Serum oxidative biomarkers associated with genital HPV infection and cervical lesions in women.

Human papillomavirus (HPV) infection is a major cause of cervical cancer. Studies showed HPV carcinogenesis may be induced by oxidative stress affecting the host immune system. The objective of this study is to evaluate levels of four circulating oxidative stress biomarkers associated with the HPV infection, persistence, and cervical lesion status in women. The three serum biomarkers measuring oxidative damage to biomolecules (8-oxodG, 8-oxo-7,8-dihydro-2'-deoxyguanosine [8-oxodG] for DNA, 4-hydroxy-2-nonenal [4-HNE] for lipid, and protein carbonyl [PC] for protein) and one antioxidant (glutathione, GSH) collected from 38 women were evaluated. The PC levels were significantly higher for women with oncogenic HPV infection (p = 0.047) and persistence (p = 0.053) based on the unadjusted linear model. In particular, women with ≥3 oncogenic HPV types had a higher PC level than those without HPV infection (p = 0.041). Women with low-grade squamous intraepithelial lesions showed an elevated PC (p = 0.058). These trends remained similar after adjusting for age. The GSH levels were lower for women infected with ≥3 oncogenic HPV types based on age-adjusted results (p = 0.061). This study supported that serum PC was associated with HPV infection, persistence, and cervical lesions, so it can potentially be used to monitor HPV carcinogenesis. Further large-scale studies will be needed to confirm these findings.

Exclusive liquor and cocktail consumption is associated with at-risk fibrosis among nonheavy alcohol users with metabolic dysfunction-associated steatotic liver disease.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol consumption have both increased in recent years, and there is debate as to whether nonheavy alcohol use is safe in MASLD. We analyzed the association between different nonheavy alcohol use patterns and at-risk liver fibrosis among individuals with MASLD. METHODS: We conducted a cross-sectional study of 1072 eligible National Health and Nutrition Examination Survey participants with MASLD who reported nonheavy alcohol consumption. We used vibration-controlled transient elastography to define the primary outcome of at-risk liver fibrosis as >8.2 kPa (stage F2-F4). Multivariable logistic regression models were used to determine the association of different alcohol consumption patterns (average drinks/day, drinking days/week, weekly alcohol intake, type of alcoholic beverage) and at-risk hepatic fibrosis, controlling for demographic/socioeconomic, lifestyle/dietary, and metabolic risk factors. RESULTS: Exclusive liquor or cocktail drinkers had a 5.02-fold odds of at-risk fibrosis (95% CI: 1.15-21.95) compared with non-drinkers when controlling for potential confounders. While consuming an average of 2 drinks/day, ≥3 drinking days/week, or 1-3 drinks/week appeared to have a lower association with at-risk fibrosis when controlling for demographic/socioeconomic risk factors, the association was not present after controlling for lifestyle/dietary and metabolic risk factors. CONCLUSIONS: There is an association between exclusive liquor/cocktail consumption and at-risk liver fibrosis in patients with MASLD who report nonheavy alcohol consumption.

Assessing thickness and stiffness of superficial/deep masticatory muscles in orofacial pain: an ultrasound and shear wave elastography study.

