC6. KL overexpression reversed HG-induced podocytes injury, whereas cotreatment with TRPC6 activator flufenamic acid (FFA) significantly abrogated the beneficial effects conferred by KL. Moreover, KL knockdown in podocytes resulted in actin cytoskeleton impairment, decreased Synaptopodin expression, and increased TRPC6 expression. In db/db mice, KL overexpression inhibited TRPC6 expression and attenuated diabetes-induced podocyte injury, which was accompanied by decreased albuminuria and ameliorated glomerulosclerosis. Our data provided novel mechanistic insights for KL against DN and highlighted TRPC6 as a new target for KL in podocytes to prevent DN. [ABSTRACT FROM AUTHOR]

To investigate the effects and mechanisms of resveratrol on glucolipid metabolism in diabetic humans. In this paper, we introduced the knowledge discovery theory into the data processing of the factors related to the pathogenesis of type 2 diabetes for the first time, and identified valid, potentially useful, and understandable pathogenesis patterns from a large amount of measured data. A data mining C4.5 algorithm was used to classify 17072 validated cross-sectional health survey data from the whole population according to the characteristics of type ρ diabetes data. A human model of diabetes mellitus was prepared by high sugar and high fat diet plus low dose streptozotocin (STZ, 35 mg/kg) and randomly grouped into four groups: the normal control group, the model group, the resveratrol group, and the pioglitazone group. 8 animals in each group were treated with the corresponding drugs for 8 weeks. Hepatic steatosis and damage were significantly reduced compared with the model group as observed by HE staining. Resveratrol has obvious effects on regulating glucolipid metabolism, and its mechanism of action is associated with its ability to increase the antioxidant activity of the body, activate the Akt signaling pathway, and improve liver pathological damage. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are cell-derived, membranous nanoparticles that mediate intercellular communication by transferring biomolecules between cells. As natural vehicles, EVs may exhibit higher delivery efficiency, lower immunogenicity, and better compatibility than existing RNA carriers. A major limitation of their therapeutic use is the shortage of efficient, robust, and scalable methods to load siRNA of interest. Here, we report a novel strategy using polycationic membrane-penetrating peptide TAT to encapsulate siRNAs into EVs. Three TAT peptides were co-expressed with DRBD as 3TD fusion protein. The sequence-independent binding of DRBD facilitates multiplex genes targeting of mixed siRNAs. Functional assays for siRNA-mediated gene silencing of CRPC were performed after engineered EVs treatment. EVs were isolated using differential centrifugation from WPMY-1 cell culture medium. The increase of merged yellow fluorescence in the engineered EVs showed by TIRFM and the decrease in zeta potential absolute values certified the co-localization of siRNA with EVs, which indicated that siRNA had been successfully delivered into WPMY-1 EVs. qRT-PCR analysis revealed that the mRNA level of FLOH1, NKX3, and DHRS7 was dramatically decreased when cells were treated with engineered EVs loaded with siRNAs mixtures relative to the level of untreated cells. Western and flow cytometry results indicate that delivery of siRNA mixtures by engineered EVs can effectively downregulate AR expression and induce LNCaP-AI cell apoptosis. The uptake efficiency of the EVs and the significantly downregulated expression of three genes suggested the potential of TAT as efficient siRNA carriers by keeping the function of the cargoes. [ABSTRACT FROM AUTHOR]

The problem of finite-time H ∞ output tracking control for time-delay systems with actuators failure is investigated. Firstly, a switching rule and the switching regions are presented. Then, the finite-time bounded and tracking performance analysis are proposed by using Lyapunov function and average dwell time technique. Moreover, based on the switching method, a solution for controller is derived such that the resulting closed-loop system is finite-time stable. Finally, a numerical example is given to illustrate the effectiveness of the results. [ABSTRACT FROM AUTHOR]

