Search

In this study, we examined anti-fungal and anti-inflammatory effects of the synthetic melanocortin peptide (Ac-Cys-Lys-Pro-Val-NH2)2 or (CKPV)2 against Candida albicans vaginitis. Our in vitro results showed that (CKPV)2 dose-dependently inhibited Candida albicans colonies formation. In a rat Candida albicans vaginitis model, (CKPV)2 significantly inhibited vaginal Candida albicans survival and macrophages sub-epithelial mucosa infiltration. For mechanisms study, we observed that (CKPV)2 inhibited macrophages phagocytosis of Candida albicans. Meanwhile, (CKPV)2 administration inhibited macrophage pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) release, while increasing the arginase activity and anti-inflammatory cytokine IL-10 production, suggesting macrophages M1 to M2 polarization. Cyclic AMP (cAMP) production was also induced by (CKPV)2 administration in macrophages. These above effects on macrophages by (CKPV)2 were almost reversed by melanocortin receptor-1(MC1R) siRNA knockdown, indicating the requirement of MC1R in the process. Altogether, our results suggest that (CKPV)2 exerted anti-fungal and anti-inflammatory activities against Candida albicans vaginitis probably through inducing macrophages M1 to M2 polarization and MC1R activation. [ABSTRACT FROM AUTHOR]

The work in this paper is based on the optimization software, using the exactly optimization technique. The hypersonic aerodynamic performance is calculated by numerically solving the Euler equations and the maximum surface heat flux is calculated by solving the Fay-Riddell equation. To test our method, the CTV is optimized. The Spaceship reentry capsule has been optimized as a particular instance. This research work can be as the groundwork for the reentry capsule optimization. [ABSTRACT FROM AUTHOR]

The mammalian cardiac myocytes not only synthesize and secrete atrial natriuretic peptide (ANP), but also express cholecystokinin (CCK) and its receptors (CCK 1 R and CCK 2 R). However, atrial CCK expression patterns and its effects on ANP secretion during hypoxia are unclear. Therefore, this study is aimed to investigate the effect of hypoxia on the expression levels of CCK and its receptors, as well as the underlying mechanisms involved in regulating hypoxia-induced ANP secretion in isolated beating atria. The results of this study showed that acute hypoxia significantly upregulated expression of CCK and CCK 1 R as well as CCK 2 R through activation of hypoxia-inducible factor 1α–apelin signaling. Endogenous CCK induced by hypoxia markedly upregulated the expression of silent information regulator factor 2-related enzyme 1 (Sirt1) and its downstream nuclear factor erythroid‑2‑related factor 2 (Nrf2) via the activation of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), leading to increase of activating T cell factor (TCF) 3 and TCF4/ lymphoid enhancer factor (LEF) 1, ultimately promoting hypoxia-induced ANP secretion. In addition, siRNA-mediated knockdown of LEF1 dramatically attenuated hypoxia-induced increase of ANP expression in HL-1 atrial myocytes. These results indicated endogenous CCK induced by hypoxia promoted hypoxia-induced ANP secretion by activation of NOX4–Sirt1–TCF3/4–LEF1 signaling pathway. • HIF-1α-apelin enhanced the expression of endogenous CCK and its receptors, increasing ANP secretion under hypoxic conditions. • NOX4-Sirt1 controlled by CCK regulated ANP secretion under hypoxic conditions. • TCF/LEF regulated by Nrf2 was associated with hypoxia-induced ANP secretion. • The correlation of CCK regulating ANP under hypoxic conditions can be delineated as follows: CCK NOX4 Sirt1 Nrf2 TCF3/4/LEF1. [ABSTRACT FROM AUTHOR]

[Display omitted] • Low-dose telmisartan inhibited glioma proliferation and migration in co-cultures. • Astrocyte-derived IL-6 promoted glioma cell proliferation and migration. • Telmisartan inhibits IL-6/STAT3 pathway between astrocyte and glioma. • Telmisartan exerts the anti-tumor effects via PPARγ activation. Telmisartan, an angiotensin II type 1 receptor (AT1R) blocker, exhibits broad anti-tumor activity. However, in vitro, anti-proliferative effects are shown at doses far beyond the therapeutic plasma concentration. Considering the role of tumor microenvironment in glioma progression, glioma-astrocyte co-cultures were employed to test the anti-tumor potential of low-dose telmisartan. When a high dose was required for a direct anti-proliferative effect on glioma cell lines, a low dose significantly inhibited glioma cell proliferation and migration in the co-culture system. Under co-culture conditions, upregulated IL-6 expression in astrocytes played a critical role in glioma progression. Silencing IL-6 in astrocytes or IL-6R in glioma cells reduced proliferation and migration. Telmisartan (5 μM) inhibited astrocytic IL-6 expression, and its anti-tumor effects were reversed by silencing IL-6 or IL-6R and inhibiting signal transducer and activator of transcription 3 (STAT3) activity in glioma cells. Moreover, the telmisartan-driven IL-6 downregulation was not imitated by losartan, an AT1R blocker with little capacity of peroxisome proliferator-activated receptor-gamma (PPARγ) activation, but was eliminated by a PPARγ antagonist, indicating that the anti-glioma effects of telmisartan rely on its PPARγ agonistic activity rather than AT1R blockade. This study highlights the importance of astrocytic IL-6-mediated paracrine signaling in glioma growth and the potential of telmisartan as an adjuvant therapy for patients with glioma, especially those with hypertension. [ABSTRACT FROM AUTHOR]

