ß-sitosterol alleviates dextran sulfate sodium-induced experimental colitis via inhibition of NLRP3/Caspase-1/GSDMD-mediated pyroptosis.

Background: Inflammation-related NLRP3/Caspase-1/GSDMD-mediated pyroptosis is involved in the progression of ulcerative colitis (UC). ß-sitosterol (SIT) was reported to have anti-inflammatory effects on experimental colitis, while the regulation of SIT on pyroptosis is unclear. Therefore, the present study aimed to define the protective and healing effects of SIT on dextran sulfate sodium (DSS)-induced experimental UC rats and human epithelial colorectal adenocarcinoma cells (Caco-2) and explore the underlying mechanisms that are responsible for its effects on NLRP3/Caspase-1/GSDMD-mediated pyroptosis in UC. Methods: UC model rats were established by oral 4% DSS. Following colitis injury, the animals received SIT (doses of 50, 100, and 200 mg/kg) treatment for 2 weeks. For in vitro study, we exposed Caco-2-50 mg/mL DSS with or without SIT (concentrations of 8 and 16 µg/mL). Disease activity index (DAI) and histopathological injury were assessed in vivo. Activation proteins of nuclear factor kappa B (NF-κB) signaling axis, and tight junction-related proteins of zonula occludens-1 (ZO-1) and occludin were detected in colon tissues. TNF-α, IL-1ß, and IL-18 in serum and cell supernatant were measured by enzyme-linked immunosorbent assay (ELISA). Changes in NLRP3/Caspase-1/GSDMD-mediated pyroptosis signaling pathway activation were analyzed both in tissues and cells. Results: Our findings suggested that SIT treatment attenuated the severity of 4% DSS-induced UC by protecting rats from weight and colon length loss, and macroscopic damage. SIT also reduced proinflammatory factors production (TNF-α, IL-1ß, and IL-18) in serum and cell supernatant. Mechanistically, SIT downregulated the expression levels of pyroptosis-related proteins including Caspase-1, cleaved-Caspase-1, NLRP3, GSDMD, and GSDMD-N in colon tissues and Caco-2 cells. Further analysis indicated that SIT maintained the colonic barrier integrity by enhancing the protein expression of ZO-1 and occludin. Conclusion: We confirmed that SIT exerts protective and therapeutic effects on DSS-induced colitis injury by suppressing NLRP3/Caspase-1/GSDMD-mediated pyroptosis and inflammation response. These findings demonstrated that SIT could be a potential medication for UC treatment.

Selenium attenuates the association of co-exposure to arsenic, cadmium, and lead with cognitive function among Chinese community-dwelling older adults.

The effects of interactions between the toxic and essential metal mixtures on cognitive function are poorly understood. This study aims to identify the joint association of arsenic (As), cadmium (Cd), and lead (Pb) with cognitive function in older adults and the moderating role of selenium (Se), zinc (Zn), and copper (Cu) in this association. This study included 1000 community-dwelling older adults. Cognitive function was assessed by the Mini-Mental State Examination (MMSE). Blood concentrations of As, Cd, Pb, Se, Zn, and Cu were measured using inductively coupled plasma mass spectrometry. Linear regression and Bayesian kernel machine regression (BKMR) models were applied to assess the individual and joint associations of As, Cd, and Pb with cognitive function and to examine whether Se, Zn, and Cu (individually and as a mixture) modified these associations. In the adjusted single-metal models, both Cd (ß = - 0.37, 95% CI: - 0.73 to - 0.01) and Pb (ß = - 0.44, 95% CI: - 0.86 to - 0.02) were associated with MMSE scores, while Se (ß = 0.71, 95% CI: 0.30 to 1.13) exhibited a positive relationship with MMSE scores. Univariate exposure-response functions from BKMR models showed similar results. Moreover, the toxic metal mixture (As, Cd, and Pb) exhibited a significant negative association with MMSE scores in a dose-response pattern, with Pb being the greatest contributor within the mixture. The negative association of Pb alone or the toxic metal mixture with MMSE scores became weaker at higher concentrations of Se within its normal range, especially when Se levels were greater than the median (89.18 µg/L). Our findings support that Se can attenuate the negative associations of exposure to single Pb or the As, Cd, and Pb mixtures with cognitive function. Future prospective studies are needed to replicate our findings.