Background. To compare the efficacies of transcatheter arterial chemoembolization (TACE) with radiofrequency ablation (RFA) (TACE + RFA) and TACE alone in patients with hepatocellular carcinoma (HCC) and macrovascular invasion (MVI). Methods. In total, 664 patients having HCC with MVI were included. Of these patients, 141 were treated with TACE + RFA, 254 with TACE alone, and 269 with supportive therapy (control group). The overall survival (OS) was compared among these groups. Propensity score matching (PSM) was performed for balancing the characteristics of the three groups. Results. After one-to-one PSM, the 12-month OS rates were higher in the TACE and TACE + RFA groups than in the control group (p = 0.0009 and p = 0.0017 , respectively). Furthermore, higher 12-month OS rates were observed in the TACE + RFA group than in the TACE group (p = 0.0192). The 12-month OS rates of patients were remarkably higher in α-fetoprotein (AFP) < 400 ng/ml, tumor < 3, tumor diameter < 5 cm, or portal vein tumor thrombosis (PVTT) group who were treated with TACE + RFA than in those who were treated with TACE (p = 0.0122 , p = 0.0090 , p = 0112 , and p = 0.0071 , respectively). Conclusions. TACE + RFA provides a superior survival outcome than TACE alone in HCC patients, especially in AFP <400 ng/ml, tumor <3, tumor diameter <5 cm, or PVTT group. [ABSTRACT FROM AUTHOR]

Background. Portal vein tumor thrombosis (PVTT) is one of the major predictive factors for patients with hepatocellular carcinoma (HCC). The objective of this study was to establish a prognostic nomogram for identifying individual survival outcomes in patients with HCC and PVTT on conservative treatment based on specific factors. Methods. Two hundred and ten patients with HCC and PVTT on conservative treatment in Beijing Ditan Hospital between June 2008 and May 2017 were studied retrospectively as a derivation cohort. We built a nomogram based on independent risk factors for survival prediction. The concordance index (c-index) and a calibration curve were used to evaluate the predictive accuracy. During the study, 102 patients were included at the Putuo Hospital and Third People's Hospital of Changzhou as a validation cohort. Results. In the derivation cohort, the independent factors for overall survival were identified by multivariate analysis, namely, aspartate aminotransferase ≥119 IU/L, gamma-glutamyl transferase ≥115 IU/L, Child–Pugh class C liver function, creatinine ≥91 μmoI/L, α-fetoprotein ≥400 ng/ml, and largest tumor diameter ≥5 cm. The nomogram had a c-index of 0.737 (95% confidence interval, 0.692–0.782) and the calibration curves fitted well. The median survival time was 4.2 months in the derivation cohort, with an MST of 5 months for BCLC C stage and 1.8 months for BCLC D stage patients. Kaplan–Meier analysis showed significant statistical differences in the 6-month overall survival rates of the primary and validation cohorts after the total scores were divided into three quartiles (low risk: 0–85; intermediate risk: 86–210; high risk: ≥211; p < 0.0001 in both cohorts). Conclusions. The nomogram can be a more accurate and individualized prediction for 6-month overall survival of patients with HCC and PVTT on conservative treatment, and it is possible to consider further active interventions for patients in the low-risk group (0–85 scores) to achieve the aim of prolonging survival. [ABSTRACT FROM AUTHOR]

The proteasome inhibitor pathway serves a crucial role in cell cycle progression and apoptosis, and in the activation of transcription factors and cytokines in tumor cells. The aim of the current study was to investigate the effect of the proteasome inhibitor, MG132, on transforming growth factor (TGF)-β1-induced expression of extracellular matrix proteins in rat renal interstitial fibroblasts (NRK-49F cells) and to better elucidate the mechanism by which MG132 functions. The level of connective tissue growth factor (CTGF), α-smooth muscle actin (SMA), fibronectin (FN) and collagen type III (Col III) in the MG132-pretreated groups was significantly decreased compared with groups treated with TGF-β1 alone. MG132 significantly decreased mRNA and the protein levels of fibrosis-associated factors induced by TGF-β1 treatment. The MG132-pretreated groups exhibited lower phosphorylated-mothers against decapentaplegic homolog (p-Smad)2, p-Smad3 and FN protein expression compared with the groups treated with TGF-β1 alone. In conclusion, MG132 reduced mRNA and protein expression of fibrosis-associated factors. It can successfully inhibit the inflammatory reaction induced by TGF-β via the Smad signaling pathway. These results indicate that MG132 appears to have a potent effect in counteracting renal fibrosis. MG132 may be applied in the treatment of patients with chronic kidney disease. [ABSTRACT FROM AUTHOR]

