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Abstract Background Previous studies reported divergent results on nutraceutical actions and free radical scavenging capability of ginseng extracts. Variations in ginsenoside profile of ginseng due to different soil and cultivating season may contribute to the inconsistency. To circumvent this drawback, we assessed the effect of major ginsenoside-Rg1 (Rg1) on skeletal muscle antioxidant defense system against exhaustive exercise-induced oxidative stress. Methods Forty weight-matched rats were evenly divided into control (N = 20) and Rg1 (N = 20) groups. Rg1 was orally administered at the dose of 0.1 mg/kg bodyweight per day for 10-week. After this long-term Rg1 administration, ten rats from each group performed an exhaustive swimming, and remaining rats considered as non-exercise control. Tibialis anterior (TA) muscles were surgically collected immediately after exercise along with non-exercise rats. Results Exhaustive exercise significantly (p Conclusions This study provide compelling evidences that Rg1 supplementation can strengthen antioxidant defense system in skeletal muscle and completely attenuate the membrane lipid peroxidation induced by exhaustive exercise. Our findings suggest that Rg1 can use as a nutraceutical supplement to buffer the exhaustive exercise-induced oxidative stress.

Objective: This cross-sectional study examined the influence of sedentary behavior (SB) time substitution with physical activity (PA) on depressive symptoms among adults with overweight/obesity. SB time was replaced with equal amount of walking/bicycling or leisure-time moderate-to-vigorous PA (MVPA)., Methods: Data of the 18344 adults, who were overweight and obesity was obtained from the National Health and Nutrition Examination Survey 2006-2018. PA of participants was measured by the Global Physical Activity Questionnaire. Depressive symptoms, including overall, somatic, and cognitive depressive symptoms were assessed by the Patient Health Questionnaire-9 (PHQ-9). Isotemporal substitution model based on weighted multiple linear regression was used to assess the association of SB time substitution with PA on depressive symptoms., Results: Independent model analysis showed that 30 min/day SB time was significantly associated with higher PHQ-9 depressive symptoms, while engage in walking/bicycling or leisure-time MVPA for 30 min/day was associated with lower depressive symptoms. Isotemporal substitution analyses revealed that replacing 30 min/day SB time with equal amount of walking/bicycling or leisure-time MVPA was associated with significant lower PHQ-9 total scores (walking/bicycling: β = -0.088, 95%CI = -0.129, -0.047, P  < 0.01; MVPA: β = -0.160, 95%CI = -0.185, -0.134, P  < 0.01). Moreover, cognitive depressive symptoms (walking/bicycling: β = -0.035, 95%CI = -0.058, -0.013, P  < 0.01; MVPA: β = -0.074, 95%CI = -0.088, -0.060, P  < 0.01), and somatic depressive symptoms (walking/bicycling: β = -0.053, 95%CI = -0.075, -0.030, P  < 0.01; MVPA: β = -0.085, 95%CI = -0.100, -0.071, P  < 0.01) were also significantly lower after replacing SB time with either walking/bicycling or MVPA. However, replacing 30 min/day PA with SB time represented with higher depressive symptoms., Conclusions: Replacing SB time with walking/bicycling or MVPA is beneficial in lowering the depressive symptoms among overweight/obese adults. Owing to the benefits of PA on depression, strategies promoting PA participation, are necessary for better social/mental well-being and healthy society., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: This study investigates the effects of birth season and sex on the development of gross and fine motor skills in 2-year-old children in Jinhua, Eastern China., Methods: Conducted in Jinhua, a city in central Zhejiang Province, Eastern China, this research involved 225 children, assessing their gross and fine motor skills using the Peabody Developmental Motor Scales, Second Edition. Scores were adjusted for age in months to avoid the relative age effect. Statistical analyses included MANOVA to evaluate the impacts of season and sex., Results: Sex had no significant impact on overall motor development scores ( p > 0.05). However, the season of birth significantly affected fine motor quotient (FMQ) and total motor quotient (TMQ) ( p < 0.05). Boys' motor skills were generally unaffected by season, whereas girls born in winter exhibited superior fine motor skills compared to those born in summer., Conclusions: Seasonal environmental factors significantly influence early motor development, particularly fine motor skills in girls. These findings highlight the importance of considering seasonal variations in early childhood interventions aimed at enhancing exercise physiology and sports performance.

Background: Perivascular adipose tissue (PVAT) dysfunction impairs vascular homeostasis. Impaired inflammation and bone morphogenetic protein-4 (BMP4) signaling are involved in thoracic PVAT dysfunction by regulating adipokine secretion and adipocyte phenotype transformation. We investigated whether aerobic exercise training could ameliorate high-fat diet (HFD)-induced PVAT dysfunction via improved inflammatory response and BMP4-mediated signaling pathways., Methods: Sprague-Dawley rats ( n = 24) were divided into three groups, namely control, high-fat diet (HFD), and HFD plus exercise (HEx). After a 6-week intervention, PVAT functional efficiency and changes in inflammatory biomarkers (circulating concentrations in blood and mRNA expressions in thoracic PVAT) were assessed., Results: Chronic HFD feeding caused obesity and dyslipidemia in rats. HFD decreased the relaxation response of PVAT-containing vascular rings and impaired PVAT-regulated vasodilatation. However, exercise training effectively reversed these diet-induced pathological changes to PVAT. This was accompanied by significantly ( p < 0.05) restoring the morphological structure and the decreased lipid droplet size in PVAT. Furthermore, HFD-induced impaired inflammatory response (both in circulation and PVAT) was notably ameliorated by exercise training ( p < 0.05). Specifically, exercise training substantially reversed HFD-induced WAT-like characteristics to BAT-like characteristics as evidenced by increased UCP1 and decreased FABP4 protein levels in PVAT against HFD. Exercise training promoted transcriptional activation of BMP4 and associated signaling molecules (p38/MAPK, ATF2, PGC1α, and Smad5) that are involved in browning of adipose tissue. In conjunction with gene expressions, exercise training increased BMP4 protein content and activated downstream cascades, represented by upregulated p38/MAPK and PGC1α proteins in PVAT., Conclusion: Regular exercise training can reverse HFD-induced obesity, dyslipidemia, and thoracic PVAT dysfunction in rats. The browning of adipose tissue through exercise appears to be modulated through improved inflammatory response and/or BMP4-mediated signaling cascades in obese rats., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Liu, Jiang, Hu, Ding, Lee, Korivi, Qian, Li, Wang and Li.)

The Peabody Developmental Motor Scales-2 (PDMS-2) has been used to assess the gross and fine motor skills of children (0-6 years); however, the measurement properties of the PDMS-2 are inconclusive. Here, we aimed to systematically review the measurement properties of PDMS-2, and synthesize the quality of evidence using the Consensus-based Standards for the Selection of Health Measurements Instruments (COSMIN) methodology. Electronic databases, including PubMed, EMBASE, Web of Science, CINAHL and MEDLINE, were searched for relevant studies through January 2023; these studies used PDMS-2. The methodological quality of each study was assessed by the COSMIN risk-of-bias checklist, and the measurement properties of PDMS-2 were evaluated by the COSMIN quality criteria. Modified GRADE was used to evaluate the quality of the evidence. We included a total of 22 articles in the assessment. Among the assessed measurement properties, the content validity of PDMS-2 was found to be sufficient with moderate-quality evidence. The structural validity, internal consistency, test-retest reliability and interrater reliability of the PDMS-2 were sufficient for high-quality evidence, while the intrarater reliability was sufficient for moderate-quality evidence. Sufficient high-quality evidence was also found for the measurement error of PDMS-2. The overall construct validity of the PDMS-2 was sufficient but showed inconsistent quality of evidence. The responsiveness of PDMS-2 appears to be sufficient with low-quality evidence. Our findings demonstrate that the PDMS-2 has sufficient content validity, structural validity, internal consistency, reliability and measurement error with moderate to high-quality evidence. Therefore, PDMS-2 is graded as 'A' and can be used in motor development research and clinical settings., (© 2024. The Author(s).)