Increased levels of serum adenosine deaminase and increased risk of diabetic peripheral neuropathy in type 2 diabetes.

Background: Increased serum adenosine deaminase (ADA) levels have been shown to be involved in metabolic abnormalities and immune disequilibrium, which may in turn contribute to inflammatory diseases. This study aimed to determine whether increased serum ADA levels are related to diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes (T2D). Methods: This study was part of a series exploring the potential risks for DPN. All patients received DPN assessment based on neuropathic symptoms, neuropathic signs, and nerve conduction studies to calculate the composite Z score of nerve latency, amplitude and conduction velocity (NCV). DPN was confirmed by both at least a presentation of neuropathic symptoms/signs and an abnormal nerve conduction index. Serum ADA levels were also synchronously detected. Results: A total of 384 eligible patients with T2D were recruited for this study, and 24.5% (n=94) were determined to have DPN. Increases in serum ADA levels were closely associated with increases in composite Z score of latency (ß=0.263, t=5.273, p<0.001) and decreases in composite Z score of amplitude (ß=-0.126, t=-2.352, p=0.019) and NCV (ß=-0.201, t=-3.841, p<0.001) after adjusting for other clinical covariates. Moreover, each 5 U/L increase in serum ADA levels was associated with a 1.781-fold increased adjusted odds ratio of having DPN (95% confidence interval: 1.271-2.495). Furthermore, the optimal cut-off value of serum ADA levels to discriminate DPN was ≥14.2 U/L (sensitivity=59.57%, specificity=75.52% and Youden index=0.351) after analysis by receiver operating characteristic curve. Conclusions: Increased serum ADA levels may be a potential risk factor for DPN in patients with T2D.

High-normal serum carcinoembryonic antigen levels and increased risk of diabetic peripheral neuropathy in type 2 diabetes.

BACKGROUND: Increased serum carcinoembryonic antigen (CEA) levels are reported to be associated with various metabolic and inflammatory diseases. This study assessed whether high-normal serum CEA is related to diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes (T2D). METHODS: All subjects received DPN assessment based on neuropathic symptoms, neuropathic signs, and nerve conduction studies to calculate composite Z scores of nerve latency, amplitude and conduction velocity (NCV). DPN was confirmed by both at least a presentation of neuropathic symptoms/signs and an abnormal nerve conduction index. Serum CEA levels and other clinical indices were also synchronously detected. Multivariable linear regression analyses were used to determine the independent effects of serum CEA levels on nerve conduction indices, multivariable logistic regression analyses were used to determine the independent impact of CEA levels on the risk of DPN, and receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic capability of CEA levels to discriminate DPN. RESULTS: We ultimately recruited 402 eligible subjects with normal ranges of serum CEA for this study, and 25.4% (n = 102) were determined to have DPN. After adjusting for other clinical covariates, serum CEA levels were independently associated with the composite Z score for latency (ß = 0.132, t = 2.330, p = 0.021), amplitude (ß = - 0.164, t = - 2.838, p = 0.005) and NCV (ß = - 0.210, t = - 3.662, p < 0.001). Moreover, the prevalence of DPN in the first, second, third and fourth quartiles of CEA level was 12.9%, 19.0%, 29.4% and 40.4%, respectively (p for trend < 0.001); the corresponding adjusted odds ratios and 95% CIs for DPN in CEA quartiles were 1, 1.47 (0.45-4.82), 1.72 (0.54-5.53) and 4.58 (1.39-15.06), respectively. Furthermore, the optimal cut-off value of high-normal serum CEA to discriminate DPN was ≥ 2.66 ng/mL, with a Youden index of 0.28, sensitivity of 66.67% and specificity of 61.00%. CONCLUSIONS: Increased serum CEA levels within the normal range are closely linked to dysfunction of peripheral nerve conduction and the risk of DPN, and high-normal serum CEA levels are a potential risk factor for DPN in T2D.

Synthesis and biological evaluation of marine natural product, Cryptoechinuline D derivatives as novel antiangiogenic agents.