Background: Elevated serum γ-glutamyltransferase (γ-GT) levels are related to an increased cancer risk and worse prognosis in many cancers. We evaluated the effects of γ-GT stratification on the occurrence of macrovascular invasion (MVI) in patients with hepatocellular carcinoma (HCC) who underwent hepatic resection (HR), transcatheter arterial chemoembolization (TACE), or TACE combined with radiofrequency ablation (TACE-RFA). Patients and methods: A total of 903 patients with HCC in Barcelona Clinic Liver Cancer Stage A or B were included. Of these patients, 118 underwent HR, 445 underwent TACE-RFA, 256 underwent TACE, and 84 patients received conservative treatment only (control group). γ-GT, albumin, γ-fetoprotein, and intervention were selected as significant predictive factors for MVI in 1 year by forward selection. The optimal cutoff value of γ-GT was 39 IU/L according to receiver operating characteristic analysis, with a sensitivity and specificity of 87.0% and 45.6%, respectively. Results:  The 1-year MVI incidence of patients with HCC in the group with γ-GT ≥39 IU/L was higher than that of the group with γ-GT <39 IU/L treated with HR, TACE-RFA, or TACE (P=0.0166, P=0.0041, and P<0.001, respectively). The MVI rates at 1 year were similar in the group with γ-GT ≥39 IU/L that underwent HR, TACE-RFA, or TACE and the control group (P=0.4402, P=0.2214, and P=0.4159, respectively). Different effects of various treatments with γ-GT <39 IU/L group on the occurrence of MVI are not significant (P=0.5167). However, the incidence of MVI after TACE was significantly higher than that after HR or TACE-RFA in γ-GT ≥39 IU/L group (P=0.0253). Conclusion: Baseline serum γ-GT stratification may help select the appropriate treatment to reduce the MVI incidence. [ABSTRACT FROM AUTHOR]

Erectile dysfunction (ED) is a prevalent disease that causes sexual dysfunction in males. Inflammation-induced endothelial dysfunction is a fundamental pathophysiological symptom of ED, which is impacted by cell death. Pyroptosis is a type of programmed cell death mediated by the inflammasome that was discovered in inflammatory disorders. The activation of nucleotide-binding oligomerization domain-like receptors, particularly downstream inflammatory factors, such as IL-1β and IL-18, is indicative of caspase-dependent pyroptosis. Although the underlying mechanisms of pyroptosis have been investigated in several disorders, the role of pyroptosis in ED remains to be fully elucidated. At present, studies on pyroptosis have focused on improving the understanding of ED pathogenesis and promoting the development of novel therapeutic options. The present review article aimed to discuss the literature surrounding the mechanisms underlying pyroptosis, and summarize the role of pyroptosis in the development and progression of inflammation-mediated ED. [ABSTRACT FROM AUTHOR]

Clinical and pathological features are important factors that affect the prognosis and treatment strategies of patients with gastric cancer (GC). An upper gastrointestinal barium X-ray examination is commonly used to show gastric mucosa and morphological changes. The aim of the present study was to evaluate the association between gastric morphological type and the clinicopathological features of patients with GC, based on double-contrast barium X-ray imaging. A total of 329 patients with GC who underwent upper gastrointestinal barium X-ray examination were analyzed. The gastric morphological type was divided into four types on barium X-ray images: Horn-type, hook-type, weak-type and waterfall-type stomach. The χ2 test or Fisher's exact test was used to assess the association between gastric morphological type and the clinicopathological features. There was a statistically significant difference in the location of GC between different types of gastric morphology. Hook-type and horn-type GC were commonly present in the lower region of the stomach, while waterfall-type GC was mainly located in the upper region of the stomach. The incidence of waterfall-type non-poorly differentiated GC was higher than that of other gastric types. The incidence of waterfall-type intestinal-type GC was higher than that of other gastric types, and horn-type GC was more common in mixed-type GC. There was a statistically significant difference in the T-staging of GC between different types of gastric morphology. In conclusion, gastric morphological type correlates with the location and T-stage distribution of GC. [ABSTRACT FROM AUTHOR]