INTRODUCTION: Sonoelastography has been increasingly used for non-invasive evaluation of the mechanical features of human tissues. The interplay between orofacial pain and regional muscle activity appears clinically paramount, although only few imaging studies have investigated this association. Using shear wave sonoelastography (SWS), this study ascertained whether orofacial pain induced alterations in the stiffness of superficial and deep masticatory muscles. METHODS: All participants were systematically evaluated for oral/facial-related conditions, including the area and intensity of pain. SWS was applied to measure the stiffness of the bilateral masseter, temporalis, and lateral pterygoid muscles. The association between orofacial pain and muscle stiffness/thickness was investigated using a generalized estimating equation for adjusting the influence of age, sex, laterality, and body mass index on muscle thickness/stiffness. RESULTS: A total of 98 participants were included in the present study: 48 asymptomatic controls, 13 patients with unilateral pain, and 37 patients with bilateral orofacial pain. The reliability, quantified by the intraclass correlation coefficient for muscle stiffness measurement, ranged from 0.745 to 0.893. Orofacial pain at the individual muscle level was significantly associated with masseter muscle stiffness. A trend of increased stiffness (p = 0.06) was also observed in relation to the painful side of the temporalis muscle. No significant correlation was identified between the numeric rating scales for pain and stiffness measurements. CONCLUSIONS: SWS provides reliable stiffness measurements for the superficial and deep masticatory muscles. The ipsilateral masseter and temporalis muscles might be stiffer than those on the side without orofacial pain. Future studies using the present sonoelasotography protocol can be designed to investigate the stiffness changes in the target muscles after interventions.

Shear wave sonoelastography (SWS) can reliably assess the stiffness of masticatory muscles.Orofacial pain, particularly affecting the ipsilateral masseter muscles, exhibited increased stiffness, with a similar trend observed in the temporalis muscle as revealed by SWS. However, the stiffness of the lateral pterygoid muscle appeared to remain unaffected.These findings establish a foundational framework for the objective and quantitative assessment of orofacial pain and indicate the potential utility of SWS as a tool for evaluating treatment outcomes.

Sugar-Sweetened Beverages and Artificially Sweetened Beverages Consumption and the Risk of Nonalcoholic Fatty Liver (NAFLD) and Nonalcoholic Steatohepatitis (NASH).

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are fast becoming the most common chronic liver disease and are often preventable with healthy dietary habits and weight management. Sugar-sweetened beverage (SSB) consumption is associated with obesity and NAFLD. However, the impact of different types of SSBs, including artificially sweetened beverages (ASBs), is not clear after controlling for total sugar intake and total caloric intake. The aim of this study was to examine the association between the consumption of different SSBs and the risk of NAFLD and NASH in US adults. The representativeness of 3739 US adults aged ≥20 years old who had completed 24 h dietary recall interviews and measurements, including dietary, SSBs, smoking, physical activity, and liver stiffness measurements, were selected from the National Health and Nutrition Examination Survey 2017-2020 surveys. Chi-square tests, t-tests, and weighted logistic regression models were utilized for analyses. The prevalence of NASH was 20.5%, and that of NAFLD (defined without NASH) was 32.7% of US. adults. We observed a higher prevalence of NASH/NAFLD in men, Mexican-Americans, individuals with sugar intake from SSBs, light-moderate alcohol use, lower physical activity levels, higher energy intake, obesity, and medical comorbidities. Heavy sugar consumption through SSBs was significantly associated with NAFLD (aOR = 1.60, 95% CI = 1.05-2.45). In addition, the intake of ASBs only (compared to the non-SSB category) was significantly associated with NAFLD (aOR = 1.78, 95% CI = 1.04-3.05), after adjusting for demographic, risk behaviors, and body mass index. A higher sugar intake from SSBs and exclusive ASB intake are both associated with the risk of NAFLD.

The Effects of a Curcumin Derivative and Osimertinib on Fatty Acyl Metabolism and Mitochondrial Functions in HCC827 Cells and Tumors.