Tumor angiogenesis is an important biological process involved in the proliferation and migration of endothelial cells, regulated by Ang/Tie-2 signaling pathways, which is essential for tumor growth and metastasis. Therefore, blocking Ang/Tie-2 signaling pathways is a promising anti-angiogenic strategy for tumor treatment. 2,5-Diketopiperazines (DKPs) are a kind of bioactive compounds derived from marine fungi and they present a wide spectrum of pharmacological properties, particularly in the field of cancer treatment. Herein, a DKP marine natural product, Cryptoechinuline D (Cry D) was applied to structural modification and twelve derivatives were synthesized. Among which, compound 5 showed significant inhibitory activity against HUVECs with an IC50 value of 12.6 µmol/L, which weakened the proliferation, migration and invasion of HUVECs by inhibiting the Ang2/Tie-2 signaling pathway. The results of these evaluations indicated that compound 5 might be a promising anti-angiogeneic agent and worth further optimization and development for cancer therapy.

Increased serum cystatin C levels and responses of pancreatic α- and ß-cells in type 2 diabetes.

Background: Increased serum cystatin C (CysC) can predict the onset of type 2 diabetes (T2D). Meanwhile, impaired pancreatic α- and ß-cell functions get involved in the pathophysiological processes of T2D. So this study was to explore the relationships between serum CysC levels and pancreatic α- and ß-cell functions in T2D. Methods: In this cross-sectional observational study, a total of 2634 patients with T2D were consecutively recruited. Each recruited patient received a serum CysC test and oral glucose tolerance test for synchronous detection of serum C-peptide and plasma glucagon. As components of pancreatic ß-cell function, insulin secretion and sensitivity indices were evaluated by C-peptide area under the curve (AUC-CP) and C-peptide-substituted Matsuda's index (Matsuda-CP), respectively. Fasting glucagon (F-GLA) and post-challenge glucagon calculated by glucagon area under the curve (AUC-GLA) were used to assess pancreatic α-cell function. These skewed indices and were further natural log-transformed (ln). Results: With quartiles of serum CysC levels ascending, AUC-CP, F-GLA and AUC-GLA were increased, while Matsuda-CP was decreased (P for trend <0.001). Moreover, serum CysC levels were positively related to lnAUC-CP, lnF-GLA and lnAUC-GLA (r= 0.241, 0.131 and 0.208, respectively, P < 0.001), and inversely related to lnMatsuda-CP (r= -0.195, P < 0.001). Furthermore, after controlling for other relevant variables via multivariable linear regression analysis, serum CysC levels were identified to account for lnAUC-CP (ß= 0.178, t= 10.518, P < 0.001), lnMatsuda-CP (ß= -0.137, t= -7.118, P < 0.001), lnF-GLA (ß= 0.049, t= 2.263, P = 0.024) and lnAUC-GLA (ß= 0.121, t= 5.730, P < 0.001). Conclusions: Increased serum CysC levels may be partly responsible for increased insulin secretion from ß-cells, decreased systemic insulin sensitivity, and elevated fasting and postprandial glucagon secretion from α-cells in T2D.

m6A modification: recent advances, anticancer targeted drug discovery and beyond.

Abnormal N6-methyladenosine (m6A) modification is closely associated with the occurrence, development, progression and prognosis of cancer, and aberrant m6A regulators have been identified as novel anticancer drug targets. Both traditional medicine-related approaches and modern drug discovery platforms have been used in an attempt to develop m6A-targeted drugs. Here, we provide an update of the latest findings on m6A modification and the critical roles of m6A modification in cancer progression, and we summarize rational sources for the discovery of m6A-targeted anticancer agents from traditional medicines and computer-based chemosynthetic compounds. This review highlights the potential agents targeting m6A modification for cancer treatment and proposes the advantage of artificial intelligence (AI) in the discovery of m6A-targeting anticancer drugs. Three stages of m6A-targeting anticancer drug discovery: traditional medicine-based natural products, modern chemical modification or synthesis, and artificial intelligence (AI)-assisted approaches for the future.

Probing Indole Diketopiperazine-Based Hybrids as Environmental-Induced Products from Aspergillus sp. EGF 15-0-3.