• Yindan Jiedu Granules (YDJDG) is a new Chinese herbal formula for COVID-19. • YDJDG could shorten the course and delay the progression of COVID-19. • We provide clinical, bioinformatics and experiment basis for COVID-19 treatment with YDJDG. • YDJDG may suppressing inflammation via targeting the NF-κB pathway. Coronavirus disease 2019 (COVID-19) is a pandemic that has caused a high number of deaths worldwide. Inflammatory factors may play important roles in COVID-19 progression. Yindan Jiedu granules (YDJDG) can inhibit the progression of COVID-19, but the associated mechanism is unclear. To evaluate the therapeutic effects of YDJDG on COVID-19 and explore its underlying mechanism. We recruited 262 participants and randomly assigned 97 patients each to the YDJDG and control groups using one-to-one propensity score matching (PSM). Clinical effects were observed and serum inflammatory and immune indicators were measured. The target network model of YDJDG was established by predicting and determining the targets of identified compounds. The main constituents of the YDJDG extracts were identified and evaluated using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and molecular docking. Besides, the anti-inflammatory effects of YDJDG and its specific biological mechanism of action were studied. After PSM, the results showed that compared with the control group, the YDJDG group had a shorter time of dissipation of acute pulmonary exudative lesions (p < 0.0001), shorter time to negative conversion of viral nucleic acid (p < 0.01), more rapid decrease in serum amyloid A level and erythrocyte sedimentation rate (p < 0.0001), and a higher rate of increase in CD4+ T cell count (p = 0.0155). By overlapping the genes of YDJDG and COVID-19, 213 co-targeted genes were identified. Metascape enrichment analysis showed that 25 genes were significantly enriched in the NF-κB pathway, which were mainly targets of luteolin, quercetin, and kaempferol as confirmed by MS analysis. Molecular docking revealed that the ligands of three compounds had strong interaction with NF-κB p65 and IκBα. In vivo , YDJDG significantly protected animals from lipopolysaccharide (LPS)-induced acute lung injury (ALI), decreasing the lung wet/dry weight ratio, ALI score, and lung histological damage. In LPS-treated RAW264.7 cells, YDJDG suppressed nuclear translocation of NF-κB p65. In vivo and in vitro , YDJDG exerted anti-inflammatory effects by inhibiting the production of inflammatory cytokines (IL-6, IL-1β, and TNF-α). These effects were accompanied by the inhibition of NF-ĸB activation and IκBα phosphorylation. YDJDG may shorten the COVID-19 course and delay its progression by suppressing inflammation via targeting the NF-κB pathway. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Coronavirus disease 2019 (COVID-19) is a pandemic that has caused a high number of deaths worldwide. Inflammatory factors may play important roles in COVID-19 progression. Yindan Jiedu granules (YDJDG) can inhibit the progression of COVID-19, but the associated mechanism is unclear.Purpose: To evaluate the therapeutic effects of YDJDG on COVID-19 and explore its underlying mechanism.Methods: We recruited 262 participants and randomly assigned 97 patients each to the YDJDG and control groups using one-to-one propensity score matching (PSM). Clinical effects were observed and serum inflammatory and immune indicators were measured. The target network model of YDJDG was established by predicting and determining the targets of identified compounds. The main constituents of the YDJDG extracts were identified and evaluated using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and molecular docking. Besides, the anti-inflammatory effects of YDJDG and its specific biological mechanism of action were studied.Results: After PSM, the results showed that compared with the control group, the YDJDG group had a shorter time of dissipation of acute pulmonary exudative lesions (p < 0.0001), shorter time to negative conversion of viral nucleic acid (p < 0.01), more rapid decrease in serum amyloid A level and erythrocyte sedimentation rate (p < 0.0001), and a higher rate of increase in CD4+T cell count (p = 0.0155). By overlapping the genes of YDJDG and COVID-19, 213 co-targeted genes were identified. Metascape enrichment analysis showed that 25 genes were significantly enriched in the NF-κB pathway, which were mainly targets of luteolin, quercetin, and kaempferol as confirmed by MS analysis. Molecular docking revealed that the ligands of three compounds had strong interaction with NF-κB p65 and IκBα. In vivo, YDJDG significantly protected animals from lipopolysaccharide (LPS)-induced acute lung injury (ALI), decreasing the lung wet/dry weight ratio, ALI score, and lung histological damage. In LPS-treated RAW264.7 cells, YDJDG suppressed nuclear translocation of NF-κB p65. In vivo and in vitro, YDJDG exerted anti-inflammatory effects by inhibiting the production of inflammatory cytokines (IL-6, IL-1β, and TNF-α). These effects were accompanied by the inhibition of NF-ĸB activation and IκBα phosphorylation.Conclusion: YDJDG may shorten the COVID-19 course and delay its progression by suppressing inflammation via targeting the NF-κB pathway. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is a common malignant tumor with limited treatment options. Conventional antitumor therapy combined with traditional Chinese medicine (TCM) to limit tumor progression has gradually become the focus of complementary and alternative therapies for HCC treatment. The Fuzheng Jiedu Xiaoji formulation (FZJDXJ) alleviates the clinical symptoms of patients and inhibits tumor progression, but its curative effect still requires extensive clinical research and mechanistic analysis.Purpose: To explore the effectiveness of FZJDXJ in HCC patients and investigate its biological function and mechanism underlying anticancer therapy.Methods: This randomized controlled clinical trial enrolled 291 HCC patients receiving transcatheter arterial chemoembolization (TACE) therapy; patients received either FZJDXJ combined with standard treatment, or standard treatment alone, for 48 weeks. Statistical analyses were performed according to survival time at the end of the trial. The main constituents of the FZJDXJ extracts were identified and evaluated using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and molecular docking. The antitumor effects of FZJDXJ and its specific biological mechanism of action were studied.Results: After 48 weeks of treatment, one-year overall survival (OS) and progression-free survival (PFS) were significantly different between the two groups. Co-administration of FZJDXJ and TACE prolonged the OS of HCC patients, especially in BCLC A or B stage. FZJDXJ and TACE treatment effectively extended the PFS of patients, especially in the BCLC B stage. HPLC-MS/MS identified 1619 active constituents of FZJDXJ, including formononetin, chlorogenic acid (CGA), caffeic acid, luteolin, gallic acid, diosgenin, ergosterol endoperoxide, and lupeol, which may function through the AKT/CyclinD1/p21/p27 pathways. Through molecular docking, CGA and gallic acid could effectively combine with Thr308, an important phosphorylation site of AKT1. FZJDXJ inhibited tumor growth in nude mice. In vitro, FZJDXJ-mediated serum inhibited the proliferation, migration, and invasion of liver cancer cells, and promoted cell apoptosis.Conclusion: Clinically, FZJDXJ combined with TACE therapy significantly prolonged OS and PFS and reduced the mortality rate of HCC patients. Mechanistically, FZJDXJ effectively inhibited the proliferation and migration of liver cancer cells through the modulation of the AKT/CyclinD1/p21/p27 pathways, and may be a promising TCM drug for anti-HCC therapy. [ABSTRACT FROM AUTHOR]