Purpose: Interlukin-15 (IL-15) is an inflammatory cytokine that plays a vital role in immunology and obesity-associated metabolic syndrome. We performed this systematic review and meta-analysis to investigate whether exercise promotes circulating IL-15 concentrations in adults., Methods: We searched PubMed, Web of Science, and Scopus from inception to May, 2023 and identified original studies that investigated the effectiveness of acute and/or chronic exercise on serum/plasma IL-15 levels in adults. Standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated using random effect models. Subgroup analyses were performed based on type of exercise, and training status, health status and body mass indexes (BMI) of participants., Results: Fifteen studies involving 411 participants and 12 studies involving 899 participants were included in the acute and chronic exercise analyses, respectively. Our findings showed that acute exercise increased circulating IL-15 concentrations immediately after exercise compared with baseline [SMD=0.90 (95% CI: 0.47 to 1.32), p=0.001], regardless of exercise type and participants' training status. Similarly, acute exercise was also associated with increased IL-15 concentrations even one-hour after exercise [SMD=0.50 (95% CI: 0.00 to 0.99), p=0.04]. Nevertheless, chronic exercise did not have a significant effect on IL-15 concentrations [SMD=0.40 (95% CI: -0.08 to 0.88), p=0.10]., Conclusion: Our results confirm that acute exercise is effective in increasing the IL-15 concentrations immediately and one-hour after exercise intervention, and thereby playing a potential role in improving metabolism in adults., Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display&#95;record.php?RecordID=445634, identifier CRD42023445634., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision, (Copyright © 2024 Khalafi, Maleki, Symonds, Sakhaei, Rosenkranz, Ehsanifar, Korivi and Liu.)

Purpose: This study investigated the influence of parenting and grandparenting caregiving styles on fundamental motor skills (FMS) of preschool children., Method: A total of 1,326 preschool children (698 boys, 628 girls) aged 4-6 years were recruited from the kindergartens of Jinhua City, China. Locomotor skills (LM), ball skills (BS), and total fundamental movement skills (TS) of children were assessed by the Test of Gross Motor Development-3rd edition (TGMD-3)., Results: There were 978 children in parenting and 348 children in grandparenting caregiving styles. The LM, BS and TS scores of children were considerably ( p < 0.001) increased with age (irrespective of sex or caregiving style). For the sex comparisons, BS scores of boys were significantly higher than girls ( p < 0.001), while LM and TS scores were not different between boys and girls. For the caregiving style comparison, parenting is superior to grandparenting in developing of children's FMS. Parenting boys of 4-, 5-, and 6-years old showed better BS compared to age-matched parenting girls, whereas boys of 5-years old in grandparenting only showed better BS compared to same-age grandparenting girls ( p < 0.05). Furthermore, parenting boys of 6-years reported higher LM ( p < 0.01), BS ( p < 0.001), and TS ( p < 0.001) scores compared to grandparenting boys, but girls' FMS at all ages were not significantly different between the caregiving styles., Conclusion: Parenting caregiving style is positively associated with proper development of FMS among children. Girl children with poor FMS in grandparenting may need a special care or intervention programs to promote their FMS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hu, Zhang, Ye, Zhu, Zhou, Lu, Chen and Korivi.)

Introduction: We conducted a systematic review and meta-analysis to investigate the effect of exercise training on body composition outcomes in postmenopausal women., Methods: PubMed, Web of Science, CINAHL, and Medline were searched to identify the randomized controlled trials which evaluated effect of exercise training versus control in postmenopausal women. Standardized mean differences (SMD), weighted mean differences (WMD) and 95% confidence intervals (95% CIs) were calculated using random effects model., Results: One hundred and one studies involving 5,697 postmenopausal women were included in the meta-analysis. Results indicated that exercise training effectively increased muscle mass/ volume, muscle and fiber cross-sectional area and fat-free mass, and decreased fat mass, body fat percentage, waist circumference and visceral fat. Furthermore, subgroup analyses results revealed that aerobic and combined training had greater beneficial effects on fat mass outcomes, whereas resistance and combined training had greater beneficial effects on muscle mass outcomes., Discussion: Overall, our results revealed that exercise training is effective for improving body composition in postmenopausal women. To be specific, aerobic training is effective on fat loss, whereas resistance training is effective on muscle gain. However, combination of aerobic and resistance trainings may be considered a viable strategy to improve body composition in postmenopausal women., Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021283425., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Khalafi, Habibi Maleki, Sakhaei, Rosenkranz, Pourvaghar, Ehsanifar, Bayat, Korivi and Liu.)

Developing an efficient and cost-effective wound-healing substance to treat wounds and regenerate skin is desperately needed in the current world. Antioxidant substances are gaining interest in wound healing, and green-synthesized silver nanoparticles have drawn considerable attention in biomedical applications due to their efficient, cost-effective, and non-toxic nature. The present study evaluated in vivo wound healing and antioxidant activities of silver nanoparticles from Azadirachta indica (AAgNPs) and Catharanthus roseus (CAgNPs) leaf extracts in BALB/c mice. We found rapid wound healing, higher collagen deposition, and increased DNA and protein content in AAgNPs- and CAgNPs (1% w / w )-treated wounds than in control and vehicle control wounds. Skin antioxidant enzyme activities (SOD, catalase, GPx, GR) were significantly ( p < 0.05) increased after 11 days CAgNPs and AAgNPs treatment. Furthermore, the topical application of CAgNPs and AAgNPs tends to suppress lipid peroxidation in wounded skin samples. Histopathological images evidenced decreased scar width, epithelium restoration, fine collagen deposition, and fewer inflammatory cells in CAgNPs and AAgNPs applied wounds. In vitro, the free radical scavenging activity of CAgNPs and AAgNPs was demonstrated by DPPH and ABTS radical scavenging assays. Our findings suggest that silver nanoparticles prepared from C. roseus and A. indica leaf extracts increased antioxidant status and improved the wound-healing process in mice. Therefore, these silver nanoparticles could be potential natural antioxidants to treat wounds.

Background and Aim: Both cardiorespiratory fitness (CRF) and muscular strength are reported to decrease with age and menopause, which considered to be risk for cardiovascular diseases (CVDs). Previous relevant meta-analyses are inconclusive on the beneficial effects of exercise, particularly in post-menopausal women. In this systematic review and meta-analysis, we investigated the effects of exercise modalities on CRF and muscular strength in post-menopausal women, and identified the effective exercise type and duration., Methods: A comprehensive search was conducted on PubMed, Web of Science, CINAHL, and Medline to identify the randomized controlled trials, which evaluated exercise effect on CRF, lower- and upper-body muscular strength, and/or handgrip strength in post-menopausal women and compared the results with control. Standardized mean differences (SMD), weighted mean differences (WMD), and 95% confidence intervals (95% CIs) were calculated using random effects models., Results: A total of 129 studies comprising 7,141 post-menopausal women with mean age and BMI ranging from ∼53 to 90 years and 22 to 35 kg/m 2 , respectively, were included in the meta-analysis. Overall, exercise training effectively increased CRF (SMD: 1.15; 95% CI: 0.87, 1.42; p  = 0.001), lower-body muscular strength (SMD: 1.06; 95% CI: 0.90, 1.22; p  = 0.001), upper-body muscular strength (SMD: 1.11; 95% CI: 0.91, 1.31; p  = 0.001), and handgrip strength (WMD: 1.78 kg; 95% CI: 1.24, 2.32; p  = 0.001) in post-menopausal women. These increments were found to be irrespective of ages and intervention durations. Regarding exercise type, aerobic, resistance, and combined training significantly increased CRF and lower-body muscular strength, while resistance and combined training effectively increased handgrip strength. However, only resistance training increased the upper-body muscular strength in women., Conclusion: Our findings suggest that exercise training is effective in increasing CRF and muscular strength in post-menopausal women, which might be cardioprotective. Both aerobic and resistance training alone or in combination increased CRF and lower-body muscular strength, but only resistance training increased upper-body strength in women., Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display&#95;record.php?RecordID=283425, identifier: CRD42021283425., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Khalafi, Sakhaei, Habibi Maleki, Rosenkranz, Pourvaghar, Fang and Korivi.)

The present study investigated the cardioprotective properties of 6-gingerol against alcohol-induced ROS-mediated cardiac tissue damage in rats. Experiments were conducted on 4 groups of rats, orally treated with control, 6-gingerol (10 mg/kg body weight), alcohol (6 g/kg body weight) and combination of 6-gingerol plus alcohol for two-month. In the results, we found 6-ginger treatment to alcohol-fed rats substantially suppressed ROS production in cardiac tissue. Alcohol-induced elevated 8-OHDG and protein carbonyls which represent oxidative modification of DNA and proteins were completely reversed by 6-gingerol. This was further endorsed by restored superoxide dismutase and catalase activities with 6-gingerol against alcohol-induced loss. The elevated cardiac biomarkers (CK-MB, cTn-T, cTn-I) and dyslipidemia in alcohol-intoxicated rats was significantly reversed by 6-gingerol. Furthermore, alcohol-induced apoptosis characterized by overexpression of cytochrome C, caspase-8 and caspase-9 was diminished with 6-gingerol treatment. Transmission electron microscope images conferred the cardioprotective properties of 6-gingerol as we have seen less structural derangements in mitochondria and reappearance of myofilaments. Our findings conclude that 6-ginger effectively protect alcohol-induced ROS-mediated cardiac tissue damage, which may be due to its potent antioxidant efficacy. Therefore, 6-gingerol could be a potential therapeutic molecule that can be used in the treatment of alcohol-induced myocardial injury.