Comprehensive analyses of the metabolite spectra of Aspergillus sp. EGF 15-0-3 under different culture conditions revealed the presence of unique environmental-induced metabolites exclusively from the rice medium. Subsequent target isolation afforded four unprecedented indole diketopiperazine-based hybrids with a pyrano[3',2':7,8]isochromeno[4,3-b]pyrazino[2,1-i]indole core (1 and 2) or a spiro[piperazine-2,2'-pyrano[3,4,5-de]chromene] scaffold (3 and 4). Putative biosynthetic pathways for 1-4, with Diels-Alder cycloadditions as key steps, were proposed. 1-4 exhibited selective cytotoxicities among several human cancer cells.

The Impact of Non-Invasive Ventilation Combined with Montelukast on Clinical Efficiency and Pulmonary Function in Patients with Bronchial Asthma Complicated by Obstructive Sleep Apnea Hypopnea Syndrome.

PURPOSE: Our study aims to explore the impact of non-invasive ventilation (NIV) alone or combined with montelukast on clinical efficiency and pulmonary function (PF) in treating patients with bronchial asthma complicated by obstructive sleep apnea hypopnea syndrome (OSAHS). METHODS: A total of 386 patients with bronchial asthma underwent sleep monitoring. Patients were divided into 3 groups according to the different treatment methods. The changes in PF, apnea hypopnea index (AHI) score and the level of inflammatory factors in all patients before and after treatment were recorded, and the clinical effect following treatment was noted. RESULTS: Following treatment, the clinical efficiency of Group 2 was significantly better than that of both Group 1and the control group, and the therapeutic effect in Group 1 was better than in the control group (P < .05). Before treatment, vital capacity (VC), peak expiratory flow (PEF), forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) and asthma control test (ACT) scores, AHI scores, C-reactive protein (CRP), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) index were compared between the 3 groups (P > .05). In contrast, after treatment the VC, PEF, FEV1/FVC and ACT, AHI, CRP and TNF-α scores and the IL-6 index in the 3 groups were improved compared with before treatment. The indices in Groups 1 and 2 were better than in the control group, and the VC, PEF, FEV1/FVC and ACT, AHI, CRP, and TNF-α scores and IL-6 index in Group 2 reported greater beneficial effect than in Group 1. CONCLUSION: The combination of NIV and montelukast exerts a beneficial effect in treating patients with bronchial asthma complicated with OSAHS, which holds the potential of effectively improving clinical symptoms and PF, reducing ACT and AHI scores and alleviating inflammatory reactions. Hence, the combination is valid and appropriate for clinical application.

Autosomal dominant tubulointerstitial kidney disease with a novel heterozygous missense mutation in the uromodulin gene: A case report.

BACKGROUND: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a progressive chronic disease that is inherited in an autosomal dominant fashion. Symptoms include hyperuricemia, gout, interstitial nephritis, renal cysts, and progressive renal damage that can lead to end-stage renal disease. Mutations in the uromodulin gene (UMOD) characterize the ADTKD-UMOD clinical subtype of this disease. To date, > 100 UMOD mutations have been identified. Early diagnosis of ADTKD-UMOD is important to treat the disease, slow down disease progression, and facilitate the identification of potentially affected family members. CASE SUMMARY: We report a 40-year-old man harboring a novel heterozygous missense mutation in UMOD (c.554G>T; p. Arg185Leu). The patient had hyperuricemia, gout, and chronic kidney disease. The same mutation was detected in his daughter, aunt and cousin. CONCLUSION: A single nucleotide substitution in exon 3 of UMOD was responsible for the heterozygous missense mutation (c.554G>T, p.Arg185Leu).

IL-6/STAT3 signaling activation exacerbates high fructose-induced podocyte hypertrophy by ketohexokinase-A-mediated tristetraprolin down-regulation.