Drug combination therapy is a key approach in cancer treatments, aiming to improve therapeutic efficacy and overcome drug resistance. Evaluation of intracellular response in cancer cells to drug treatment may disclose the underlying mechanism of drug resistance. In this study, we aimed to investigate the effect of osimertinib, a tyrosine kinase inhibitor (TKI), and a curcumin derivative, 35d, on HCC827 cells and tumors by analyzing alterations in metabolome and related regulations. HCC827 tumor-bearing SCID mice and cultured HCC827 cells were separately examined. The treatment comprised four conditions: vehicle-only, 35d-only, osimertinib-only, and a combination of 35d and osimertinib. The treated tumors/cells were subsequently subjected to metabolomics profiling, fatty acyl analysis, mitochondrial potential measurement, and cell viability assay. Osimertinib induced changes in the ratio of short-chain (SC) to long-chain (LC) fatty acyls, particularly acylcarnitines (ACs), in both tumors and cells. Furthermore, 35d enhanced this effect by further lowering the SC/LC ratio of most ACs. Osimertinib and 35d also exerted detrimental effects on mitochondria through distinct mechanisms. Osimertinib upregulated the expression of carnitine palmitoyltransferase I (CPTI), while 35d induced the expression of heat shock protein 60 (HSP60). The alterations in ACs and CPTI were correlated with mitochondrial dysfunction and inhibited cell growth. Our results suggest that osimertinib and 35d disrupted the fatty acyl metabolism and induced mitochondrial stress in cancer cells. This study provides insights into the potential application of fatty acyl metabolism inhibitors, such as osimertinib or other TKIs, and mitochondrial stress inducers, such as curcumin derivatives, as combination therapy for cancer.

Mediation of BMI on 25-Hydroxyvitamin D Levels in U.S. Adults with Sugar-Sweetened Beverages Consumption.

Body mass index (BMI) as well as sugar-sweetened beverages (SSB) has been suggested to independently decrease 25-hydroxyvitamin D (25(OH)D). However, the relationship between SSB, BMI, and 25(OH)D is uncertain. This study aimed to investigate the potential mediating role of BMI in the association between SSB intake and 25(OH)D. A total of 4505 representative U.S. adults aged above 20 years and without liver conditions were selected from the 2013-2014 NHANES. All analyses were performed under survey modules with appropriate sampling weights. The prevalence of 25(OH)D insufficiency and deficiency was 37.8% and 24.1% in U.S. adults, respectively. Compared with non-SSB consumers, an increased risk of vitamin D deficiency was found in either heavy SSB consumers or soda consumers, respectively (aOR = 2.10, 95% CI = 1.25-3.54 in heavy SSB consumers; aOR = 1.61, 95% CI = 1.06-2.44 in soda consumers). Around 21.3% of the total effect of sugar intake from SSB on decreased 25(OH)D was explained by BMI. In conclusion, high total sugar intake from SSB and BMI independently contribute to lower 25(OH)D, and BMI mediates the inverse association between total sugar intake from SSB intake and 25(OH)D. Furthermore, an increased risk of having vitamin D deficiency was found in the population who consumed higher levels of sugar from SSB or soda drinks.

Dietary and Serum Antioxidants Associated with Prostate-Specific Antigen for Middle-Aged and Older Men.

High prostate-specific antigen (PSA) levels can indicate potential prostate problems and are a warning sign of prostate cancer. The impact of antioxidants on the PSA of generally healthy men is understudied. This study aims to evaluate 14 dietary and endogenous antioxidants associated with PSA levels for United States (US) men. We assessed 7398 men using the 2003-2010 US population-based National Health and Nutrition Examination Survey (NHANES). The PSA levels were categorized into three groups: Normal, borderline, and elevated levels. We performed analyses for middle-aged and older groups aged 40-64.9 and ≥65, respectively. The weighted multinomial regressions were performed to evaluate antioxidants associated with the PSA status. For results, 0.3% and 3.4% of middle-aged and older men, respectively, had elevated PSA (>10 ng/mL). Men with a higher serum albumin level had a lower risk of an elevated PSA, adjusting for age. The magnitude of albumin's impact on PSA is larger in middle-aged men than in older men (OR of elevated PSA = 0.82 and 0.90, respectively, interaction p = 0.002). Other antioxidants are not associated with PSA. Our findings support men with low serum albumin tend to have an elevated PSA level, so related interventions can be considered to decrease PSA for maintaining prostate health.

Effect of MMR Vaccination to Mitigate Severe Sequelae Associated With COVID-19: Challenges and Lessons Learned.