Abstract: Because both c-Src and iNOS are key regulatory enzymes in tumorigenesis, a new series of 4-heteroarylamino-3-quinolinecarbonitriles as potent dual inhibitors of both enzymes were designed, prepared, and evaluated for blocking multiple signaling pathways in cancer therapy. All compounds were evaluated by two related enzyme inhibition assays and an anti-proliferation assay in vitro. The results showed that most compounds could inhibit both enzymes, and several of them showed potent inhibition activity against different cancer cell lines. The best compound 20 (CPU-Y020) showed the IC50 values of 6.58 and 7.61μM toward colon cancer HT-29 and liver cancer HepG2 cell lines. [Copyright &y& Elsevier]

Background: The neutrophil to lymphocyte ratio (NLR) is a marker of inflammation and is associated with poor outcomes. We aimed to evaluate the role of the pretreatment NLR in predicting the outcomes after preoperative chemotherapy in patients with colorectal liver metastases (CRLM).Methods: A retrospective review was performed for 183 patients with CRLM. The NLR was measured before chemotherapy, and a receiver operating characteristic (ROC) curve was used to estimate the cutoff value. Logistic regressions were applied to analyze potential predictors of the pathological response. The Cox proportional hazard method was used to analyze survival.Results: The pre-chemotherapy NLR was 2.4 ± 1.1, whereas the post-chemotherapy NLR was 2.1 ± 1.6 (p < 0.001). The pretreatment NLR of 2.3 was a significant predictive marker for the pathological response. The pathological response rates were 67.1% in the patients with an NLR ≤ 2.3 and 48.1% in patients with an NLR > 2.3 (p = 0.01). Multivariate analysis revealed that the factors independently associated with pathological responses were a low pretreatment NLR (p = 0.043), radiological response to chemotherapy (p < 0.001), first-line chemotherapy (p = 0.001), and targeted therapy (p = 0.002). The median overall survival (OS) and recurrence-free survival (RFS) were worse in the increased NLR cohort than in the low NLR cohort (OS: 31.1 vs. 43.1 months, p = 0.012; RFS: 6.5 vs. 9.4 months, p = 0.06). According to multivariate analyses, a high pretreatment NLR was a significant predictor for both worse OS (HR = 2.43, 95%CI = 1.49-3.94, p < 0.001) and RFS (HR = 1.53, 95%CI = 1.08-2.18, p = 0.017).Conclusions: An increased pretreatment NLR was a significant predictor of a poor pathological response and worse prognosis after preoperative chemotherapy. The NLR is a simple biomarker for assessing chemotherapy efficacy. [ABSTRACT FROM AUTHOR]

XK469 is identified as a potent quinoxaline antineoplastic agent based on its significant clinical efficacy. It probably exerts its activity via DNA topoisomerase II (topo II) inhibition. To obtain more effective antineoplastic agents, a spectrum of peptidomimetic-type quinoxaline analogues of XK469 was herein designed, synthesized, and evaluated. Few compounds ( e.g . 13a and 13b ) exhibited obvious cytotoxicity indicated by in vitro anti-proliferative assay. SAR investigation revealed that introducing of hydrophobic tert -butylamine or dodecylamine moiety at the 3-position of quinoxaline core is favorable for achieving a better anti-proliferative potency, while peptidomimetic derivatives only yielded moderate cytotoxicity. Compounds with improved anti-proliferative activities also demonstrated decent anti-metastatic potencies comparable with that of doxorubicin (Doxo) based on in vivo mouse model study. The topo II-mediated kinetoplast DNA ( k DNA) decatenation assay as well as molecular docking studies implicated that these compounds tend to be potent topo II inhibitors. Overall, compounds 13a and 13b , 13b in particular, standed out from various assessments and might be promising candidates for further chemical optimization. [ABSTRACT FROM AUTHOR]

Highlights: [•] A novel peptide with the sequence of Asp-Pro-Asp-Ala-Asp-IIe-Leu-Gln was isolated from stiff silkworm. [•] This peptide shows the strong potency in reducing platelet aggregation. [•] This peptide shows low cytotoxicity to venous endothelial cell. [Copyright &y& Elsevier]