Glomerular hypertrophy is a crucial factor of severe podocyte damage and proteinuria. Our previous study showed that high fructose induced podocyte injury. The current study aimed to explore a novel molecular mechanism underlying podocyte hypertrophy induced by high fructose. Here we demonstrated for the first time that high fructose significantly initiated the hypertrophy in rat glomeruli and differentiated human podocytes (HPCs). Consistently, it induced inflammatory response with the down-regulation of anti-inflammatory factor zinc-finger protein tristetraprolin (TTP) and the activation of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling in these animal and cell models. Subsequently, high-expression of microRNA-92a-3p (miR-92a-3p) and its target protein cyclin-dependent kinase inhibitor p57 (P57) down-regulation, representing abnormal proliferation and apoptosis, were observed in vivo and in vitro. Moreover, high fructose increased ketohexokinase-A (KHK-A) expression in rat glomeruli and differentiated HPCs. Exogenous IL-6 stimulation up-regulated IL-6/STAT3 signaling and miR-92a-3p, reduced P57 expression and promoted podocyte proliferation, apoptosis and hypertrophy in vitro. The data from anti-inflammatory agent maslinic acid treatment or TTP siRNA transfection showed that high fructose may decrease TTP to activate IL-6/STAT3 signaling in podocyte overproliferation and apoptosis, causing podocyte hypertrophy. Whereas, KHK-A siRNA transfection remarkably restored high fructose-induced TTP down-regulation, IL-6/STAT3 signaling activation, podocyte overproliferation, apoptosis and hypertrophy in differentiated HPCs. Taken together, these results suggested that high fructose possibly increased KHK-A expression to down-regulate TTP, subsequently activated IL-6/STAT3 signaling to interfere with podocyte proliferation and apoptosis by up-regulating miR-92a-3p to suppress P57 expression, causing podocyte hypertrophy. Therefore, the inactivation of IL-6/STAT3 to relieve podocyte hypertrophy mediated by inhibiting KHK-A to increase TTP may be a novel strategy for high fructose diet-associated podocyte injury and proteinuria.

The relationship between adenosine deaminase and heart rate-corrected QT interval in type 2 diabetic patients.

BACKGROUND: Prolonged heart rate-corrected QT (QTc) interval may reflect poor prognosis of patients with type 2 diabetes (T2D). Serum adenosine deaminase (ADA) levels are related to hyperglycemia, insulin resistance (IR) and inflammation, which may participate in diabetic complications. We investigated the association of serum ADA levels with prolonged QTc interval in a large-scale sample of patients with T2D. METHODS: In this cross-sectional study, a total of 492 patients with T2D were recruited. Serum ADA levels were determined by venous blood during fasting. QTc interval was estimated from resting 12-lead ECGs, and prolonged QTc interval was defined as QTc > 440 ms. RESULTS: In this study, the prevalence of prolonged QTc interval was 22.8%. Serum ADA levels were positively associated with QTc interval (r = 0.324, P < 0.0001). The proportion of participants with prolonged QTc interval increased significantly from 9.2% in the first tertile (T1) to 24.7% in the second tertile (T2) and 39.0% in the third tertile (T3) of ADA (P for trend < 0.001). After adjusting for other possible risk factors by multiple linear regression analysis, serum ADA level was still significantly associated with QTc interval (ß = 0.217, t = 3.400, P < 0.01). Multivariate logistic regression analysis showed that female (OR 5.084, CI 2.379-10.864, P < 0.001), insulin-sensitizers treatment (OR 4.229, CI 1.290-13.860, P = 0.017) and ADA (OR 1.212, CI 1.094-1.343, P < 0.001) were independent contributors to prolonged QTc interval. CONCLUSIONS: Serum ADA levels were independently associated with prolonged QTc interval in patients with T2D.

Inverse relationship between serum adenosine deaminase levels and islet beta cell function in patients with type 2 diabetes.

OBJECTIVE: Type 2 diabetes (T2D) is a chronic low-grade inflammatory disease, which characterized by islet beta cell dysfunction. Serum adenosine deaminase (ADA) is an important enzyme that regulates the biological activity of insulin, and its levels are greatly increased in inflammatory diseases with insulin resistance. The present study was designed to explore the relationship between serum ADA levels and islet beta cell function in patients with T2D. METHODS: This cross-sectional study recruited 1573 patients with T2D from the Endocrinology Department of the Affiliated Hospital 2 of Nantong University between 2015 and 2018. All participants were received serum ADA test and oral glucose tolerance test (OGTT). Insulin sensitivity index (assessed by Matsuda index using C-peptide, ISIM-cp), insulin secretion index (assessed by ratio of area under the C-peptide curve to glucose curve, AUCcp/glu) and islet beta cell function (assessed by insulin secretion-sensitivity index 2 using C-peptide, ISSI2cp) were derived from OGTT. And other clinical parameters, such as HbA1c, were also collected. RESULTS: It was showed that HbA1c was significantly increased, while ISIM-cp, AUCcp/glu and ISSI2cp significantly decreased, across ascending quartiles of serum ADA levels. Moreover, serum ADA levels were negatively correlated with ISSI2cp (r = - 0.267, p < 0.001). Furthermore, after adjusting for other clinical parameters by multiple linear regression analysis, serum ADA levels were still independently associated with ISSI2cp (ß = - 0.125, t = - 5.397, p < 0.001, adjusted R2 = 0.459). CONCLUSIONS: Serum ADA levels are independently associated with islet beta cell function in patients with T2D.