Mortality in COVID-19 cases was strongly associated with progressive lung inflammation and eventual sepsis. There is mounting evidence that live attenuated vaccines commonly administered during childhood, also provide beneficial non-specific immune effects, including reduced mortality and hospitalization due to unrelated infections. It has been proposed that live attenuated vaccine-associated non-specific effects are a result of inducing trained innate immunity to function more effectively against broader infections. In support of this, our laboratory has reported that immunization with a live attenuated fungal strain induces a novel form of trained innate immunity which provides protection against various inducers of sepsis in mice via myeloid-derived suppressor cells. Accordingly, we initiated a randomized control clinical trial with the live attenuated Measles, Mumps, Rubella (MMR) vaccine in healthcare workers in the greater New Orleans area aimed at preventing/reducing severe lung inflammation/sepsis associated with COVID-19 (ClinicalTrials.gov Identifier: NCT04475081). Included was an outcome to evaluate the myeloid-derived suppressor cell populations in blood between those administered the MMR vaccine vs placebo. The unanticipated emergency approval of several COVID-19 vaccines in the midst of the MMR clinical trials eliminated the ability to examine effects of the MMR vaccine on COVID-19-related health status. Unfortunately, we were also unable to show any impact of the MMR vaccine on peripheral blood myeloid-derived suppressor cells due to several inherent limitations (low percentages of blood leukocytes, small sample size), that also included a collaboration with a similar trial (CROWN CORONATION; ClinicalTrials.gov Identifier: NCT04333732) in St. Louis, MO. In contrast, monitoring the COVID-19 vaccine response in trial participants revealed that high COVID-19 antibody titers occurred more often in those who received the MMR vaccine vs placebo. While the trial was largely inconclusive, lessons learned from addressing several trial-associated challenges may aid future studies that test the non-specific beneficial immune effects of live attenuated vaccines.

Impact of Dietary Quality on Genital Oncogenic Human Papillomavirus Infection in Women.

BACKGROUND: Most cervical cancers are directly linked to oncogenic or high-risk human papillomavirus (HR-HPV) infection. This study evaluates associations between diet quality and genital HPV infection in women. METHODS: This study included 10 543 women from the 2003-2016 National Health and Nutrition Examination Survey. The outcome was the genital HPV infection status (HPV-negative, low-risk [LR] HPV, and HR-HPV). Dietary quality was evaluated using the Healthy Eating Index (HEI), in which a higher score indicates a better diet quality. RESULTS: Women who did not consume total fruits (15.8%), whole fruits (27.5%), or green vegetables and beans (43%) had a significantly higher risk of HR-HPV infection than women who complied with the Dietary Guidelines for Americans (HR-HPV odds ratio = 1.76, 1.63, and 1.48 for a HEI score of 0 vs 5, respectively) after adjusting confounding factors. Similar results of these food components on LR-HPV infection were found. In addition, intake of whole grains and dairy was inversely associated with LR-HPV infection. CONCLUSIONS: This study showed that women who did not eat fruits, dark-green vegetables, and beans had a higher risk of genital HR-HPV infection. Intake of these food components is suggested for women to prevent HPV carcinogenesis.

Differential Expression of miRNAs Contributes to Tumor Aggressiveness and Racial Disparity in African American Men with Prostate Cancer.

Prostate cancer is the leading cancer in incidence and second leading cause of cancer mortality in US men. African American men have significantly higher incidence and mortality rates from prostate cancer than European American men. Previous studies reported that the disparity in prostate cancer survival or mortality can be explained by different biological backgrounds. microRNAs (miRNAs) regulate gene expression of their cognate mRNAs in many cancers. Therefore, miRNAs may be a potentially promising diagnostic tool. The role of miRNAs in prostate cancer aggressiveness and racial disparity has not been fully established. The goal of this study is to identify miRNAs associated with aggressiveness and racial disparity in prostate cancer. Here we report miRNAs that are associated with tumor status and aggressiveness in prostate cancer using a profiling approach. Further, downregulated miRNAs in African American tissues were confirmed by qRT-PCR. These miRNAs have also been shown to negatively regulate the expression of the androgen receptor in prostate cancer cells. This report provides a novel insight into understanding tumor aggressiveness and racial disparities of prostate cancer.