Defective antioxidant system as well as mitochondrial dysfunction contributes to the pathogenesis and progression of diabetic kidney disease (DKD). Nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated signaling is the central defensive mechanism against oxidative stress and therefore pharmacological activation of Nrf2 is a promising therapeutic strategy. In this study, using molecular docking we found that Astragaloside IV (AS-IV), an active ingredient from traditional formula of Huangqi decoction (HQD), exerted a higher potential to promote Nrf2 escape from Keap1-Nrf2 interaction via competitively bind to amino acid sites in Keap1. When podocyte exposed to high glucose (HG) stimulation, mitochondrial morphological alterations and podocyte apoptosis were presented and accompanied by Nrf2 and mitochondrial transcription factor A (TFAM) downregulation. Mechanistically, HG promoted a decrease in mitochondria-specific electron transport chain (ETC) complexes, ATP synthesis and mtDNA content as well as increased ROS production. Conversely, all these mitochondrial defects were dramatically alleviated by AS-IV, but suppression of Nrf2 with inhibitor or siRNA and TFAM siRNA simultaneously alleviated the AS-IV efficacy. Moreover, experimental diabetic mice exhibited significant renal injury as well as mitochondrial disorder, corresponding with the decreased expression of Nrf2 and TFAM. On the contrary, AS-IV reversed the abnormality and the Nrf2 and TFAM expression were also restored. Taken together, the present findings demonstrate the improvement of AS-IV on mitochondrial function, thereby resistance to oxidative stress-induced diabetic kidney injury and podocyte apoptosis, and the process is closely associated with activation of Nrf2-ARE/TFAM signaling. [Display omitted] • AS-IV inhibited oxidative stress-induced podocyte apoptosis and diabetic kidney injury. • AS-IV activated Nrf2-ARE/TFAM signaling to ameliorate mitochondrial disorder. • AS-IV is a potential candidate to delay diabetic kidney disease progression. [ABSTRACT FROM AUTHOR]