We performed a meta-analysis to investigate the effects of high-intensity interval exercise (HIIE) as compared to moderate-intensity exercise (MIE) and a control condition (CON) on postprandial glucose (PPG) and insulin (PPI) responses. PubMed, Web of Science, and Scopus were comprehensively searched to identify relevant studies until October 2021. Separate analyses were conducted for HIIE versus MIE and HIIE versus CON. A total of 30 studies comprising 36 intervention arms and involving 467 participants (350 adults) were included in the meta-analysis. HIIE reduced PPG and PPI when compared with CON. Based on subgroup analyses, reductions in PPG and PPI were significant for both children and adult participants, as well as for healthy participants and participants with metabolic disorders, with larger effects in those with metabolic disorders. There were no significant differences between HIIE and MIE for PPG or PPI. However, when comparing studies matched for total work performed, HIIE was more effective for decreasing PPG as compared with MIE. HIIE is effective for reducing PPG and PPI in both children and adult participants, particularly in those with metabolic disorders. In addition, HIIE has superior effects for reducing PPG as compared with MIE, when equivalent work was performed at both intensity levels., (© 2022 World Obesity Federation.)

Greater muscular strength is generally associated with superior sports performance, for example, in jumping, sprinting, and throwing. This meta-analysis aims to compare the effects of variable-resistance training (VRT) and constant-resistance training (CRT) on the maximum strength of trained and untrained subjects. PubMed, Web of Science, and Google Scholar were comprehensively searched to identify relevant studies published up to January 2022. Fourteen studies that met the inclusion criteria were used for the systematic review and meta-analysis. Data regarding training status, training modality, and type of outcome measure were extracted for the analyses. The Cochrane Collaboration tool was used to assess the risk of bias. The pooled outcome showed improved maximum strength with VRT, which was significantly higher than that with CRT (ES = 0.80; 95% CI: 0.42−1.19) for all the subjects. In addition, trained subjects experienced greater maximum-strength improvements with VRT than with CRT (ES = 0.57; 95% CI: 0.22−0.93). Based on subgroup analyses, maximum-strength improvement with a VRT load of ≥80% of 1 repetition maximum (1RM) was significantly higher than that with CRT (ES = 0.76; 95% CI: 0.37−1.16) in trained subjects, while no significant differences were found between VRT and CRT for maximum-strength improvement when the load was <80% (ES = 0.00; 95% CI: −0.55−0.55). The untrained subjects also achieved greater maximum strength with VRT than with CRT (ES = 1.34; 95% CI: 0.28−2.40). Interestingly, the improved maximum strength of untrained subjects with a VRT load of <80% of 1RM was significantly higher than that with CRT (ES = 2.38; 95% CI: 1.39−3.36); however, no significant differences were noted between VRT and CRT when the load was ≥80% of 1RM (ES = −0.04; 95% CI: −0.89−0.81). Our findings show that subjects with resistance training experience could use a load of ≥80% of 1RM and subjects without resistance training experience could use a load of <80% of 1RM to obtain greater VRT benefits.

The age range of 3−6 years is considered as a critical period in developing and learning fundamental motor skills (FMS). To make the formulation of future FMS guidance programs more targeted, we examined gender differences in children’s FMS proficiency using a meta-analysis. Structured electronic databases including PubMed, Scopus and Web of Science were systematically searched using key terms, and the Joanna Briggs Institute (JBI) was used to assess the quality of included literature. Finally, 38 articles (39 studies) met the pre-specified inclusion criteria. The results showed that boys had higher proficiency in total FMS and object control skills than girls (SMD = 0.17 (95% CI 0.03, 0.31), p = 0.02; SMD = 0.48 (95% CI 0.38, 0.58), p < 0.00001), and gender differences in locomotor skill proficiency approached significance, trending in favor of girls (SMD = −0.07 (95 % CI −0.15, 0.01), p = 0.09, I2 = 66%). Meta-regression shows that age is associated with gender differences in object control skills (p < 0.05). In addition, through subgroup analysis, we found that boys’ advantage in object control skills increased with age (3 years: SMD = 0.27 (95% CI 0.00, 0.54), p < 0.00001; 4 years: SMD = 0.58 (95% CI 0.38, 0.77), p < 0.00001; 5 years: SMD = 0.59 (95% CI 0.31, 0.88), p < 0.00001; 6 years: SMD = 0.81 (95% CI 0.61, 1.01), p < 0.00001). In this meta-analysis, we found gender differences in FMS levels in children aged 3−6 years. Notably, gender differences in skill proficiency in object control were influenced by age. We recommend focusing on and developing girls’ object control skills starting at age 3.

Background: The urbanization process may affect the lifestyle of rural residents in China. Limited information exists on the extent of sedentarism and physical activity (PA) level of rural residents in middle-income countries. This is the first survey on sedentary time (ST) and PA among rural residents in eastern China., Methods: This cross-sectional observational study randomly samples rural adults from Zhejiang Province in eastern China ( n = 1,320). Participants' ST and PA levels were determined from the International Physical Activity Questionnaire Short Form through face-to-face interviews, and the influencing factors of PA levels were assessed through multi-class logistic regression analysis., Results: The findings showed that the daily ST of the participants ranged from 30 to 660 min, with a median of 240 min (P25, P75:120, 240 min), and 54.6% of participants were sedentary for 240 min or above. The daily ST in men, people aged 18 to 44 years, people with bachelors' degree and above, people working for government agencies or institutions, people with unmarried status, and people with an average income of < 2,000 Yuan was longer than that of other respective groups ( p < 0.01). In contrast, the daily ST of people with hypertension or with patients with osteoporosis or osteopenia was less than that of normal people ( p < 0.01). Additionally, 69.4% of participants generally had a low level of PA (LPA). Compared with those living in northern Zhejiang, people living in southern Zhejiang who were aged 18-44 years, had bachelor's degree or above, were farmers, and had household incomes below 10,000 Yuan per month were more likely to engage in LPA compared to people > 60 years, with high school or technical education levels or with junior college degrees, working in government agencies and institutions, and with household income above 10,000 Yuan per month ( p < 0.05). Furthermore, there was no correlation between ST and PA levels., Conclusion: Most rural residents in the Zhejiang Province of eastern China had longer daily ST and a LPA. This was predominant in men, young people, highly educated people, unmarried people, and middle to high-income people. Health education programs should be targeted toward specific population groups to decrease the ST and increase PA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Wang, Korivi, Chen and Zhu.)

Background/Purpose: In this systematic review and meta-analysis, we assessed the effects of exercise (EX) combined with calorie restriction (CR) intervention on inflammatory biomarkers, and correlations between biomarkers and participants' characteristics were calculated in overweight and obese adults. Methods: An article search was conducted through PubMed, Web of Science, EMBASE, the Cochrane database, Scopus, and Google Scholar to identify articles published up to April 2021. Studies that examined the effect of EX + CR intervention on inflammatory biomarkers, including C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), and compared them with a CR trial in overweight and obese adults were included. We calculated the pooled effect by meta-analysis, identified the correlations (between inflammatory biomarkers and participants' characteristics) through meta-regression, and explored the beneficial variable through subgroup analysis. The Cochrane risk of bias tool and Methodological Index for Non-randomized Studies were used to assess the risk of bias for the included trials. Results: A total of 23 trials, including 1196 overweight and obese adults, were included in the meta-analysis. The pooled effect showed that EX + CR intervention significantly decreased CRP levels ( P = 0.02), but had no effect on IL-6 ( P = 0.62) and TNF-α ( P = 0.11). Meta-regression analysis showed that the effect of EX + CR on CRP, IL-6, and TNF-α changes was correlated with lifestyle behavior of adults (Coef. = -0.380, P = 0.018; Coef. = -0.359, P = 0.031; Coef. = -0.424, P = 0.041, respectively), but not with age and BMI. The subgroup analysis results revealed that participants with sedentary lifestyle behavior did not respond to EX + CR intervention, as we found no changes in CRP, IL-6, and TNF-α concentrations ( P = 0.84, P = 0.16, P = 0.92, respectively). However, EX + CR intervention significantly decreased CRP ( P = 0.0003; SMD = -0.39; 95%CI: -0.60 to -0.18), IL-6 ( P = 0.04; SMD = -0.21; 95%CI: -0.40 to -0.01) and TNF-α ( P = 0.006; SMD = -0.40, 95%CI: -0.68 to -0.12) in adults without a sedentary lifestyle or with a normal lifestyle. Furthermore, the values between sedentary and normal lifestyle subgroups were statistically significant for CRP, IL-6, and TNF-α. Conclusion: Our findings showed that combination EX + CR intervention effectively decreased CRP, IL-6, and TNF-α in overweight and obese adults with active lifestyles, but not with sedentary lifestyle behavior. We suggest that 'lifestyle behavior' is a considerable factor when designing new intervention programs for overweight or obese adults to improve their inflammatory response., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Hong, Lebaka, Mohammed, Ji, Zhang and Korivi.)