Centipedes have been used as traditional medicine for thousands of years in China. Centipede venoms consist of many biochemical peptides and proteins. Factor Xa (FXa) is a serine endopeptidase that plays the key role in blood coagulation, and has been used as a new target for anti-thrombotic drug development. A novel FXa inhibitor, a natural peptide with the sequence of Thr-Asn-Gly-Tyr-Thr (TNGYT), was isolated from the venom of Scolopendra subspinipes mutilans using a combination of size-exclusion and reverse-phase chromatography. The molecular weight of the TNGYT peptide was 554.3 Da measured by electrospray ionization mass spectrometry. The amino acid sequence of TNGYT was determined by Edman degradation. TNGYT inhibited the activity of FXa in a dose-dependent manner with an IC value of 41.14 mg/ml. It prolonged the partial thromboplastin time and prothrombin time in both in vitro and ex vivo assays. It also significantly prolonged whole blood clotting time and bleeding time in mice. This is the first report that an FXa inhibiting peptide was isolated from centipedes venom. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to assess the efficacy and accuracy of posterior screw fixation for unstable Hangman's fracture using intraoperative 3D fluoroscopy-based navigation. Methods: 14 patients with unstable Hangman's fractures (11 males and 3 females), ranging in age from 21 to 59 years, received posterior fixation assisted by an intraoperative 3D fluoroscopy-based navigation system: 11 Levine-Edwards type II and three type IIA cases. The American Spine Injury Association grade was D in 2 and E in 12 cases. Results: Operation time was 110 min (range 90-140 min). Hospital stay was 7.6 days (range 5-12 days). All the patients were observed for an average of 28.8 months (range 15-50 months). No screw-related injury to nerve, or vertebral artery was observed intraoperatively. An average of four screws/patient were inserted. Pedicle screws were placed into C2 and C3, and 5 screws were into the lateral mass of C3. Screw placement accuracy was evaluated using postoperative CT, according to the modified classification of Gertzbein and Robbins; one screw was grade 2 in C2, and three screws were grade 2 in the pedicle of C3. No grade 3 misplacement or clinical deficits were noted. C3 lateral mass screws were successfully inserted. Neck pain was relieved in each case. Neurologic status improved from D to E in 2 cases. Solid fusion was demonstrated in all the cases by static and dynamic films during the final follow-up. Conclusions: This case series demonstrates that intraoperative 3D fluoroscopy-based navigation is a safe, accurate, and effective tool for screw placement in patients with unstable Hangman's fracture. [ABSTRACT FROM AUTHOR]

Abstract: Previously, we demonstrated that LYG-202, a newly synthesized flavonoid with a piperazine substitution, exhibited obvious antitumor activity in vivo and in vitro. The exact mechanism of this new compound remains unclear. In the present study, we examined the effects of LYG-202 on reactive oxygen species (ROS) production and the downstream signaling pathway in the apoptosis of human hepatocellular carcinoma HepG2 cells. Pretreatment with NAC (N-acetylcysteine), a ROS production inhibitor, partly inhibited the apoptosis induced by LYG-202 via blocking the ROS generation. Further data revealed that LYG-202 induced ROS accumulation followed by a decrease in mitochondrial membrane potential (MMP), release of cytochrome c (Cyt c) and apoptosis-inducing factor (AIF) to cytosol, which induced apoptosis of the cells. Moreover, the mitogen-activated protein kinases (MAPK), the downstream effect of ROS accumulation including c-Jun N-terminal kinase (JNK) and p38 MAPK, could be activated by LYG-202. Taken together, the generation of ROS might play an important role in LYG-202-induced mitochondrial apoptosis pathway, which provided further support for LYG-202 as a novel anticancer therapeutic candidate. [Copyright &y& Elsevier]

Androgenetic alopecia (AGA) is the most common type of hair loss dysfunction. Secreted frizzled related protein 1 (SFRP1) is found to be associated with hair loss, but its role in AGA and the regulation mechanism of its transcription level is unclear. The aim of our study is to explore the expression of SFRP1 in AGA samples and its transcriptional mechanism. Male frontal and occipital scalp hair follicles from AGA patients were collected, and human dermal papilla cells (DPCs) were isolated and cultured. SFRP1 gene was cloned and constructed into recombinant plasmids to perform dual-luciferase reporter assay. Transcription factor binding sites were predicted through the Jaspar website and further confirmed by the chromatin immunoprecipitation (ChIP) assay. Expression of genes in DPCs was determined by immunofluorescence (IF) staining, quantitative real-time PCR (qRT-PCR) and western blotting. Our findings showed that SFRP1 was highly expressed in DPCs of AGA patients. The core promoter region of SFRP1 was from −100 to +50 bp and was found to be positively regulated by forkhead box C1 (FOXC1), a transcription factor related to hair growth, both at mRNA and protein level in DPCs. Our study suggests that FOXC1 plays an important role in regulating SFRP1 transcription, which may provide new insights into the development of therapeutic strategies for the treatment of AGA. [ABSTRACT FROM AUTHOR]

Background: Toxocara canis, the most prevalent helminth in dogs and other canines, is one of the socioeconomically important zoonotic parasites, particularly affecting pediatric and adolescent populations in impoverished communities. However, limited information is available regarding the proteomes of female and male adult T. canis. To address this knowledge gap, we performed a comprehensive proteomic analysis to identify the proteins with differential abundance (PDAs) and gender-specifically expressed proteins between the two sexes adult T. canis., Methods: The comparative proteomic analysis was carried out by the Orbitrap mass spectrometry (MS) with asymmetric track lossless (Astral) analyzer. The difference analysis was conducted using t-test and the proteins verification was achieved through parallel reaction monitoring (PRM). The potential biological functions of identified adult T. canis proteins and PDAs were predicted by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. The domain, transcription factor and subcellular localization of the identified proteins and PDAs were analyzed by InterPro, AnimalTFDB 4.0 and Cell-mPLOC 2.0 databases, respectively., Results: A total of 8565 somatic proteins of adult T. canis were identified. Compared to male adult, 682 up-regulated PDAs and 844 down-regulated PDAs were identified in female adult with P-values < 0.05 and |log 2 FC | > 1, including 139 proteins exclusively expressed in female and 272 proteins exclusively expressed in male. The GO annotation analysis using all PDAs revealed that the main biological processes, cellular components and molecular functions corresponded to aminoglycan metabolic process, extracellular region and protein tyrosine phosphatase activity, respectively. The KEGG analysis using all PDAs showed that the pathways were mainly associated with adipocytokine signaling pathway, proximal tubule bicarbonate reclamation and PPAR signaling pathway., Conclusions: This study reveals the differential protein expression between female and male adult T. canis, providing valuable resource for developing the novel intervention strategies against T. canis infection in humans and animals, especially from the perspective of sexual development and reproduction., (© 2024. The Author(s).)