Diarylheptanoid 35d overcomes EGFR TKI resistance by inducing hsp70-mediated lysosomal degradation of EGFR in EGFR-mutant lung adenocarcinoma.

Epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD) patients often respond to EGFR tyrosine kinase inhibitors (TKIs) initially but eventually develop resistance to TKIs. The switch of EGFR downstream signaling from TKI-sensitive to TKI-insensitive is a critical mechanism-driving resistance to TKIs. Identification of potential therapies to target EGFR effectively is a potential strategy to treat TKI-resistant LUADs. In this study, we developed a small molecule diarylheptanoid 35d, a curcumin derivative, that effectively suppressed EGFR protein expression, killed multiple TKI-resistant LUAD cells in vitro, and suppressed tumor growth of EGFR-mutant LUAD xenografts with variant TKI-resistant mechanisms including EGFR C797S mutations in vivo. Mechanically, 35d triggers heat shock protein 70-mediated lysosomal pathway through transcriptional activation of several components in the pathway, such as HSPA1B, to induce EGFR protein degradation. Interestingly, higher HSPA1B expression in LUAD tumors associated with longer survival of EGFR-mutant, TKI-treated patients, suggesting the role of HSPA1B on retarding TKI resistance and providing a rationale for combining 35d with EGFR TKIs. Our data showed that combination of 35d significantly inhibits tumor reprogression on osimertinib and prolongs mice survival. Overall, our results suggest 35d as a promising lead compound to suppress EGFR expression and provide important insights into the development of combination therapies for TKI-resistant LUADs, which could have translational potential for the treatment of this deadly disease.

Interactions of SNPs in Folate Metabolism Related Genes on Prostate Cancer Aggressiveness in European Americans and African Americans.

BACKGROUND: Studies showed that folate and related single nucleotide polymorphisms (SNPs) could predict prostate cancer (PCa) risk. However, little is known about the interactions of folate-related SNPs associated with PCa aggressiveness. The study's objective is to evaluate SNP-SNP interactions among the DHFR 19-bp polymorphism and 10 SNPs in folate metabolism and the one-carbon metabolism pathway associated with PCa aggressiveness. METHODS: We evaluated 1294 PCa patients, including 690 European Americans (EAs) and 604 African Americans (AAs). Both individual SNP effects and pairwise SNP-SNP interactions were analyzed. RESULTS: None of the 11 individual polymorphisms were significant for EAs and AAs. Three SNP-SNP interaction pairs can predict PCa aggressiveness with a medium to large effect size. For the EA PCa patients, the interaction between rs1801133 (MTHFR) and rs2236225 (MTHFD1), and rs1801131 (MTHFR) and rs7587117 (SLC4A5) were significantly associated with aggressive PCa. For the AA PCa patients, the interaction of DHFR-19bp polymorphism and rs4652 (LGALS3) was significantly associated with aggressive PCa. CONCLUSIONS: These SNP-SNP interactions in the folate metabolism-related genes have a larger impact than SNP individual effects on tumor aggressiveness for EA and AA PCa patients. These findings can provide valuable information for potential biological mechanisms of PCa aggressiveness.

In vitro and in vivo anti-tumor activity of Coenzyme Q0 against TWIST1-overexpressing HNSCC cells: ROS-mediated inhibition of EMT/metastasis and autophagy/apoptosis induction.