In our in vitro and in vivo studies, we used Acalypha indica root methanolic extract (AIRME), and investigated their free radical scavenging/antioxidant and anti-inflammatory properties. Primarily, phytochemical analysis showed rich content of phenols (70.92 mg of gallic acid/g) and flavonoids (16.01 mg of rutin/g) in AIRME. We then performed HR-LC-MS and GC-MS analyses, and identified 101 and 14 phytochemical compounds, respectively. Among them, ramipril glucuronide (1.563%), antimycin A (1.324%), swietenine (1.134%), quinone (1.152%), oxprenolol (1.118%), choline (0.847%), bumetanide (0.847%) and fenofibrate (0.711%) are the predominant phytomolecules. Evidence from in vitro studies revealed that AIRME scavenges DPPH and hydroxyl radicals in a concentration dependent manner (10-50 μg/mL). Similarly, hydrogen peroxide and lipid peroxidation were also remarkably inhibited by AIRME as concentration increases (20-100 μg/mL). In vitro antioxidant activity of AIRME was comparable to ascorbic acid treatment. For in vivo studies, carrageenan (1%, sub-plantar) was injected to rats to induce localized inflammation. Acute inflammation was represented by paw-edema, and significantly elevated ( p < 0.05) WBC, platelets and C-reactive protein (CRP). However, AIRME pretreatment (150/300 mg/kg bodyweight) significantly ( p < 0.05) decreased edema volume. This was accompanied by a significant ( p < 0.05) reduction of WBC, platelets and CRP with both doses of AIRME. The decreased activities of superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase in paw tissue were restored ( p < 0.05 / p < 0.01) with AIRME in a dose-dependent manner. Furthermore, AIRME attenuated carrageenan-induced neutrophil infiltrations and vascular dilation in paw tissue. For the first time, our findings demonstrated the potent antioxidant and anti-inflammatory properties of AIRME, which could be considered to develop novel anti-inflammatory drugs.

Aerobic exercise has been confirmed to improve endothelial function (EF). However, the effect of resistance exercise (RE) on EF remains controversial. We conducted this systematic review and meta-analysis on randomized controlled trials (RCTs) to determine the effect of RE and its intensities on EF. We searched Web of Science, PubMed/MEDLINE, Scopus, and Wiley Online Library, and included 15 articles (17 trials) for the synthesis. Overall, RE intervention significantly improved flow-mediated dilatation (FMD) in brachial artery (SMD = 0.76; 95% CI: 0.47, 1.05; p < 0.00001), which represents improved EF. Meta-regression showed that the RE intensity was correlated with changes in FMD (Coef. = -0.274, T = -2.18, p = 0.045). We found both intensities of RE improved FMD, but the effect size for the low- to moderate-intensity (30-70%1RM) was bigger (SMD = 1.02; 95% CI: 0.60, 1.43; p < 0.0001) than for the high-intensity (≥70%1RM; SMD = 0.48; 95% CI: 0.21, 0.74; p = 0.005). We further noticed that RE had a beneficial effect (SMD = 0.61; 95% CI: 0.13, 1.09; p = 0.01) on the brachial artery baseline diameter at rest (BAD rest ), and the age variable was correlated with the changes in BAD rest after RE (Coef. = -0.032, T = -2.33, p = 0.038). Young individuals (<40 years) presented with a bigger effect size for BAD rest (SMD = 1.23; 95% CI: 0.30, 2.15; p = 0.009), while middle-aged to elderly (≥40 years) were not responsive to RE (SMD = 0.07; 95% CI: -0.28, 0.42; p = 0.70). Based on our findings, we conclude that RE intervention can improve the EF, and low- to moderate-intensity is more effective than high-intensity.

Mango ( Mangifera indica L.), known as the king of fruits, has an attractive taste and fragrance and high nutritional value. Mango is commercially important in India, where ~55% of the global crop is produced. The fruit has three main parts: pulp, peel, and kernel. The pulp is the most-consumed part, while the peel and kernel are usually discarded. Mango pulp is a source of a variety of reducing sugars, amino acids, aromatic compounds, and functional compounds, such as pectin, vitamins, anthocyanins, and polyphenols. Mango processing generates peels and kernels as bio-wastes, though they also have nutraceutical significance. Functional compounds in the peel, including protocatechuic acids, mangiferin and β-carotene are known for their antimicrobial, anti-diabetic, anti-inflammatory, and anti-carcinogenic properties. The mango kernel has higher antioxidant and polyphenolic contents than the pulp and peel and is used for oil extraction; it's possible usage in combination with corn and wheat flour in preparing nutraceuticals is being increasingly emphasized. This review aims to provide nutraceutical and pharmacological information on all three parts of mango to help understand the defense mechanisms of its functional constituents, and the appropriate use of mangoes to enhance our nutrition and health.

Background: Capsinoids (CSN), the novel non-pungent capsaicin analogs have been reported to promote metabolic health and exercise tolerance. However, the effect of CSN on fat oxidation and changes in skeletal muscle glycogen levels during post-exercise recovery has not been investigated in humans., Purpose: We examined the effect of CSN supplementation on energy reliance, glycogen resynthesis and molecular proteins in the skeletal muscle of young adults during post-exercise recovery., Methods: In this crossover-designed study, nine healthy adult male volunteers (aged 21.4±0.2 years, BMI 21.9±1.3 kg/m2) completed a 60-min cycling exercise at 70% VO2max. Participants consumed either CSN (12 mg, single dosage) or placebo capsules with a high-carbohydrate meal (2 g carb/kg bodyweight) immediately after exercise. Biopsied muscle samples (vastus lateralis), blood, and gaseous samples were obtained during 3h postexercise recovery period., Results: We found that oral CSN supplementation right after exercise significantly altered the energy reliance on fat oxidation during recovery. This was evidenced by lower respiratory exchange ratio (RER) and higher fat oxidation rate in CSN trial. Despite this, acute CSN dosage does not contribute in enhancing the glycogen replenishment in skeletal muscle during 3h recovery. We identified no significant differences in postprandial glucose and insulin area under the curve in both trials. Western blot data showed an increased muscle GLUT4 expression, but no significant response of p-Akt/Akt ratio with CSN during post-exercise recovery., Conclusion: Our findings conclude that acute CSN intake could change energy reliance on fat oxidation but is unable to enhance muscle glycogen resynthesis during post-exercise recovery. Thus, ergogenic properties of CSN in relevance to muscle glycogen restoration following exercise needs to be further investigated in young adults., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background/purpose: Type 2 diabetes (T2D) is characterized by hyperglycemia resulting from the body's inability to produce and/or use insulin. Patients with T2D often have hyperinsulinemia, dyslipidemia, inflammation, and oxidative stress, which then lead to hypertension, chronic kidney disease, cardiovascular disease, and increased risk of morbidity and mortality (9th leading cause globally). Insulin and related pharmacological therapies are widely used to manage T2D, despite their limitations. Efficient drug delivery systems (DDS) that control drug kinetics may decrease side effects, allow for efficient targeting, and increase the bioavailability of drugs to achieve maximum therapeutic benefits. Thus, the development of effective DDS is crucial to beat diabetes., Methods: Here, we introduced a highly bioavailable vector, cell-penetrating peptides (CPPs), as a powerful DDS to overcome limitations of free drug administration., Results: CPPs are short peptides that serve as a potent tool for delivering therapeutic agents across cell membranes. Various cargoes, including proteins, DNA, RNA, liposomes, therapeutic molecules, and nanomaterials, generally retain their bioactivity upon entering cells. The mechanisms of CPPs/cargoes intracellular entry are classified into two parts: endocytic pathways and direct membrane translocation. In this article, we focus on the applications of CPPs/therapeutic agents in the treatment of diabetes. Hypoglycemic drugs with CPPs intervention can enhance therapeutic effectiveness, and CPP-mediated drug delivery can facilitate the actions of insulin. Numerous studies indicate that CPPs can effectively deliver insulin, produce synergistic effects with immunosuppressants for successful pancreatic islet xenotransplantation, prolong pharmacokinetics, and retard diabetic nephropathy., Conclusion: We suggest that CPPs can be a new generation of drug delivery systems for effective treatment and management of diabetes and diabetes-associated complications., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Naturally occurring tumor in animals receiving high minerals from deep oceans (DOM: hardness 600 mg/L) from 6 months of age until natural death was firstly assessed in 200 Sprague Dawley rats, randomized into four groups: Control (C), DOM (D), Fructose (F), and Fructose + DOM (FD). Fructose drink contained 11% fructose. Tumor incidence (necropsy at death) in the D group was ~40% lower than that in the C group (P < .05), together with lower body mass gain and greater locomotive activity during their initial 18 months (P < .05) but not during later life. X-ray image analysis on abnormal solid tissue among survivors at 18 and 24 months of age confirms a similar trend, exhibiting ~50% and ~65% lower tumor incidence than the C and F groups, respectively. Reduced-to-oxidized glutathione ratio (GSH/GSSG) declined with age for the first three quarters of life on all groups (P < .05), followed by a resurgence during end-life among survivors at 24 months. This resurgence is markedly associated with lower tumor expansion but unrelated with DOM supplementation. Our results demonstrate valuable application of minerals and trace elements from deep oceans, as a vastly available natural source, on tumor suppression during normal aging., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