Background: Interstitial lung disease (ILD) is the most widespread and fatal pulmonary complication of rheumatoid arthritis (RA). Existing knowledge on the prevalence and risk factors of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is inconclusive. Therefore, we designed this review to address this gap., Materials and Methods: To find relevant observational studies discussing the prevalence and/or risk factors of RA-ILD, EMBASE, Web of Science, PubMed, and the Cochrane Library were explored. The pooled odds ratios (ORs) / hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated with a fixed/ random effects model. While subgroup analysis, meta-regression analysis and sensitivity analysis were carried out to determine the sources of heterogeneity, the I 2 statistic was utilized to assess between-studies heterogeneity. Funnel plots and Egger's test were employed to assess publication bias. Following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines, our review was conducted., Results: A total of 56 studies with 11,851 RA-ILD patients were included in this meta-analysis. The pooled prevalence of RA-ILD was 18.7% (95% CI 15.8-21.6) with significant heterogeneity ( I 2 = 96.4%). The prevalence of RA-ILD was found to be more likely as a result of several identified factors, including male sex (ORs = 1.92 95% CI 1.70-2.16), older age (WMDs = 6.89, 95% CI 3.10-10.67), having a smoking history (ORs =1.91, 95% CI 1.48-2.47), pulmonary comorbidities predicted (HRs = 2.08, 95% CI 1.89-2.30), longer RA duration (ORs = 1.03, 95% CI 1.01-1.05), older age of RA onset (WMDs =4.46, 95% CI 0.63-8.29), positive RF (HRs = 1.15, 95%CI 0.75-1.77; ORs = 2.11, 95%CI 1.65-2.68), positive ACPA (ORs = 2.11, 95%CI 1.65-2.68), higher ESR (ORs = 1.008, 95%CI 1.002-1.014), moderate and high DAS28 (≥3.2) (ORs = 1.87, 95%CI 1.36-2.58), rheumatoid nodules (ORs = 1.87, 95% CI 1.18-2.98), LEF use (ORs = 1.42, 95%CI 1.08-1.87) and steroid use (HRs= 1.70, 1.13-2.55). The use of biological agents was a protective factor (HRs = 0.77, 95% CI 0.69-0.87)., Conclusion(s): The pooled prevalence of RA-ILD in our study was approximately 18.7%. Furthermore, we identified 13 risk factors for RA-ILD, including male sex, older age, having a smoking history, pulmonary comorbidities, older age of RA onset, longer RA duration, positive RF, positive ACPA, higher ESR, moderate and high DAS28 (≥3.2), rheumatoid nodules, LEF use and steroid use. Additionally, biological agents use was a protective factor.

Bromodomain-containing protein 4 (BRD4) inhibitors have been proven to be a promising option for anti-HIV-1 latency therapeutics. We herein describe the design, synthesis, and anti-HIV-1 latency bioevaluation of triazolopyridine derivatives as BRD4 inhibitors. Among them, compound 13d displayed favorable HIV-1 reactivation and prominent safety profile without triggering abnormal immune activation. It exerted strong synergism when combined with the PKC activator prostratin and has the same BRD4-targeting latency mechanism as observed with JQ1, by stimulating Tat-dependent HIV-1 elongation. Besides, it neither affected the antiviral efficacies of antiviral drugs nor caused secondary infections to uninfected cells and the latency reversing potency of 13d , in turn, was not affected by different classes of antiviral drugs., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease with strong heterogeneity, leading to variable clinical symptoms, which makes diagnosis and activity evaluation difficult., Methods: The original dataset of GSE88884 was analyzed to screen differentially expressed genes (DEGs) of SLE and the correlation between DEGs and clinical parameters (SLEDAI, anti-dsDNA, C3, and C4). The result was validated by microarray GSE121239 and SLE patients with RT-qPCR. Next, receiver operator characteristic (ROC) analysis, correlation analysis, and ordinal logistic regression were applied, respectively, to evaluate the capability of diagnosis and prediction of the candidate biomarker. Subsequently, the biological functions of the candidate biomarker were investigated through KEGG and GO enrichment, protein-protein interaction network, and the correlation matrix., Results: A total of 283 DEGs were screened, and seven of them were overlapped with SLE-related genes. DDX60 was identified as the candidate biomarker. Analyses of GSE88884, GSE121239, and SLE patients with RT-qPCR indicated that DDX60 expression level is significantly higher in patients with high disease activity. ROC analysis and the area under the ROC curve (AUC = 0.8818) suggested that DDX60 has good diagnostic performance. DDX60 expression level was positively correlated with SLEDAI scores ( r = 0.24). For every 1-unit increase in DDX60 expression value, the odds of a higher stage of activity of SLE disease are multiplied by 1.47. The function of DDX60 mainly focuses on IFN-I-induced antiviral activities, RIG-I signaling, and innate immune. Moreover, DDX60 plays a synergistic role with DDX58, IFIH1, OASL, IFIT1, and other related genes in the SLE pathogenesis . Conclusions . DDX60 is differently expressed in SLE, and it is significantly related to both serological indicators and the disease activity of SLE. We suggested that DDX60 might be a potential biomarker for SLE diagnosis and management., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Wu Chen et al.)