1ß-OH-arenobufagin induces mitochondrial apoptosis in hepatocellular carcinoma through the suppression of mTOR signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Chansu, dried secretions from Bufonidae, has long been used for cancer treatment as a traditional Chinese medicine. In searching for effective anti-hepatoma agents from Chansu, our preliminary drug screening found that a bufadienolide, namely 1ß-hydroxyl-arenobufagin (1ß-OH-ABF), displays anti-hepatoma activities. However, the anti-hepatoma effects and molecular mechanisms of 1ß-OH-ABF have not been defined. AIM OF THE STUDY: To evaluate the anti-hepatoma activity of 1ß-OH-ABF against liver cancer Hep3B and HepG2 cells in vitro and in vivo, as well as explore the underlying mechanisms. MATERIALS AND METHODS: The anti-proliferative effects of 1ß-OH-ABF on liver cancer Hep3B, HepG2, HuH7, SK-HEP-1 and normal hepatocyte LO2 cells were examined by MTT assay and colony formation assay. Hoechst 33258 staining and Annexin V-FITC/PI staining assay were used to analyze apoptosis induced by 1ß-OH-ABF. The collapse of the mitochondrial membrane potential (ΔΨm) was detected by JC-1 staining assay. Western blotting was used to examine the expression levels of targeted proteins. The role of mTOR in 1ß-OH-ABF-induced apoptosis was investigated using small interfering RNA (siRNA) transfection. Zebrafish xenograft model was established to evaluate the anti-hepatoma effects of 1ß-OH-ABF in vivo. RESULTS: We found that 1ß-OH-ABF inhibits the proliferation of Hep3B, HepG2, HuH7, SK-HEP-1 cells but has little cytotoxicity towards LO2 cells. 1ß-OH-ABF induces mitochondria dysfunction and triggers mitochondria apoptotic pathway, which is accompanied by the loss of ΔΨm, upregulation and translocation of Bax, as well as cleavages of caspase-9, caspase-3 and PARP. Mechanistically, 1ß-OH-ABF markedly decreases the expression level of p-AKT/AKT and p-mTOR (Ser2248 and Ser2481)/mTOR in a time-dependent manner. Inhibition of mTOR by siRNA strengthens 1ß-OH-ABF-mediated apoptosis. Critically, 1ß-OH-ABF shows a marked in vivo anti-hepatoma effect on human Hep3B cell xenografts in zebrafish model. CONCLUSION: 1ß-OH-ABF induces mitochondrial apoptosis through the suppression of mTOR signaling in vitro and in vivo, indicating that 1ß-OH-ABF may serve as a potential agent for the treatment of liver cancer.

Clinical features and risk factors in patients with asthma complicated with obstructive sleep apnea-hypopnea syndrome: a hospital-based study.