Equipped with anti-oxidative properties, cerium oxide nanoparticles (CNPs) are gradually being adopted over the years in the field of oxidative stress research. However, the effects of CNPs may be diminished when under the influence of prolonged and substantially elevated levels of oxidative stress. Therefore, it is imperative to enhance the efficacy of CNPs to resist oxidative stress. In this study, our approach involves the fabrication of titanium surface CNPs coatings doped with different concentrations of lanthanum ions (La3+) and the investigation of their local anti-oxidative stress potential. The physicochemical characterization showed that the La-CNPs groups had a substantial increase in the generation of oxygen vacancies within the CNPs structure with the increase of La doping concentration. In vitro findings proofed that the cytocompatibility of different La-CNPs coatings showed a trend of increasing first and then decreasing with the increase of La doping concentration under oxidative stress microenvironment. Among these groups, the 30 % La-CNPs group presented the best cell proliferation and osteogenic differentiation which could activate the FoxO1 pathway, then upregulated the expression of SOD1 and CAT, and finally resulted in the inhibition of ROS production. In vivo results further confirmed that the 30 % La-CNPs group showed significant osteogenic effects in two rat models (osteoporosis and diabetes models). In conclusion, we believe that the 30 % La-CNPs coating holds promising potential for its implant applications in patients with oxidative stress-related diseases. [Display omitted] • The first study on improving the oxidation resistance of cerium coating by La doping. • La-CNPs had a substantial increase in oxygen vacancy with the increase of La doping. • 30 % La-CNPs had the best osteoinduction ability by activating FoxO1/CAT/SOD pathway. • 30 % La-CNPs obviously promoted early osteogenesis of osteoporosis and diabetes rats. [ABSTRACT FROM AUTHOR]