Purpose: This study examined the protective effects and mechanism of Lycium barbarum polysaccharides (LBP) in the context of intestinal barrier function and intestinal microbiota in mice with dextran sulfate sodium (DSS)-induced chronic ulcerative colitis (UC)., Methods: C57BL/6J male mice were assigned to a standard normal diet without DSS (control group), a normal diet with DSS (DSS group, 2% DSS given discontinuously for 3 weeks) or a normal diet supplemented with LBP (1% dry feed weight, LBP group, 2% DSS given discontinuously for 3 weeks) for a total of 8 weeks, at which point colonic tissues and caecal contents were collected., Results: LBP exerted a significant effect against colitis by increasing body weight, colon length, DAI and histopathological scores. LBP inhibited proinflammatory cytokines (IL-1β, IL-6, iNOS and TNF-α) expression, improved anti-inflammatory cytokine (IL-10) expression, promoted the expression of tight junction proteins (Occludin and ZO-1) via nuclear factor erythroid 2-related factor 2 (Nrf2) activation and decreased Claudin-2 expression to maintain the intestinal mucosal barrier. In addition, the abundances of some probiotics ( Ruminococcaceae , Lactobacillus , Butyricicoccus , and Akkermansia) were decreased with DSS treatment but increased obviously with LBP treatment. And LBP reduced the abundance of conditional pathogens associated with UC ( Mucispirillum and Sutterella ). Furthermore, LBP improved the production of short-chain fatty acids (SCFAs), including acetic acid, propionic acid, butyric acid and isobutyric acid., Conclusion: LBP can alleviate DSS-induced UC by regulating inflammatory cytokines and tight junction proteins. Moreover, LBP promotes probiotics, suppresses conditional pathogens and increases SCFAs production, showing a strong prebiotic effect.

WNT signaling plays an important role in cardiac development, but abnormal activity is often associated with cardiac hypertrophy, myocardial infarction, remodeling, and heart failure. The effect of WNT signaling on regulation of atrial natriuretic peptide (ANP) secretion is unclear. Therefore, the purpose of this study was to investigate the effect of Wnt agonist 1 (Wnta1) on ANP secretion and mechanical dynamics in beating rat atria. Wnta1 treatment significantly increased atrial ANP secretion and pulse pressure; these effects were blocked by U73122, an antagonist of phospholipase C. U73122 also abolished the effects of Wnta1-mediated upregulation of protein kinase C (PKC) β and γ expression, and the PKC antagonist Go 6983 eliminated Wnta1-induced secretion of ANP. In addition, Wnta1 upregulated levels of phospho-transforming growth factor-β activated kinase 1 (p-TAK1), TAK1 banding 1 (TAB1) and phospho-activating transcription factor 2 (p-ATF2); these effects were blocked by both U73122 and Go 6983. Wnta1-induced ATF2 was abrogated by inhibition of TAK1. Furthermore, Wnta1 upregulated the expression of T cell factor (TCF) 3, TCF4, and lymphoid enhancer factor 1 (LEF1), and these effects were blocked by U73122 and Go 6983. Tak1 inhibition abolished the Wnta1-induced expression of TCF3, TCF4, and LEF1 and Wnta1-mediated ANP secretion and changes in mechanical dynamics. These results suggest that Wnta1 increased the secretion of ANP and mechanical dynamics in beating rat atria by activation of PKC-TAK1-ATF2-TCF3/LEF1 and TCF4/LEF1 signaling mainly via the WNT/Ca2+ pathway. It is also suggested that WNT-ANP signaling is implicated in cardiac physiology and pathophysiology.

Silent information regulator factor 2‑related enzyme 1 (Sirt1) is involved in the regulation of cell senescence, gene transcription, energy balance and oxidative stress. However, the effect of Sirt1 on atrial natriuretic factor (ANF) secretion, especially under hypoxic conditions is unclear. The present study aimed to investigate the effect of Sirt1, regulated by NADPH oxidase 4 (NOX4), on ANF secretion in isolated beating rat atria during hypoxia. ANF secretion was analyzed using radioimmunoassays and protein expression levels were determined by western blotting and immunofluorescence staining. Intra‑atrial pressure was recorded using a physiograph. Hypoxia significantly upregulated Sirt1 and nuclear factor erythroid‑2‑related factor 2 (Nrf2) protein expression levels, together with significantly increased ANF secretion. Hypoxia‑induced protein expression of Sirt1 was significantly blocked by a NOX4 inhibitor, GLX351322, and Nrf2 protein expression levels were significantly abolished using the Sirt1 inhibitor, EX527. Hypoxia also significantly elevated the protein expression levels of phosphorylated‑Akt and sequestosome 1 and significantly downregulated Kelch‑like ECH‑associated protein 1 protein expression levels. These effects were significantly blocked by EX527, preventing hypoxia‑induced Nrf2 expression. An Nrf2 inhibitor, ML385, significantly abolished the hypoxia‑induced upregulation of activating transcription factor (ATF)3, ATF4, T cell factor (TCF)3 and TCF4/lymphoid enhancer factor 1 (LEF1) protein expression levels, and significantly attenuated hypoxia‑induced ANF secretion. These results indicated that Sirt1 and Nrf2, regulated by NOX4, can potentially stimulate TCF3 and TCF4/LEF1 signaling via ATF3 and ATF4 activation, thereby potentially participating in the regulation of ANF secretion in beating rat atria during hypoxia. In conclusion, intervening with the Sirt1/Nrf2/ATF signaling pathway may be an effective strategy for resisting oxidative stress damage in the heart during hypoxia.