In the present study, economically viable NiO nanoparticles were produced by biogenic preparation using stevia leaf broth and their in-vitro antioxidant and antimicrobial activities were evaluated. The properties of the prepared NiO nanoparticles were confirmed by analytical techniques such as Ultraviolet-Visible (UV-Vis), X-ray diffraction (XRD), FE-SEM, and Fourier transform infrared spectroscopy (FTIR) analyses. Morphological studies using scanning electron microscopy (SEM) and transmission electron microscopy (TEM) showed that the size of synthesized nanoparticles ranged from 20 to 50 nm, most of which were spherical and few of which were agglomerated. The role of the biological moieties, which reduce and cap the nanoparticles, was studied using FTIR analysis. The prepared nanoparticles strongly inhibited gram-negative bacteria, which is a camper with gram-positive bacteria and fungi. Furthermore, it performs an effective in-vitro activity through α,α-diphenyl-β-picrylhydrazyl (DPPH) reduction. Thus, it can be concluded that the effective and easy green synthesis process used for NiO nanoparticles provides potential antimicrobial agents against multidrug-resistant microbes.

We investigated the effect of chronic seaweed ( Gracilaria asiatica ) supplementation on maximal carrying capacity, muscle mass, and oxidative stress in rats following high-intensity resistance exercise (RE). Forty Sprague-Daley rats were equally categorized into control, exercise, seaweed, and exercise plus seaweed (ES) groups. Rats in respective groups performed RE (once per 2 days) or received seaweed (250 mg/kg bodyweight, orally) for 10 weeks. Results showed that seaweed consumption in combination with RE significantly ( p < 0.05) increased maximal weight carrying capacity compared to RE alone. FHL muscle mass was significantly higher in both exercise and ES groups. Notably, high-intensity RE-induced lipid peroxidation, as evidenced by elevated thiobarbituric acid reactive substances (TBARS) in muscle, was substantially diminished ( p < 0.05) by seaweed treatment. This antioxidative effect of seaweed was further represented by augmented superoxide dismutase activity and glutathione levels in seaweed groups. We noticed increased insulin concentrations and HOMA-IR, while the fasting blood glucose levels remained stable in seaweed and ES groups. Our findings conclude that seaweed in combination with RE enhanced maximal carrying strength and attenuated oxidative stress through improved antioxidant capacity. Seaweed could be a potential nutritional supplement to boost performance and to prevent exercise-induced muscle damage., Competing Interests: All authors declare no conflicts of interest.

This study examined the effects of exercise intervention on the quality of life (QoL), social functioning (SF), and physical functioning (PF) of breast cancer survivors, and identified the responsible and optimal exercise characteristics for amelioration of outcomes. Randomized controlled trials (RCTs) that adopted exercise intervention and measured the QoL, SF, and PF of breast cancer patients were included. We used meta-analysis to calculate the pooled effect, and meta-regression to identify the responsible exercise characteristics (type, frequency, duration, and time). Subgroup analysis assessed the optimal "time of session" for an improved QoL. The Cochrane risk-of-bias tool was used to determine the quality of studies. In the systematic review, we included 26 RCTs with a total of 1892 breast cancer patients, whilst 18 trials were considered for meta-analysis (exercise = 602; control = 603). The pooled effect showed that exercise intervention substantially improved the QoL (standardized mean difference (SMD) = 0.35; I 2 = 61%; 95% confidence internal (CI): 0.15-0.54; p = 0.0004), SF (SMD = 0.20; I 2 = 16%; 95% CI:0.08-0.32; p = 0.001), and PF (SMD = 0.32; I 2 = 32%; 95% CI:0.20-0.44; p < 0.00001). Meta-regression analysis showed that improved QoL was associated ( p = 0.041) with the "time of session". More specifically, sessions conducted for medium-time (>45 to ≤60 min; p = 0.03) and longer-time (>60 to 90 min; p = 0.005) considerably improved the QoL, whilst shorter-time (≤45 min; p = 0.15) did not. To summarize, exercise interventions improved the QoL, SF, and PF of breast cancer survivors, where the "time of session" appeared to be crucial for an effective improvement in the QoL.

We investigated the influence of resistance exercise (RE) with different intensities on HbA1c, insulin and blood glucose levels in patients with type 2 diabetes (T2D). Diabetes trials that compared RE group with a control were included in meta-analysis. Exercise intensities were categorized into low-to-moderate-intensity and high-intensity subgroups. Intensity effect on glycemic control was determined by meta-regression analysis, and risk-of-bias was assessed using Cochrane Collaboration tool. 24 trials met the inclusion criteria, comprised of 962 patients of exercise ( n = 491) and control ( n = 471). Meta-regression analysis showed decreased HbA1c ( p = 0.006) and insulin ( p = 0.015) after RE was correlated with intensity. Subgroup analysis revealed decreased HbA1c was greater with high intensity (-0.61; 95% CI -0.90, -0.33) than low-to-moderate intensity (-0.23; 95% CI -0.41, -0.05). Insulin levels were significantly decreased only with high intensity (-4.60; 95% CI -7.53, -1.67), not with low-to-moderate intensity (0.07; 95% CI -3.28, 3.42). Notably, values between the subgroups were statistically significant for both HbA1c ( p = 0.03) and insulin ( p = 0.04), indicative of profound benefits of high-intensity RE. Pooled outcomes of 15 trials showed only a decreased trend in blood glucose with RE ( p = 0.09), and this tendency was not associated with intensity. Our meta-analysis provides additional evidence that high-intensity RE has greater beneficial effects than low-to-moderate-intensity in attenuation of HbA1c and insulin in T2D patients., Competing Interests: The authors declare no conflicts of interest.