Podocyte apoptosis plays an important role in the pathogenesis of diabetic nephropathy (DN). Astragaloside IV (AS-IV) has been shown to protect against podocyte apoptosis. Here we aim to investigate the mechanism responsible for the protective effects of AS-IV. Diabetic db/db mice and high glucose (HG)-cultured podocytes were treated with AS-IV. Renal function and histopathological changes were measured to evaluate the therapeutic effects of AS-IV against DN. Adenovirus-mediated Klotho overexpression, Klotho siRNA, and PPARγ inhibitor were applied in vitro to investigate the potential mechanism. The expression levels of mRNA and proteins were analyzed by qRT-PCR, western blot or immunofluorescence. Intracellular ROS and mitochondrial superoxide were detected by DHE and MitoSOx Red, respectively. Cell apoptosis was evaluated by TUNEL staining and flow cytometry. AS-IV improved renal function and ameliorated podocyte injury in db/db mice accompanied with enhanced Klotho expression in glomerular podocytes. In vitro, AS-IV inhibited HG-induced podocyte apoptosis and restored HG-inhibited Klotho expression, whereas Klotho knockdown abrogated the anti-apoptosis action of AS-IV. Further study showed that adenovirus-mediated Klotho overexpression enhanced Forkhead transcription factor O1 (FoxO1)-dependent antioxidant activity and attenuated HG-evoked oxidative stress and apoptosis. AS-IV prevented HG-induced FoxO1 inhibition and oxidative stress, whereas Klotho knockdown reversed these effects. Cotreatment with PPARγ inhibitor T0070907 abolished AS-IV-induced Klotho expression and anti-apoptosis action. These data suggested that AS-IV attenuated podocyte apoptosis presumably by inhibiting oxidative stress via activating PPARγ-Klotho-FoxO1 signaling pathway, thereby ameliorating DN. This study provided new insights into the molecular mechanisms of AS-IV against DN. [ABSTRACT FROM AUTHOR]

Oxidative stress plays a key role in the pathogenesis of diabetic nephropathy (DN). The anti-aging protein Klotho has been demonstrated to have antioxidant capacity. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a central transcription factor regulating antioxidant responses. The present study aimed to explore the effects of Klotho on DN and the underlying mechanisms related to Nrf2. Low glucose (LG) or high glucose (HG) medium-cultured podocytes and diabetic db/db mice were overexpressed with Klotho via adenoviral transfer to evaluate the effects of Klotho on Nrf2 signaling, oxidative stress, podocyte apoptosis, and renal function and histopathology. Klotho overexpression significantly induced the expression and activation of Nrf2 as well as its downstream targets SOD2 and NQO1 in podocytes. Moreover, Klotho overexpression inhibited HG-induced oxidative stress and apoptosis in podocytes. Co-treatment with Nrf2 inhibitor trigonelline prevented Klotho-induced expression of SOD2 and NQO1, and abolished Klotho-conferred antioxidant and anti-apoptotic effects. In db/db mice, Klotho overexpression also activated Nrf2 signaling, and suppressed diabetes-induced oxidative stress and podocyte apoptosis, which were accompanied by improved renal function and decreased glomerulosclerosis. Our data highlight a novel Nrf2-mediated antioxidant mechanism underlying the protective effects of Klotho in podocytes and indicate the therapeutic potential of targeting Klotho to activate Nrf2 in DN. • Klotho induced the expression and activation of Nrf2 in podocytes. • Klotho ameliorated oxidative stress and podocyte apoptosis in DN. • Klotho attenuated HG-induced podocyte apoptosis via activating Nrf2 pathway. [ABSTRACT FROM AUTHOR]

The genetic variations of the apolipoprotein L1 (APOL1) gene are associated with non-diabetic kidney diseases. However, very little is known about the role of ApoL1 in glomerular damage. Here, we aimed to identify the function and mechanism of ApoL1 in glomerular damage. The mice were randomly divided into two groups: one group was intraperitoneally injected with phosphate buffer saline (PBS), while the other group was intraperitoneally injected with recombinant ApoL1 every other day for 3 months. Hematoxylin and eosin (HE) and periodic acid Schiff (PAS) staining were used to demonstrate the effects of ApoL1 on kidney inflammation and injury. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) analyses revealed that ApoL1-treated mice exhibited enhanced expression of various inflammation markers in the kidney and serum compared to the PBS-treated mice. Immunofluorescence staining revealed that ApoL1 accumulated in kidney podocytes. Treatment with ApoL1 dose-dependently increased the expression of inflammation markers and apoptotic markers. The abnormal gene expression associated with ApoL1-mediated podocyte inflammation was evaluated using microarray analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that the upregulated genes were enriched in the inflammation-related processes, such as the RIG-I/NF-κB signaling pathway. Consistently, the knockdown of RIG-I significantly mitigated the ApoL1-induced upregulation of inflammatory and apoptotic markers in the human podocytes. Additionally, the ApoL1-induced glomerular damage was attenuated in AAV-shRIG-I mice. Therefore, the effects of ApoL1 on glomerular damage may be, at least partially, through inducing abnormal expression of inflammatory molecules, which may have important implications for treatment of kidney diseases. • ApoL1 induced glomerular damage and kidney inflammation. • RIG-I knockdown could rescue the effects of ApoL1-mediated glomerular damage and kidney inflammation. • ApoL1 induced kidney inflammation through RIG-I/NF-κB activation. [ABSTRACT FROM AUTHOR]