Biologically active bacterial cellulose (BC) was efficiently synthesized in situ using wine pomace and its hydrolysate. The structural and biomechanical properties together with the biological functions of the BC were investigated. Functional BC from wine pomace and its enzymatic hydrolysate were of high purity and had higher crystallinity indexes (90.61% and 89.88%, respectively) than that from HS medium (82.26%). FTIR results proved the in-situ bindings of polyphenols to the functionalized BC. Compared to BC from HS medium, wine pomace-based BC had more densely packed ultrafine fibrils, higher diameter range distributions of fiber ribbon, but lower thermal decomposition temperatures, as revealed by the SEM micrographs and DSC data. Meanwhile, wine pomace-based BC exhibited higher loads in tensile strength and higher hardness (4.95 ± 0.31 N and 5.13 ± 0.63 N, respectively) than BC in HS medium (3.43 ± 0.14 N). Furthermore, BC synthesized from wine pomace hydrolysate exhibited a slower release rate of phenolic compounds, and possessed more antioxidant activities and better bacteriostatic effects than BC from wine pomace. These results demonstrate that BC synthesized in situ from wine pomace (especially from enzymatic hydrolysate) is a promising biomolecule with a potential application in wound dressing, tissue engineering, and other biomedical fields., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Severe Coronavirus Disease 2019 (COVID-19) is characterized by numerous complications, complex disease, and high mortality, making its treatment a top priority in the treatment of COVID-19. Integrated traditional Chinese medicine (TCM) and western medicine played an important role in the prevention, treatment, and rehabilitation of COVID-19 during the epidemic. However, currently there are no evidence-based guidelines for the integrated treatment of severe COVID-19 with TCM and western medicine. Therefore, it is important to develop an evidence-based guideline on the treatment of severe COVID-19 with integrated TCM and western medicine, in order to provide clinical guidance and decision basis for healthcare professionals, public health personnel, and scientific researchers involved in the diagnosis, treatment, and care of COVID-19 patients. We developed and completed the guideline by referring to the standardization process of the "WHO handbook for guideline development", the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system, and the Reporting Items for Practice Guidelines in Healthcare (RIGHT)., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

A cellulose-producing bacterium Komagataeibacter rhaeticus K15 was isolated from kombucha tea, and its metabolic pathways and cellulose synthesis operon were analyzed by genome sequencing. Different from the reported K. rhaeticus, the K15 produced little gluconic acid (2.26 g/L) when glucose was the sole carbon source and has the capacity for high cellulose production (4.76 g/L) with other carbon sources. Furthermore, six nitrogen-fixing genes were found to be responsible for the survival of K15 on a nitrogen-free medium. Based on its fermentation characteristics, K15 was cultured in a kitchen waste medium as a strategy for green and sustainable bacterial cellulose production. The SEM, XRD, and FTIR results indicated that synthesized cellulose has a mean diameter of 40-50 nm nanofiber, good crystallinity, and the same chemical structure. The K15 strain provides a highly viable alternative strategy to reduce the costs of bacterial cellulose production using agro-industrial residues as nutrient sources., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Here we aimed to investigate the difference in clinical characteristics and outcomes between pediatric and adult patients with COVID-19., Methods: A total of 333 consecutive patients with laboratory-confirmed SARS-CoV-2 infection treated in the departments of Internal medicine of Shenzhen Third People's Hospital from January 11 th to February 10 th , 2020 were included. The data were obtained from electronic medical records. The epidemiological data, clinical characteristics, length of hospital stays, and outcomes of pediatric and adult patients were compared., Results: Compared with adult patients, pediatric patients had a shorter time of symptom onset to hospitalization than adults [median time, 1 ( IQR , 1.0-1.0) d vs. 3 ( IQR , 2.0-6.0) d, P < 0.001], milder or fewer symptoms, less severe chest CT findings. The clinical severity classification of children was less severe than adults. Up to 15 th March, the end of the follow-up, 33 (100%) children and 292 (97.3%) adult patients had been discharged from hospital. Only 2 (0.7%) adult patients died, with an overall case mortality of 0.6%. The median length of hospital stay of pediatric patients was shorter than that of adult patients [19 (95% CI : 16.6-21.4) d vs. 21 (95% CI : 19.9-22.1) d, P = 0.024]., Conclusion: Pediatric patients with COVID-19 had milder or less clinical symptoms, less evident pulmonary imaging changes, better prognosis, and shorter length of hospital stay., (Copyright © 2020 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