HNSCC (Head and Heck Squamous Cell Carcinoma) is a reasonably prevalent cancer with a high mortality rate. In this study, we tried to examine the anti-metastasis and apoptosis/autophagy actions of Coenzyme Q0 (CoQ0, 2,3-dimethoxy-5-methyl-1,4-benzoquinone), a derivative of Antrodia camphorata in HNCC TWIST1 overexpressing (FaDu-TWIST1) cells as well as in vivo tumor xenograft mice model. Using fluorescence based cellular assays, western blot and nude mice tumor xenografts, we determined that CoQ0 effectively reduced cell viability and displayed rapid morphological changes in FaDu-TWIST1 cells compared to FaDu cells. Non/sub-cytotoxic concentrations of CoQ0 treatment reduces the cell migration by downregulating TWIST1 and upregulating E-cadherin. Apoptosis produced by CoQ0 was mostly related with caspase-3 activation, PARP cleavage, and VDAC-1 expression. The FaDu-TWIST1 cells treated with CoQ0 exhibits autophagy-mediated LC3-II accumulation and acidic vesicular organelles (AVOs) formation. Pre-treatment with 3-MA and CoQ effectively prevented CoQ0-induced cell death and CoQ0-triggered autophagy in FaDu-TWIST cells as a death mechanism. CoQ0 induces ROS production in FaDu-TWIST1 cells and NAC pre-treatment significantly reduces anti-metastasis, apoptosis, and autophagy. Likewise, ROS-mediated AKT inhibition regulates CoQ0-induced apoptosis/autophagy in FaDu-TWIST1 cells. In vivo studies exhibit, CoQ0 effectively delays and reduces the tumor incidence and burden in FaDu-TWIST1-xenografted nude mice. Current findings display, CoQ0 exhibits a novel anti-cancer mechanism hence, it might be appropriate for anticancer therapy, and a new potent drug for HNSCC.

Alcohol use, physical activity, and muscle strength moderate the relationship between body composition and frailty risk among people living with HIV.

BACKGROUND: Antiretroviral therapy has improved life expectancy among people living with HIV (PLWH). Despite increased longevity, PLWH are at increased risk of age-related comorbidities, including frailty. We examined the relationship between body composition and frailty among PLWH, and moderation of this relationship by substance use, physical activity (PA), and physical function. METHODS: Participants (n = 341; 71% male, 48 ± 10 years, body mass index (BMI) = 27.3 ± 7.0 kg/m2 ) enrolled in the New Orleans Alcohol Use in HIV (NOAH) study underwent measures of body composition, muscle strength, and gait speed. Whole blood phosphatidylethanol (PEth) was measured, and substance use and PA were self-reported. Frailty risk measures included the 58-Item Deficit Index (DI58) and the Veterans Aging Cohort Study (VACS) Index 1.0, where higher scores indicate greater frailty risk. RESULTS: Multivariable linear regression adjusted for age, sex, and race showed that higher fat-free mass index (FFMI), body fat (%), waist-to-hip ratio, and body mass index (BMI) ≥ 25.0 kg/m2 vs. < 25.0 kg/m2 were significantly (p < 0.05) associated with decreased frailty risk measured by the VACS Index, whereas adjusted analyses showed no association between body composition variables and the DI58 score. Recent alcohol use, muscle strength, and PA, but not lifetime alcohol use or gait speed, significantly moderated associations between body composition variables and frailty risk with medium-to-large effect sizes. Subgroup analyses revealed a negative relationship between DI58 and FFMI among people with PEth > 8 ng/ml and negative relationships of VACS Index with FFMI and WHR in people with lower muscle strength. Overweight or obese BMI categories were positively associated with DI58 in people with lower muscle strength or higher PA level but negatively associated in those with higher muscle strength. CONCLUSIONS: Our findings indicate that body composition has significant modulatory effects on frailty risk in PLWH, where obesity increases the risk of frailty and greater muscle mass may be protective, even in individuals who use alcohol. These results highlight the importance of considering body composition, physical activity, and physical function in assessing frailty risk in PLWH, particularly among individuals who use alcohol. Moreover, they support the implementation of physical activity interventions to ameliorate the risk of frailty in aging PLWH.