Background: Typhonium is the largest genus in the Araceae family (~70 species), distributed in South Asia, Southeast Asia and Australia. Typhonium is well-known for its ethnopharmacological uses, and Southeast Asians consider it as an alternative medicine to treat cancer. This review elucidated the confirmed chemical structures of the isolated compounds of Typhonium and emphasized on their anticancer activities against various human cancer cells., Methods: Among several species, Typhonium blumei, T. flagelliforme, T. divaricatum and T. giganteum were extensively studied due to the presence of a class of secondary metabolites. All the available reports on Typhonium were included and discussed in this article., Results: Until now several groups of compounds, namely amino acids (1, 2), cinnamic acid (3), fatty acids (4-14), glycerol derivatives (15-18) and cerebrosides (19-34), flavonoids (35), hydantoins (36-38), lignin monomers (39-44), nucleobases (45-48), pheophorbides (49-52), phthalate (53), terpene and steroids (54-59) and vitamins (60, 61) were isolated and characterized from Typhonium. These phytochemicals were investigated for their anticancer properties, and results confirmed the promising growth inhibitory effect and anticancer activities against human lung, breast, prostate and colon cancer cells. The anticancer activity of these compounds appears to be mediated through the induction of apoptotic cell death. These phytochemicals further reported to exhibit other pharmacological efficacies, including anti-inflammatory, antioxidant, antiviral, anti-allergic, neuroprotective and hepato-protective properties., Conclusion: This is the first review to summarize the anticancer properties of all isolated compounds of Typhonium genus with confirmed chemical structures. Further advanced studies are necessary to establish the detailed signaling pathways that are involved in the anticancer property of the compounds., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: UVA irradiation-induced skin damage/photoaging is associated with redox imbalance and collagen degradation., Objective: Dermato-protective efficacies of trans-cinnamic acid (t-CA), a naturally occurring aromatic compound have been investigated against UVA irradiation, and elucidated underlying molecular mechanism., Methods: Human foreskin fibroblast-derived (Hs68) cells and nude mice were treated with t-CA prior to UVA exposure, and assayed the anti-photoaging effects of t-CA., Results: We found t-CA (20-100 μM) pretreatment substantially ameliorated UVA (3 J/cm 2 )-induced cytotoxicity, and inhibited intracellular ROS production in Hs68 cells. UVA-induced profound upregulation of metalloproteinase (MMP)-1/-3 and degradation of type I procollagen in dermal fibroblasts were remarkably reversed by t-CA, possibly through inhibition of AP-1 (c-Fos, but not c-Jun) translocation. The t-CA-mediated anti-photoaging properties are associated with increased nuclear translocation of Nrf2. Activation of Nrf2 signaling is accompanied with induction of HO-1 and γ-GCLC expressions in t-CA-treated fibroblasts. Furthermore t-CA-induced Nrf2 translocation is mediated through PKC, AMPK, CKII or ROS signaling cascades. This phenomenon was confirmed with respective pharmacological inhibitors, GF109203X, Compound C, CKII inhibitor or NAC, which blockade t-CA-induced Nrf2 activation. Silencing of Nrf2 signaling with siRNA showed no anti-photoaging effects of t-CA against UVA-induced ROS production, loss of HO-1 and type I collagen degradation in fibroblasts. In vivo evidence on nude mice revealed that t-CA pretreatment (20 or 100 mM/day) significantly suppressed MMP-1/-3 activation and maintained sufficient type I procollagen levels in biopsied skin tissue against UVA irradiation (3 J/cm 2 /day for 10-day)., Conclusion: t-CA treatment diminished UVA-induced photoaging/collagen degradation, and protected structural integrity of the skin., (Copyright © 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Ultraviolet A (UVA) irradiation is toxic to skin as it penetrates deep into the dermis and damages cellular components through excessive reactive oxygen species (ROS) production, which accelerates photoaging and skin cancer. We evaluated the dermato-protective efficacies of zerumbone (natural sesquiterpene of Zingiber zerumbet) in UVA-irradiated human skin keratinocyte (HaCaT) cells and mouse epidermis. Zerumbone pretreatment (2-10 μM) substantially suppressed UVA (15 J/cm 2 )-induced HaCaT cell death and lactate dehydrogenase release in a dose-dependent manner. UVA-induced excessive ROS production, DNA single-strand breaks, apoptotic DNA fragmentation and a dysregulated Bax/Bcl-2 ratio were remarkably reversed by zerumbone in keratinocytes. Zerumbone-mediated cytoprotective properties were associated with increased nuclear translocation of nuclear factor-E2-related factor-2 (Nrf2) and elevated antioxidant response element (ARE) luciferase activity. Activation of Nrf2/ARE signaling was accompanied by induction of heme oxygenase-1 (HO-1) and γ-glutamyl cysteine ligase (γ-GCLC) genes in zerumbone-treated keratinocytes. Zerumbone-induced Nrf2 transcriptional activation was mediated by the p38 MAPK, PI3K/AKT and PKC signaling cascades. Notably, silencing of Nrf2 (siRNA transfection) significantly diminished zerumbone-mediated cytoprotective effects, as evidenced by impaired antioxidant genes, uncontrolled ROS/apoptotic DNA fragmentation and keratinocytes death, following UVA irradiation. In vivo evidence demonstrated that zerumbone treatment to nude mice (55 and 110 μg/day) significantly ameliorated UVA (15 J/cm 2 /every 2-day/14-day) cytotoxicity via increased nuclear localization of Nrf2 and Nrf2-dependent antioxidant genes (HO-1 and γ-GCLC) in UVA-treated skin tissues. Our findings emphasized the significance of Nrf2/ARE-signaling in zerumbone-mediated induction of antioxidant genes against UVA-toxicity. The molecular evidence suggests zerumbone can be a natural medicine to treat/prevent UVA-induced skin damage/photoaging., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Flavokawain B (FKB), a naturally occurring chalcone in kava extracts, has been reported to possess anticancer activity. However, the effect of FKB on gastric cancer remains unclear. We examined the in vitro and in vivo anticancer activity and autophagy involvement of FKB and determined the underlying molecular mechanisms. FKB is potently cytotoxic to human gastric cancer cells (AGS/NCI-N87/KATO-III/TSGH9201) and mildly toxic towards normal (Hs738) cells and primary mouse hepatocytes. FKB-induced AGS cell death was characterized by autophagy, not apoptosis, as evidenced by increased LC3-II accumulation, GFP-LC3 puncta and acidic vesicular organelles (AVOs) formation, without resulting procaspase-3/PARP cleavage. FKB further caused p62/SQSTM1 activation, mTOR downregulation, ATG4B inhibition, and Beclin-1/Bcl-2 dysregulation. Silencing autophagy inhibitors CQ/3-MA and LC3 (shRNA) significantly reversed the FKB-induced cell death of AGS cells. FKB-triggered ROS generation and ROS inhibition by NAC pre-treatment diminished FKB-induced cell death, LC3 conversion, AVO formation, p62/SQSTM1 activation, ATG4B inhibition and Beclin-1/Bcl-2 dysregulation, which indicated ROS-mediated autophagy in AGS cells. Furthermore, FKB induces G 2 /M arrest and alters cell-cycle proteins through ROS-JNK signaling. Interestingly, FKB-induced autophagy is associated with the suppression of HER-2 and PI 3 K/AKT/mTOR signaling cascades. FKB inhibits apoptotic Bax expression, and Bax-transfected AGS cells exhibit both apoptosis and autophagy; thus, FKB-inactivated Bax results in apoptosis inhibition. In vivo data demonstrated that FKB effectively inhibited tumor growth, prolonged the survival rate, and induced autophagy in AGS-xenografted mice. Notably, silencing of LC3 attenuated FKB-induced autophagy in AGS-xenografted tumors. FKB may be a potential chemopreventive agent in the activation of ROS-mediated autophagy of gastric cancer cells.

Pearl powder, a well-known traditional mineral medicine, is reported to be used for well-being and to treat several diseases from centuries in Taiwan and China. We investigated the in vitro antihemolytic and antioxidant properties of pearl powder that could protect erythrocytes against 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH)-induced oxidative damage to membrane proteins/lipids. Human erythrocytes were incubated with different concentrations of pearl powder (50-200 μg/mL) for 30 minutes and then exposed to AAPH for 2-6 hours. We found that AAPH alone time dependently increased the oxidative hemolysis of erythrocytes, while pearl powder pretreatment substantially inhibited the hemolysis in a concentration-/time-dependent manner. AAPH-induced oxidative damage to erythrocyte membrane lipids was evidenced by the elevated malondialdehyde (MDA) levels. However, pearl powder remarkably inhibited the malondialdehyde formation, and the 200 μg/mL concentration showed almost similar malondialdehyde values to the control. Furthermore, pearl powder suppressed the AAPH-induced high-molecular-weight protein formation and concomitantly increased the low-molecular-weight proteins in erythrocytes. Antioxidant potential that was measured as superoxide dismutase activity and glutathione content was significantly dropped by AAPH incubation, which suggests the vulnerability of erythrocytes to AAPH-induced oxidative stress. Noteworthy, erythrocytes pretreated with pearl powder showed restored superoxide dismutase activity and glutathione levels against AAPH-induced loss. Our findings conclude that pearl powder attenuate free radical-induced hemolysis and oxidative damage to erythrocyte membrane lipids/proteins. The potent antioxidant property of pearl powder may offer protection from free radical-related diseases., (Copyright © 2016. Published by Elsevier B.V.)