PURPOSE: The current study was conducted to explore the clinical features and risk factors of patients with asthma complicated by obstructive sleep apnea-hypopnea syndrome (OSAHS). METHODS: Patients with asthma who underwent polysomnography in our hospital from August 2017 to December 2019 were enrolled in the study. Data on demographics, pulmonary function testing, polysomnography, blood gases, mean pulmonary artery pressure, and vascular endothelial growth factor (VEGF) were compared between the two groups. RESULTS: Of 238 patients with asthma, 93 who also had OSAHS formed the observation group and were subclassified into mild (n = 33), moderate (n = 41), and severe (n = 19) categories, while 145 patients with asthma alone were assigned to the control group. No significant differences were found in sex, age, course of disease, or pulmonary function between the two groups (P > 0.05), while the observation group showed more frequent allergic rhinitis and had greater BMI, neck circumference, mean pulmonary artery pressure (mPAP), and VEGF than those in the control group (P < 0.001). The peak expiratory flow (PEF), forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and FEV1/FVC in the mild group and the moderate group were higher than those in the severe group (P < 0.001). The durations of AHI and SaO2 < 90% in the mild group and the moderate group were shorter than that in the severe group, and the lowest level of SaO2 in the mild group and the moderate group was higher than that in the severe group (P <  0.05). The mPAP and VEGF of the mild and moderate groups were lower than those of severe group (P < 0.001), with mild group lower than moderate group (P < 0.001). CONCLUSION: Significant differences in allergic rhinitis, BMI, neck circumference, AHI, SaO2, mPAP, and VEGF were observed in patients with asthma complicated by OSAHS. These parameters are risk factors associated with asthma complicated by OSAHS.

Polydatin enhances glomerular podocyte autophagy homeostasis by improving Nrf2-dependent antioxidant capacity in fructose-fed rats.

High fructose is considered a causative factor for oxidative stress and autophagy imbalance that cause kidney pathogenesis. Antioxidant polydatin isolated from Polygonum cuspidatum has been reported to protect against kidney injury. In this study, polydatin was found to ameliorate fructose-induced podocyte injury. It activated mammalian target of rapamycin complex 1 (mTORC1) and suppressed autophagy in glomeruli of fructose-fed rats and in fructose-exposed conditionally immortalized human podocytes (HPCs). Polydatin also enhanced nuclear factor-E2-related factor 2 (Nrf2)-dependent antioxidant capacity to suppress fructose-induced autophagy activation in vivo and in vitro, with the attenuation of fructose-induced up-regulation of cellular light chain 3 (LC3) II/I protein levels. This effect was abolished by Raptor siRNA in fructose-exposed HPCs. These results demonstrated that polydatin ameliorated fructose-induced autophagy imbalance in an mTORC1-dependent manner via improving Nrf2-dependent antioxidant capacity during podocyte injury. In conclusion, polydatin with anti-oxidation activity suppressed autophagy to protect against fructose-induced podocyte injury.

Discovery of a novel EGFR ligand DPBA that degrades EGFR and suppresses EGFR-positive NSCLC growth.

Epidermal growth factor receptor (EGFR) activation plays a pivotal role in EGFR-driven non-small cell lung cancer (NSCLC) and is considered as a key target of molecular targeted therapy. EGFR tyrosine kinase inhibitors (TKIs) have been canonically used in NSCLC treatment. However, prevalent innate and acquired resistances and EGFR kinase-independent pro-survival properties limit the clinical efficacy of EGFR TKIs. Therefore, the discovery of novel EGFR degraders is a promising approach towards improving therapeutic efficacy and overcoming drug resistance. Here, we identified a 23-hydroxybetulinic acid derivative, namely DPBA, as a novel EGFR small-molecule ligand. It exerted potent in vitro and in vivo anticancer activity in both EGFR wild type and mutant NSCLC by degrading EGFR. Mechanistic studies disclosed that DPBA binds to the EGFR extracellular domain at sites differing from those of EGF and EGFR. DPBA did not induce EGFR dimerization, phosphorylation, and ubiquitination, but it significantly promoted EGFR degradation and repressed downstream survival pathways. Further analyses showed that DPBA induced clathrin-independent EGFR endocytosis mediated by flotillin-dependent lipid rafts and unaffected by EGFR TKIs. Activation of the early and late endosome markers rab5 and rab7 but not the recycling endosome marker rab11 was involved in DPBA-induced EGFR lysosomal degradation. The present study offers a new EGFR ligand for EGFR pharmacological degradation and proposes it as a potential treatment for EGFR-positive NSCLC, particularly NSCLC with innate or acquired EGFR TKI resistance. DPBA can also serve as a chemical probe in the studies on EGFR trafficking and degradation.

Natural products as potent inhibitors of hypoxia-inducible factor-1α in cancer therapy.