Background: In predicting the risk for posthepatectomy complications, hepatectomy is traditionally classified into minor or major resection based on the number of resected segments. Recently, a new hepatectomy complexity classification was proposed. This study aimed to compare the value of the traditional and that of the new classification in perioperative outcomes prediction., Methods: Demographics, perioperative laboratory tests, intraoperative and postoperative outcomes, and follow-up data of patients with hepatocellular carcinoma who underwent liver resection were retrospectively analyzed., Results: A total of 302 patients were included in our study. Multivariable analysis of intraoperative variables showed that the complexity classification could independently predict the occurrence of blood loss > 800 mL, operation time > 4 h, intraoperative transfusion, and the use of Pringle's maneuver (all p < 0.05). For postoperative outcomes, the high-complexity group was independently associated with severe complications, and hepatic-related complications (all p < 0.05); the traditional classification was independently associated only with posthepatectomy liver failure (PHLF) (p = 0.004)., Conclusions: Complexity classification could be used to assess the difficulty of surgery and was independently associated with postoperative complications. The traditional classification did not reflect operation complexity and was associated only with PHLF.

Background: We aimed to study the incidence rate of hypoparathyroidism, its risk factors, and identify its predictive factors among patients with papillary thyroid carcinoma (PTC) who had undergone total or near-total thyroidectomy and central neck dissection (CND)., Methods: Ninety-three PTC patients who had undergone total or near-total thyroidectomy and CND were analyzed for hypoparathyroidism. The association between clinicopathological factors and hypoparathyroidism was tested by χ 2 test and multivariate logistic regression. The ROC curve and a 2×2 contingency table were used to evaluate the performance of postoperative parathyroid hormone (PTH) and serum calcium concentration in prediction of hypothyroidism., Results: Hypothyroidism was observed in 46 patients (49.5%), among whom 2 had permanent hypothyroidism. Univariate analysis showed that tumor size (P=0.034), extraglandular invasion (P=0.028), bilateral tumors (P=0.045), and bilateral CND (P=0.028) were significant risk factors of hypothyroidism. Multivariate analysis showed that extraglandular invasion (P=0.003) and bilateral CND (P=0.044) were independent risk factors. The patients with hypothyroidism had an average PTH level of 8.51 ng/L on the first day after surgery, and those without, 21.39 ng/L (P<0.001). When the PTH level on the first day after surgery was used to predict postoperative hypothyroidism, the ROC curve analysis showed that the area under curve (AUC) was 0.875., Conclusions: Hypothyroidism is a common complication of total or near-total thyroidectomy and CND, for which extraglandular invasion and bilateral CND are independently significant risk factors and the level of PTH is a reliable and early predictor., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2019.02.02). The authors have no conflicts of interest to declare., (2019 Translational Cancer Research. All rights reserved.)

Iguratimod is a new synthetic disease-modifying antirheumatic drug intended to treat patients with rheumatoid arthritis. A new method using recombinant human CYP450s yeast cells containing c-DNA expressed P450s was applied to identify the metabolic pathways of iguratimod and to prepare its metabolite. The metabolite was isolated, and its structure was identified by quadrupole time-of-flight-mass spectrometry and nuclear magnetic resonance. Furthermore, a selective and sensitive high performance liquid chromatography (HPLC) method was developed for the simultaneous quantification of iguratimod and its major metabolite in rat plasma for the first time. The results indicated that iguratimod was mainly metabolized to a metabolite by CYP2C9 and CYP2C19 in in-vitro study. The structure of the metabolite was identified as M2 (N-[3-(acetamido)-4-oxo-6-phenoxy-4H-chromen-7-yl]methanesulfonamide). HPLC assay was achieved on a C18 column using methanol-water containing 0.1% trifluoroacetic acid (55:45 v/v) at a flow rate of 1 mL/min with UV detection at 257 nm. Standard calibration curves were obtained in the concentration range of 0.5-20 µg/mL for iguratimod and its metabolite M2. The lower limits of detection of iguratimod and M2 in rat plasma were 0.1 and 0.25 µg/mL, respectively. The intra- and inter-day precision (RSD%) were within 5% for the two analytes. The average recoveries of the analytes were greater than 90%. In conclusion, recombinant human CYP450s whole-yeast transformation system could be successfully used to identify and prepare the major metabolite of iguratimod. The HPLC method we developed could be successfully applied to evaluate pharmacokinetics of iguratimod and its metabolite M2 in rats.

Purpose: We sought to determine the impact of surgical margin status on overall survival (OS) and recurrence pattern stratified by tumor burden., Materials and Methods: Data were collected from patients undergoing resection for colorectal liver metastases (CRLM). Tumor burden was calculated according to a newly proposed Tumor Burden Score (TBS) system, defined as the distance from the origin on a Cartesian plane that incorporated maximum tumor size and number of liver lesions. Patients were divided into low tumor burden group and high tumor burden group accordingly, and the impact of resection margin on overall survival was examined., Results: A total of 286 patients were available, among which R1 resection was observed in 88 patients. The median TBS for the entire cohort was 3.84. Metastases in the R1 group were characterized by more advanced disease and more complex resections. Compared with a R0 resection, a R1 resection offered an lower 5-year overall survival rate (46.8% vs. 22.1%, p = 0.001). Multivariate analysis identified R1 resection (p = 0.03), high TBS (p = 0.002), lymph nodes metastases (p = 0.003) and lymphovascular invasion (p = 0.03) of the primary colorectal tumor as the factors independently associated with worse survival. The survival benefit associated with negative margins was greater in patients with low TBS (55.7% vs. 21.7%, p = 0.021) than in patients with high TBS (31.8% vs. 24.5%, p = 0.116). R1 resection was associated with an increased true margin recurrence rate in patients with low TBS (32.3% vs. 13.4%; p = 0.014) and an increased risk of new intrahepatic metastases in patients with high TBS (43.9% vs. 26.7%; p = 0.034)., Conclusions: Negative margin is an important determinant of survival. The impact of positive margins is more pronounced in patients with low tumor burden., (Copyright © 2017. Published by Elsevier Ltd.)