Coenzyme Q 0 (CoQ 0 , 2,3-dimethoxy-5-methyl-1,4-benzoquinone) has been reported to exert anticancer properties against human breast/lung cancer cells. This study investigated the in vitro and in vivo anticancer properties of CoQ 0 on human ovarian carcinoma (SKOV-3) cells and xenografted nude mice, and revealed the underlying molecular mechanism. CoQ 0 induced G 2 /M arrest through downregulation of cyclin B1/A and CDK1/K2 expressions. CoQ 0 -induced autophagy as a survival mechanism was evidenced by increased accumulation of LC3-II, GFP-LC3 puncta, AVOs formation and Beclin-1/Bcl-2 dysregulation. Increased TUNEL-positive cells and Annexin-V/PI stained cells indicated CoQ 0 -induced late apoptosis. Both mitochondrial (caspase-3, PARP and Bax/Bcl-2 dysregulation) and ER stress (caspase-12 and Hsp70) signals are involved in execution of apoptosis. Interestingly, CoQ 0 -induced apoptosis/autophagy is associated with suppression of HER-2/neu and PI 3 K/AKT signalling cascades. CoQ 0 triggered intracellular ROS production, whereas antioxidant N-acetylcysteine prevented CoQ 0 -induced apoptosis, but not autophagy. Inhibition of apoptosis by Z-VAD-FMK suppressed CoQ 0 -induced autophagy (diminished LC3-II/AVOs), indicates CoQ 0 -induced apoptosis led to evoke autophagy. Contrary, inhibition of autophagy by 3-MA/CQ potentiated CoQ 0 -induced apoptosis (increased DNA fragmentation/PARP cleavage). Furthermore, CoQ 0 treatment to SKOV-3 xenografted nude mice reduced tumor incidence and burden. Histopathological analyses confirmed that CoQ 0 modulated xenografted tumor progression by apoptosis induction. Our findings emphasize that CoQ 0 triggered ROS-mediated apoptosis and cytoprotective autophagy.

Cigarette smoke exposure activates several cellular mechanisms predisposing to atherosclerosis, including oxidative stress, dyslipidemia, and vascular inflammation. Antrodia camphorata, a renowned medicinal mushroom in Taiwan, has been investigated for its antioxidant, anti-inflammatory, and antiatherosclerotic properties in cigarette smoke extracts (CSE)-treated vascular smooth muscle cells (SMCs), and ApoE-deficient mice. Fermented culture broth of Antrodia camphorata (AC, 200-800 µg/mL) possesses effective antioxidant activity against CSE-induced ROS production. Treatment of SMCs (A7r5) with AC (30-120 µg/mL) remarkably ameliorated CSE-induced morphological aberrations and cell death. Suppressed ROS levels by AC corroborate with substantial inhibition of CSE-induced DNA damage in AC-treated A7r5 cells. We found CSE-induced apoptosis through increased Bax/Bcl-2 ratio, was substantially inhibited by AC in A7r5 cells. Notably, upregulated SOD and catalase expressions in AC-treated A7r5 cells perhaps contributed to eradicate the CSE-induced ROS generation, and prevents DNA damage and apoptosis. Besides, AC suppressed AP-1 activity by inhibiting the c-Fos/c-Jun expressions, and NF-κB activation through inhibition of I-κBα degradation against CSE-stimulation. This anti-inflammatory property of AC was accompanied by suppressed CSE-induced VEGF, PDGF, and EGR-1 overexpressions in A7r5 cells. Furthermore, AC protects lung fibroblast (MRC-5) cells from CSE-induced cell death. In vivo data showed that AC oral administration (0.6 mg/d/8-wk) prevents CSE-accelerated atherosclerosis in ApoE-deficient mice. This antiatherosclerotic property was associated with increased serum total antioxidant status, and decreased total cholesterol and triacylglycerol levels. Thus, Antrodia camphorata may be useful for prevention of CSE-induced oxidative stress and diseases. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 2070-2084, 2017., (© 2017 Wiley Periodicals, Inc.)

Background: Existing literature on anti-oxidant capacity of ginseng has been inconsistent due to variance in the profile of ginseng steroids (Ginsenosides) that is because of differences in seasons and species., Methods: We used various doses of ginseng steroids to determine its effect on oxidative stress and anti-oxidant capacity of rat skeletal muscle against exercise., Results: Under non-exercise conditions, we found increased thiobarbituric acid reactive substance (TBARS) levels and decreased reduced/oxidized glutathione ratio (GSH/GSSG) in rat skeletal muscle as dose increases ( p < 0.05), which indicates the pro-oxidant property of ginseng steroids at baseline. Intriguingly, exhaustive exercise-induced increased TBARS and decreased GSH/GSSG ratio were attenuated with low and medium doses of ginseng steroids (20 and 40 mg per kg), but not with high dose (120 mg per kg). At rest, anti-oxidant enzyme activities, including catalase (CAT), glutathione reductase (GR) and glutathione S-transferase (GST) were increased above vehicle-treated level, but not with the high dose, suggesting a hormetic dose-response of ginseng steroids., Conclusion: The results of this study provide an explanation for the inconsistent findings on anti-oxidative property among previous ginseng studies. For optimizing the anti-oxidant outcome, ginseng supplementation at high dose should be avoided., Competing Interests: This study was sponsored by Pegasus Pharmaceuticals Group Inc. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results. Jessica Lu is a full time employee of Pegasus Pharmaceuticals Group Inc. The purpose of the study was used to develop anti-fatigue formula for the company. Jessica Lu has no influence on the results presented in this study. The rest of authors have no potential conflicts of interest, financial or otherwise, to declare.