Intake Patterns of Specific Alcoholic Beverages by Prostate Cancer Status.

BACKGROUND: Previous studies have shown that different alcoholic beverage types impact prostate cancer (PCa) clinical outcomes differently. However, intake patterns of specific alcoholic beverages for PCa status are understudied. The study's objective is to evaluate intake patterns of total alcohol and the three types of beverage (beer, wine, and spirits) by the PCa risk and aggressiveness status. METHOD: This is a cross-sectional study using 10,029 men (4676 non-PCa men and 5353 PCa patients) with European ancestry from the PCa consortium. Associations between PCa status and alcohol intake patterns (infrequent, light/moderate, and heavy) were tested using multinomial logistic regressions. RESULTS: Intake frequency patterns of total alcohol were similar for non-PCa men and PCa patients after adjusting for demographic and other factors. However, PCa patients were more likely to drink wine (light/moderate, OR = 1.11, p = 0.018) and spirits (light/moderate, OR = 1.14, p = 0.003; and heavy, OR = 1.34, p = 0.04) than non-PCa men. Patients with aggressive PCa drank more beer than patients with non-aggressive PCa (heavy, OR = 1.48, p = 0.013). Interestingly, heavy wine intake was inversely associated with PCa aggressiveness (OR = 0.56, p = 0.009). CONCLUSIONS: The intake patterns of some alcoholic beverage types differed by PCa status. Our findings can provide valuable information for developing custom alcohol interventions for PCa patients.

Bisdemethoxycurcumin-mediated Attenuation of Apoptosis Prevents Gentamicin-induced Ototoxicity in Mouse Cochlear UB/OC-2 Cells.

BACKGROUND/AIM: Gentamicin has been widely prescribed since the last two decades despite its ototoxicity and nephrotoxicity. Bisdemethoxycurcumin (BDMC) is an affordable and safe curcuminoid with medicinal properties. We aimed to understand the effects of BDMC on the gentamicin-induced hair cell damage in mouse cochlear UB/OC-2 cells, in order to elucidate the therapeutic potential of BDMC against gentamicin-induced ototoxicity. MATERIALS AND METHODS: We quantified the cell membrane potential and examined the regulators and cascade proteins in the intrinsic pathway of hair cell apoptosis. Mouse cochlear UB/OC-2 cells were treated with BDMC before exposure to gentamicin. The effects of BDMC on hair cell viability, mitochondrial function, and apoptosis-related proteins were examined by flow cytometry, western blot, and fluorescent staining. RESULTS: Our results revealed that BDMC reversed gentamicin-mediated cycle arrest at the G2/M phase, stabilizing the mitochondrial membrane potential, decreasing cleaved caspase proteins, and successfully reversing hair cell apoptosis. CONCLUSION: BDMC is a potential agent for reducing gentamicin-induced ototoxicity.

Ameliorative effect of taxifolin on gentamicin-induced ototoxicity via down-regulation of apoptotic pathways in mouse cochlear UB/OC-2 cells.

BACKGROUND: Taxifolin is a flavanonol with efficacious cytoprotective properties, such as anti-inflammatory, antioxidant, anticancer, hepatoprotective, and nephroprotective effects. However, the potential protective effects of taxifolin against gentamicin-induced ototoxicity have not been confirmed. In this study, the possible mechanisms underlying the effects of taxifolin on gentamicin-induced death of UB/OC-2 cochlear cells were investigated. METHODS: Mouse cochlear UB/OC-2 cells with or without taxifolin pretreatment were exposed to gentamicin, and the effects on cytotoxicity, reactive oxygen species (ROS) production, mitochondrial permeability transition, and apoptotic marker expression were examined using biochemical techniques, flow cytometry, western blotting, and fluorescent staining. RESULTS: Little or no apparent effect of taxifolin on cell viability was observed at concentrations less than 40 µM. Further investigations showed that gentamicin significantly inhibited cell viability in a concentration-dependent manner. Pretreatment with taxifolin attenuated gentamicin-induced lactate dehydrogenase release, as well as cellular cytotoxicity. In addition, taxifolin significantly prevented gentamicin-induced cell damage by decreasing ROS production, stabilizing mitochondrial membrane potential, and downregulating the mitochondrial pathway of apoptosis. CONCLUSION: In summary, pretreatment with taxifolin is effective for mitigating gentamicin-induced apoptotic cell death mediated by the mitochondrial pathway. Our data suggest that taxifolin provides a new approach to combat gentamicin-induced ototoxicity.