LW-213 is a derivative of Wogonin and the anticancer activities of Wogonin have been reported. To study whether LW-213 inhibits cancer cells and explore a possible mechanism, we investigate the compound in several cancer cell lines. We found LW-213 arrests G2/M cycle in breast cancer cells by suppression of Akt/Gsk3β/β-catenin signaling pathway. In compound treated cells, cell cycle-related proteins cyclin A, cyclin B1, p-CDK1, p-Cdc25C, and p-Chk2 (Thr68) were upregulated, and β-catenin nuclear translocation was inhibited. Electrophoretic mobility shift assay revealed LW-213 inhibits binding of β-catenin/LEF complex to DNA. GSK3β inhibitor LiCl and siRNA against GSK3β partially reversed G2/M arrest in breast cancer MCF-7 cells. These results suggest LW-213 triggered G2/M cell cycle arrest through suppression of β-catenin signaling. In BALB/c mice, growth of xenotransplanted MCF-7 tumor was also inhibited after treatment of LW-213. Regulation of cyclin A, cyclin B1, and β-catenin by LW-213 in vivo was the same as in vitro study. In conclusion, we found LW-213 exerts its anticancer effect on cell proliferation and cell cycle through repression of Akt/Gsk3β/β-catenin signaling pathway. LW-213 could be a potential candidate for anticancer drug development., (© 2015 Wiley Periodicals, Inc.)

Angiogenesis is associated with the progression of multiple myeloma (MM). Wogonin is an active mono-flavonoid with remarkable antitumor activity. However, its impact on MM-stimulated angiogenesis remains largely unknown. Here, we demonstrated that wogonin decreased expression and secretion of pro-angiogenic factors in MM cells via c-Myc/HIF-1α signaling axis, reducing MM-stimulated angiogenesis and MM cell proliferation in vivo. Overexpression of c-Myc in MM cells disrupted the balance between VHL SUMOylation and ubiquitination, and thus inhibited proteasome-mediated HIF-1α degradation. Impaired function of VHL ubiquitination complex in c-Myc-overexpressing cells was fully reversed by wogonin treatment via increasing HIF-1α-VHL interaction and promoting HIF-1α degradation. Collectively, our in vitro and in vivo studies reveal for the first time that wogonin represses MM-stimulated angiogenesis and tumor progression via c-Myc/VHL/HIF-1α signaling axis.

Objective: To explore the clinical application value of Provider-Initiated HIV Testing and Counseling (PITC) by analyzing the positive rate of HIV tests for people in need of PITC and that of routine HIV tests., Methods: We retrospectively analyzed the demographic and epidemiologic data about the patients seeking PITC services or undergoing routine HIV tests in Nanjing Drum Tower Hospital between January and December 2013., Results: The positive rate of initial HIV screening was 1.98% in the PITC group and 0.24% in the routine test group, while that of confirmed HIV was 0. 40% in the former and 0.07% in the latter, both with statistically significant differences between the two groups (P < 0.01). The positive rate of HIV was markedly higher in males than in females, particularly in the PITC group., Conclusion: PITC has a high clinical value in HIV detection for targeted subjects and therefore deserves general application in dermatology.

Lymph node involvement is associated with recurrence in papillary thyroid carcinoma (PTC). The central neck compartment (level VI) lymph nodes are at the greatest risk of metastases from PTC, but the role of central neck dissection (CND) remains controversial, particularly in PTC without clinical cervical lymph node metastasis (cN 0 ). The present study aimed to identify risk factors of central cervical nodal metastasis and the safety of CND in patients with cN 0 PTC. The current study retrospectively investigated 389 patients who had been followed up for 12.0-25.5 months after surgery, and were divided into positive or negative lymph node involvement groups according to the pathological results subsequent to this surgery. Univariate and multivariate analyses were used to study the risk factor of central node involvement. The mean tumor size was 0.71±0.35 cm (range, 0.1-2.0 cm). There was no significant difference in the rate of central lymph node involvement based on age (<45 or ≥45 years) or tumor focality (unifocal or multifocal). However, there were significant differences based on gender, extra-thyroid invasion and tumor size (P<0.05). The incidence of transient hypoparathyroidism and transient vocal cord paralysis following CND was 12.34 and 4.11%, respectively. No patient experienced permanent hypoparathyroidism or vocal cord paralysis. One patient (1/389; 0.23%) experienced disease recurrence during the follow-up. A larger tumor size and the male gender were significantly associated with the central nodal metastasis rate for cN 0 PTC with a tumor size of <2.0 cm. CND for cN 0 PTC patients was safe and the tumor-associated recurrence rate following CND plus total thyroidectomy was low. The present study suggests that CND should be conducted for male cN 0 PTC patients with a larger tumor size (≥0.5 cm).