We investigated the in vitro and in vivo anticancer properties of Antrodia salmonea (AS), a well-known edible/medicinal mushroom in Taiwan, on human triple-negative breast cancer (MDA-MB-231) cells and xenografted nude mice; and revealed the underlying molecular mechanisms involved in autophagic- and apoptotic-cell death. Treatment of MDA-MB-231 cells with fermented culture broth of AS (0-200 μg/mL) inhibited cell viability/growth. AS-induced autophagy was evidenced via increased LC3-II accumulation, GFP-LC3 puncta and AVOs formation in MDA-MB-231 cells. These events are associated with increased ATG7, decreased p-mTOR, vanished SQSTM1/p62 expressions and dysregulated Beclin-1/Bcl-2 ratio. AS-induced apoptosis/necrosis through increased DNA fragmentation, Annexin-V/PI stained cells and Bax expression. Both mitochondrial (caspase-9/caspase-3/PARP) and death-receptor (caspase-8/FasL/Fas) signaling pathways are involved in execution of apoptosis. Interestingly, blockade of AS-induced ROS production by N-acetylcysteine pretreatment substantially attenuated AS-induced autophagy, mitochondrial dysfunction and autophagic/apoptotic-cell death. Inhibition of apoptosis by Z-VAD-FMK suppressed AS-induced autophagic-death (decreased LC3-II/AVOs). Similarly, inhibition of autophagy by 3-methyladenine/chloroquine diminished AS-induced apoptosis (decreased DNA fragmentation/caspase-3) in MDA-MB-231 cells. Bioluminescence imaging further confirmed that AS inhibited breast tumor growth in living MDA-MB-231-luciferase-injected nude mice. Taken together, AS crucially involved in execution/propagation of autophagic- or apoptotic-death of MDA-MB-231 cells, and decreased tumor growth in xenografted nude mice., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Lucidone, which comprises a naturally occurring cyclopentenedione, has been investigated for its in vitro and in vivo wound healing properties, and the underlying molecular signaling cascades in the wound healing mechanism have been elucidated. We demonstrated the cell-/dose-specific responses of lucidone (0.5-8μM) on proliferation and migration/invasion of keratinocyte HaCaT and fibroblast Hs68 cells. In keratinocytes, lucidone-induced nuclear translocation of β-catenin was accompanied by increased transcriptional target genes, including c-Myc and cyclin-D1, through GSK3β-dependent pathway. Correspondingly, lucidone promoted the cell-cycle by increasing PCNA/CDK4 and decreasing p21/p27 expressions. Lucidone induced EMT through the downregulation of epithelial (E-cadherin/occludin) and upregulation of mesenchymal (vimentin/Twist/Snail) marker proteins. Activated MMP-9/-2 and uPA/uPAR as well as suppressed TIMP-1/-2 and PAI-1 expressions by lucidone may promote the migration/invasion of keratinocytes. Notably, lucidone activated NF-κB signaling via IKK-mediated-IκB degradation, and its inhibition abolished MMP-9 activation and keratinocyte migration. Inhibition of PI 3 K/AKT signaling impaired the lucidone-induced proliferation/migration with corresponding suppression of β-catenin/c-Myc/cyclin-D1 and NF-κB/MMP-9 expressions. Results indicate that lucidone-induced PI 3 K/AKT signaling anchored the β-catenin/NF-κB-mediated healing mechanism. β-catenin knockdown substantially diminished lucidone-induced keratinocyte migration. Furthermore, lucidone increased endothelial cell proliferation/migration and triggered angiogenesis (MMP-9/uPA/ICAM-1). In macrophages, lucidone-activated NF-κB-mediated inflammation (COX-2/iNOS/NO) and VEGF, which may contribute to the growth of keratinocytes/fibroblasts and endothelial cells. Punched wounds on mice were rapidly healed with the topical application of lucidone (5mM) compared with control ointment-treated mice. Taken together, lucidone accelerates wound healing through the cooperation of keratinocyte/fibroblast/endothelial cell growth and migration and macrophage inflammation via PI 3 K/AKT, Wnt/β-catenin and NF-κB signaling cascade activation., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Development of effective drug delivery systems (DDS) is a critical issue in health care and medicine. Advances in molecular biology and nanotechnology have allowed the introduction of nanomaterial-based drug delivery systems. Cell-penetrating peptides (CPPs) can form the basis of drug delivery systems by virtue of their ability to support the transport of cargoes into the cell. Potential cargoes include proteins, DNA, RNA, liposomes, and nanomaterials. These cargoes generally retain their bioactivities upon entering cells., Method: In the present study, the smallest, fully-active lactoferricin-derived CPP, L5a is used to demonstrate the primary contributor of cellular internalization., Results: The secondary helical structure of L5a encompasses symmetrical positive charges around the periphery. The contributions of cell-specificity, peptide length, concentration, zeta potential, particle size, and spatial structure of the peptides were examined, but only zeta potential and spatial structure affected protein transduction efficiency. FITC-labeled L5a appeared to enter cells via direct membrane translocation insofar as endocytic modulators did not block FITC-L5a entry. This is the same mechanism of protein transduction active in Cy5 labeled DNA delivery mediated by FITC-L5a. A significant reduction of transduction efficiency was observed with structurally incomplete FITC-L5a formed by tryptic destruction, in which case the mechanism of internalization switched to a classical energydependent endocytosis pathway., Conclusion: These results support the continued development of the non-cytotoxic L5a as an efficient tool for drug delivery., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Coenzyme Q (CoQ) analogs with variable number of isoprenoid units have been demonstrated as anti-inflammatory and antioxidant/pro-oxidant molecules. In this study we used CoQ0 (2,3-dimethoxy-5-methyl-1,4-benzoquinone, zero isoprenoid side-chains), a novel quinone derivative, and investigated its molecular actions against LPS-induced inflammation and redox imbalance in murine RAW264.7 macrophages and mice. In LPS-stimulated macrophages, non-cytotoxic concentrations of CoQ0 (2.5-10 μM) inhibited iNOS/COX-2 protein expressions with subsequent reductions of NO, PGE2, TNF-α and IL-1β secretions. This inhibition was reasoned by suppression of NFκB (p65) activation, and inhibition of AP-1 (c-Jun., c-Fos, ATF2) translocation. Our findings indicated that IKKα-mediated I-κB degradation and MAPK-signaling are involved in regulation of NFκB/AP-1 activation. Furthermore, CoQ0 triggered HO-1 and NQO-1 genes through increased Nrf2 nuclear translocation and Nrf2/ARE-signaling. This phenomenon was confirmed by diminished CoQ0 protective effects in Nrf2 knockdown cells, where LPS-induced NO, PGE2, TNF-α and IL-1β productions remained high. Molecular evidence revealed that CoQ0 enhanced Nrf2 steady-state level at both transcriptional and translational levels. CoQ0-induced Nrf2 activation appears to be regulated by ROS-JNK-signaling cascades, as evidenced by suppressed Nrf2 activation upon treatment with pharmacological inhibitors of ROS (N-acetylcysteine) and JNK (SP600125). Besides, oral administration of CoQ0 (5 mg/kg) suppressed LPS-induced (1 mg/kg) induction of iNOS/COX-2 and TNF-α/IL-1β through tight regulation of NFκB/Nrf2 signaling in mice liver and spleen. Our findings conclude that pharmacological actions of CoQ0 are mediated via inhibition of NFκB/AP-1 activation and induction of Nrf2/ARE-signaling. Owing to its potent anti-inflammatory and antioxidant properties, CoQ0 could be a promising candidate to treat inflammatory disorders., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Hericium erinaceus (HE) is an edible mushroom that has been shown to exhibit anticancer and anti-inflammatory activities. We investigated the antiangiogenic and antioxidant potentials of ethanol extracts of HE in human endothelial (EA.hy926) cells upon tumor necrosis factor-α- (TNF-α-) stimulation (10 ng/mL). The underlying molecular mechanisms behind the pharmacological efficacies were elucidated. We found that noncytotoxic concentrations of HE (50-200 μg/mL) significantly inhibited TNF-α-induced migration/invasion and capillary-like tube formation of endothelial cells. HE treatment suppressed TNF-α-induced activity and/or overexpression of matrix metalloproteinase-9 (MMP-9) and intercellular adhesion molecule-1 (ICAM-1). Furthermore, HE downregulated TNF-α-induced nuclear translocation and transcriptional activation of nuclear factor-κB (NF-κB) followed by suppression of I-κB (inhibitor-κB) degradation. Data from fluorescence microscopy illustrated that increased intracellular ROS production upon TNF-α-stimulation was remarkably inhibited by HE pretreatment in a dose-dependent manner. Notably, HE triggered antioxidant gene expressions of heme oxygenase-1 (HO-1), γ-glutamylcysteine synthetase (γ-GCLC), and glutathione levels, which may contribute to inhibition of ROS. Increased antioxidant status was associated with upregulated nuclear translocation and transcriptional activation of NF-E2 related factor-2 (Nrf2) in HE treated cells. Our findings conclude that antiangiogenic and anti-inflammatory activities of H. erinaceus may contribute to its anticancer property through modulation of MMP-9/NF-κB and Nrf2-antioxidant signaling pathways.

Various coenzyme Q (CoQ) analogs have been reported as anti-inflammatory and antioxidant substances. However, coenzyme Q0 (CoQ0, 2,3-dimethoxy-5-methyl-1,4-benzoquinone), a novel quinone derivative, has not been well studied for its pharmacological efficacies, and its response to cytokine stimulation remains unclear. Therefore, we investigated the potential anti-angiogenic properties of CoQ0 in human endothelial (EA.hy 926) cells against tumor necrosis factor-α (TNF-α) stimulation. We found that the non-cytotoxic concentrations of CoQ0 (2.5-10μM) significantly suppressed the TNF-α-induced migration/invasion and tube formation abilities of endothelial cells. CoQ0 suppressed TNF-α-induced activity and protein expressions of matrix metalloproteinase-9 (MMP-9) and intercellular adhesion molecule-1 (ICAM-1) followed by an abridged adhesion of U937 leukocytes to endothelial cells. CoQ0 treatment remarkably downregulated TNF-α-induced nuclear translocation and transcriptional activation of nuclear factor-κB (NF-κB) possibly through suppressed I-κBα degradation. Furthermore, CoQ0 triggered the expressions of heme oxygenase-1 (HO-1) and γ-glutamylcysteine synthetase (γ-GCLC), followed by an increased nuclear accumulation of NF-E2 related factor-2 (Nrf2)/antioxidant response element (ARE) activity. In agreement with these, intracellular glutathione levels were significantly increased in CoQ0 treated cells. More interestingly, knockdown of HO-1 gene by specific shRNA showed diminished anti-angiogenic effects of CoQ0 against TNF-α-induced invasion, tube formation and adhesion of leukocyte to endothelial cells. Our findings reveal that CoQ0 protective effects against cytokine-stimulation are mediated through the suppression of MMP-9/NF-κB and/or activation of HO-1 signaling cascades. This novel finding emphasizes the pharmacological efficacies of CoQ0 to treat inflammation and angiogenesis., (Copyright © 2015. Published by Elsevier Inc.)