2,3,4',5­Tetrahydroxystilbene­2­O­ß­D­glucoside ameliorates gentamicin­induced ototoxicity by modulating autophagy via Sesn2/AMPK/mTOR signaling.

Gentamicin is an important aminoglycoside antibiotic used in the treatment of gram­negative bacterial infections, but nephrotoxicity and ototoxicity reduce its utility. The autophagy pathway is involved in damage of auditory hair cells. With the aim of developing new strategies for attenuating gentamicin ototoxicity, the present study investigated the otoprotective mechanism of 2,3,4',5­tetrahydroxystilbene­2­O­ß­D-glucoside (THSG) in vitro using the mouse cochlear cell line UB/OC­2. MTT assay demonstrated that gentamicin reduced UB/OC­2 cell viability and western blotting showed that gentamicin upregulated autophagy­related proteins, such as Beclin, autophagy related 5 and LC3­II. THSG significantly attenuated gentamicin­induced cytotoxicity, clearly reduced LDH release observed by LDH assay and decreased the expression of autophagy­related proteins. Reverse­transcription­quantitative (RT­q) PCR and western blotting showed that THSG against gentamicin­induced autophagy via suppressing the expression of Sesn2, at both the mRNA and protein level and a possible involvement of AMP­activated protein kinase (AMPK)/mTOR signaling response. Collectively, the present study demonstrated that THSG decreased gentamicin­induced ototoxicity in UB/OC­2 cochlear cells via the autophagic signaling in regulating Sesn2/AMPK/mTOR pathway. These results suggested that THSG might be a new therapeutic agent with the potential to attenuate gentamicin ototoxicity.

Sugar-Sweetened Beverages Intake, Abdominal Obesity, and Inflammation among US Adults without and with Prediabetes-An NHANES Study.

Excessive sugar-sweetened beverages (SSB) consumption and abdominal obesity have been independently linked to numerous disorders, including diabetes and elevated C-reactive protein (CRP). This study aimed to explore the association between SSB intake, abdominal obesity, and inflammation in normal and prediabetic adults. Sugar intake from SSBs was calculated from 24-h dietary recalls and further classified into non-, medium-, and high-intake. The status of non- and prediabetes was identified based on hemoglobin A1c level. All analyses were performed under a survey module with appropriate sampling weights to control for the complex survey design. A total of 5250 eligible adults without diabetes were selected from the 2007-2010 NHANES. A 1.31-fold increased risk of developing prediabetes was observed in people who consumed high sugar from SSBs when compared to non-SSB consumers. Among individuals with prediabetes, adults who consumed a high amount of sugar from SSB had a 1.57-fold higher risk to increase CRP when compared to non-SSB consumers, even after adjusting for abdominal obesity. Furthermore, the association between the high amount of sugar intake from SSBs and elevated CRP was strengthened by abdominal obesity in prediabetes (p for interaction term = 0.030). Our findings highlight that a positive association between sugar intake from SSBs and CRP levels was only observed in US adults with prediabetes. Abdominal obesity may strengthen this effect in prediabetic adults with a high amount of sugar intake from SSBs.

Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24.

BACKGROUND: We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ. MATERIALS AND METHODS: Genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC. RESULTS: CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings. CONCLUSION: We identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.