Understanding dephasing mechanisms of strong-field-driven excitons in condensed matter is essential for their applications in quantum-state manipulation and ultrafast optical modulations. However, experimental access to exciton dephasing under strong-field conditions is challenging. In this study, using time- and spectrum-resolved quantum-path interferometry, we investigate the dephasing mechanisms of terahertz-driven excitonic Autler-Townes doublets in MoS&#95;{2}. Our results reveal a dramatic increase in the dephasing rate beyond a threshold field strength, indicating exciton dissociation as the primary dephasing mechanism. Furthermore, we demonstrate nonperturbative high-order sideband generation in a regime where the driving fields are insufficient to dissociate excitons.

Liquid biopsy as a non-invasive method has a bright future in cancer diagnosis. Tumor-related extracellular vesicles (EVs) and their components (nucleic acids, proteins, and lipids) in biofluids may exert multiple functions in tumor growth, metastasis, immune escape, and angiogenesis. Among all the components, nucleic acids have attracted the most interest due to their simplicity of extraction and detection. In this review, the biological functions of EVs in prostate cancer (PCa) genesis and progression were summarized. Moreover, the diagnostic value of EV RNA markers found in clinical body fluid samples was reviewed, including their trends, challenging isolation methods, and diagnostic efficacy. Lastly, because relatively much progress has been made in PCa, studies on EV DNA markers are also discussed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Diao, Zhu, Ding, Li, Li, Yang, Zhou, Hao and Liu.)

Background: The differentiation status of gastric cancer is related to clinical stage, treatment and prognosis. It is expected to establish a radiomic model based on the combination of gastric cancer and spleen to predict the differentiation degree of gastric cancer. Thus, we aim to determine whether radiomic spleen features can be used to distinguish advanced gastric cancer with varying states of differentiation., Materials and Methods: January 2019 to January 2021, we retrospectively analyzed 147 patients with advanced gastric cancer confirmed by pathology. The clinical data were reviewed and analyzed. Three radiomics predictive models were built from radiomics features based on gastric cancer (GC), spleen (SP) and combination of two organ position (GC+SP) images. Then, three Radscores (GC, SP and GC+SP) were obtained. A nomogram was developed to predict differentiation statue by incorporating GC+SP Radscore and clinical risk factors. The area under the curve (AUC) of operating characteristics (ROC) and calibration curves were assessed to evaluate the differential performance of radiomic models based on gastric cancer and spleen for advanced gastric cancer with different states of differentiation (poorly differentiated group and non- poorly differentiated group)., Results: There were 147 patients evaluated (mean age, 60 years ± 11SD, 111 men). Univariate and multivariate logistic analysis identified three clinical features (age, cTNM stage and CT attenuation of spleen arterial phase) were independent risk factors for the degree of differentiation of GC ( p =0.004,0.000,0.020, respectively). The clinical radiomics (namely, GC+SP+Clin) model showed powerful prognostic ability in the training and test cohorts with AUCs of 0.97 and 0.91, respectively. The established model has the best clinical benefit in diagnosing GC differentiation., Conclusion: By combining radiomic features (GC and spleen) with clinical risk factors, we develop a radiomic nomogram to predict differentiation status in patients with AGC, which can be used to guide treatment decisions., Competing Interests: Author XC is employed by the Beijing Deepwise & League of PHD Technology Company, and author CH is employed by the Beijing Deepwise & League of PHD Technology Company. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lyu, Liang, Huang, Chen, Cheng, Zhu, Liu, Yue and Gao.)