Hypoxia is a prominent feature of tumors. Hypoxia-inducible factor-1α (HIF-1α), a major subunit of HIF-1, is overexpressed in hypoxic tumor tissues and activates the transcription of many oncogenes. Accumulating evidence has demonstrated that HIF-1α promotes tumor angiogenesis, metastasis, metabolism, and immune evasion. Natural products are an important source of antitumor drugs and numerous studies have highlighted the crucial role of these agents in modulating HIF-1α. The present review describes the role of HIF-1α in tumor progression, summarizes natural products used as HIF-1α inhibitors, and discusses the potential of developing natural products as HIF-1α inhibitors for the treatment of cancer.

Molecular mechanisms of bufadienolides and their novel strategies for cancer treatment.

Bufadienolides are cardioactive C24 steroids with an α-pyrone ring at position C17. In the last ten years, accumulating studies have revealed the anticancer activities of bufadienolides and their underlying mechanisms, such as induction of autophagy and apoptosis, cell cycle disruption, inhibition of angiogenesis, epithelial-mesenchymal transition (EMT) and stemness, and multidrug resistance reversal. As Na+/K+-ATPase inhibitors, bufadienolides have inevitable cardiotoxicity. Short half-lives, poor stability, low plasma concentration and oral bioavailability in vivo are obstacles for their applications as drugs. To improve the drug potency of bufadienolides and reduce their side effects, prodrug strategies and drug delivery systems such as liposomes and nanoparticles have been applied. Therefore, systematic and recapitulated information about the antitumor activity of bufadienolides, with special emphasis on the molecular or cellular mechanisms, prodrug strategies and drug delivery systems, is of high interest. Here, we systematically review the anticancer effects of bufadienolides and the molecular or cellular mechanisms of action. Research advancements regarding bufadienolide prodrugs and their tumor-targeting delivery strategies are critically summarized. This work highlights recent scientific advances regarding bufadienolides as effective anticancer agents from 2011 to 2019, which will help researchers to understand the molecular pathways involving bufadienolides, resulting in a selective and safe new lead compound or therapeutic strategy with improved therapeutic applications of bufadienolides for cancer therapy.

The value of red blood cell distribution width, neutrophil-to-lymphocyte ratio, and hemoglobin-to-red blood cell distribution width ratio in the progression of non-small cell lung cancer.

BACKGROUND: Lung cancer is the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for 85% of all lung cancer cases. Inflammation has been proven to be one of the characteristics of malignant tumors. Chronic inflammatory response mediated by cytokines in the tumor microenvironment is an important factor in tumorigenesis. The purpose of this study was to observe and evaluate the value of red blood cell distribution width (RDW), neutrophil-to-lymphocyte ratio (NLR), and hemoglobin-to-red blood cell distribution width ratio (HRR) in the progression of NSCLC. METHODS: A total of 245 patients with NSCLC, 97 patients with benign pulmonary nodules, and 94 healthy volunteers were included in this study. Factors, such as age, gender, smoking history, histological type, lymph node metastasis, distant metastasis, TNM stage, and differentiation degree were statistically analyzed. The correlation of RDW, NLR, and HRR of patients with NSCLC with other clinical experimental parameters were also analyzed. Then, the diagnostic value of RDW, NLR, and HRR in the progression of NSCLC was evaluated. RESULTS: RDW, NLR, and HRR could be used to distinguish patients with NSCLC from healthy controls (p < 0.05). In addition, only the RDW in the NSCLC group with III-IV stage was significantly different from that in the benign pulmonary nodules group (p = 0.033), while NLR and HRR could significantly distinguish patients with NSCLC and benign pulmonary nodules (p < 0.001). RDW and NLR were positively correlated with NSCLC stage, whereas HRR was negatively correlated with NSCLC stage. RDW, NLR, and HRR were also significantly associated with the differentiation degree of NSCLC (p < 0.05). The ROC curve analysis showed that the combination of RDW with NLR, HRR, and CEA could show significantly higher diagnostic value than any one marker alone (AUC = 0.925, 95% CI: 0.897-0.954, and sensitivity and specificity of 79.60% and 93.60%, respectively). CONCLUSION: RDW, NLR, and HRR can be utilized as simple and effective biomarkers for the diagnosis and evaluation of NSCLC progression.