Machine-learning model for the prediction of acute orthostatic hypotension after levodopa administration.

BACKGROUND: Levodopa could induce orthostatic hypotension (OH) in Parkinson's disease (PD) patients. Accurate prediction of acute OH post levodopa (AOHPL) is important for rational drug use in PD patients. Here, we develop and validate a prediction model of AOHPL to facilitate physicians in identifying patients at higher probability of developing AOHPL. METHODS: The study involved 497 PD inpatients who underwent a levodopa challenge test (LCT) and the supine-to-standing test (STS) four times during LCT. Patients were divided into two groups based on whether OH occurred during levodopa effectiveness (AOHPL) or not (non-AOHPL). The dataset was randomly split into training (80%) and independent test data (20%). Several models were trained and compared for discrimination between AOHPL and non-AOHPL. Final model was evaluated on independent test data. Shapley additive explanations (SHAP) values were employed to reveal how variables explain specific predictions for given observations in the independent test data. RESULTS: We included 180 PD patients without AOHPL and 194 PD patients with AOHPL to develop and validate predictive models. Random Forest was selected as our final model as its leave-one-out cross validation performance [AUC_ROC 0.776, accuracy 73.6%, sensitivity 71.6%, specificity 75.7%] outperformed other models. The most crucial features in this predictive model were the maximal SBP drop and DBP drop of STS before medication (ΔSBP/ΔDBP). We achieved a prediction accuracy of 72% on independent test data. ΔSBP, ΔDBP, and standing mean artery pressure were the top three variables that contributed most to the predictions across all individual observations in the independent test data. CONCLUSIONS: The validated classifier could serve as a valuable tool for clinicians, offering the probability of a patient developing AOHPL at an early stage. This supports clinical decision-making, potentially enhancing the quality of life for PD patients.

Protein aggregation caused by pasteurization processing affects the foam performance of liquid egg white.

Pasteurization is necessary during the production of liquid egg whites (LEW), but the thermal effects in pasteurization could cause an unavoidable loss of foaming properties of LEW. This study intended to investigate the mechanism of pasteurization processing affects the foam performance of LEW. The foaming capacity (FC) of LEW deteriorated significantly (ΔFCmax = 72.33 %) and foaming stability (FS) increased slightly (ΔFSmax = 3.64 %) under different temperature-time combinations of pasteurization conditions (P < 0.05). The increased turbidity and the decreased solubility together with the decreased absolute value of Zeta potential indicated the generation of thermally induced aggregates and the instability of the protein particles, Rheological characterization demonstrated improved viscoelasticity in pasteurization liquid egg whites (PLEW), explaining enhanced FS. The study revealed that loss in foaming properties of PLEW resulted from thermal-induced protein structural changes and aggregation, particularly affecting FC. This provided a theoretical reference for the production and processing of LEW products.

Synergistic antitumor effects of Peiminine and Doxorubicin on breast cancer through enhancing DNA damage via ZEB1.

Peiminine, the primary biologically active compound from Fritillaria thunbergii Miq., has demonstrated significant pharmacological activities. Doxorubicin is one of the most potent chemotherapeutic agents for breast cancer (BC). This study was designed to investigate the efficacy and underlying mechanisms of Peiminine combined with Doxorubicin in treating BC. Our results demonstrated that the combination of Peiminine and 1 mg/kg Doxorubicin exhibited more significant suppression of tumor growth compared with the monotherapy in MDA-MB-231 xenograft nude mice model, which is comparable to the effect of 3 mg/kg Doxorubicin in vivo. Notably, the 3 mg/kg Doxorubicin monotherapy resulted in organ toxicity, specifically in the liver and heart, whereas no toxicity was observed in the combination group. In vitro, this combined treatment exhibited a synergistic reduction on the viability of BC cells. Peiminine enhanced the cell cycle arrest and DNA damage induced by Doxorubicin. Furthermore, the combination treatment effectively blocked DNA repair by inhibiting the MAPKs signaling pathways. And ZEB1 knockdown attenuated the combined effect of Peiminine and Doxorubicin on cell viability and DNA damage. In conclusion, our study found that the combination of Peiminine and Doxorubicin showed synergistic inhibitory effects on BC both in vivo and in vitro through enhancing Doxorubicin-induced DNA damage. These findings support that their combination is a novel and promising therapeutic strategy for treating BC.

Nuts and seeds consumption impact on adolescent obesity: sex-specific associations from 2003 to 2018 National Health and Nutrition Examination Survey.

The nutritional benefits and immunological advantages of consuming nuts and seeds are well-established. However, the link between nuts and seeds consumption and the susceptibility of being overweight or obese among adolescents is not clear. This study aims to explore this relationship in adolescents aged 12-19. Using a weighted multiple logistic regression model, we analysed data of the Food Patterns Equivalents Database and the U.S. National Health and Nutrition Examination Survey (NHANES) from 2003 to 2018. We found a significant association between nuts and seeds consumption and a reduced odds of being overweight or obese in females. Specifically, females who habitually consumed nuts and seeds had lower odds of being overweight or obese (OR = 0.55, 95% CI: 0.32-0.94). Additionally, we found an L-shaped relationship between nuts and seeds consumption and appropriate waist-to-height ratio in males. The findings suggest that nuts and seeds consumption may contribute to healthier physical development in adolescents.

Current status and development trends in CKD with frailty research from 2000 to 2021: a bibliometric analysis.

INTRODUCTION: The prevalence of chronic kidney disease (CKD) is gradually increasing in the elderly population. At the same time, frailty has become one of the research hotspots in the field of geriatrics. Bibliometric analyses help to understand the direction of a field. Therefore, this study aimed to analyze the status and emerging trends of frailty in CKD patients. DATA AND METHODS: The Web of Science Core Collection (WoSCC) database was screened for relevant literature published between 1 January 2000 and 31 December 2021. Next, publications were analyzed for information including authors, journals, cited references, citing journals, institutions, countries and regions, high-frequency keywords and co-citations using VOSviewer, Microsoft Excel, and R software. RESULTS: A total of 2223 articles were obtained, from which 613 relevant articles were selected based on title and abstract screening. There was an upward trend in the number of annual publications and Johansen KL was considered the most contributing author in the field. The Clinical Journal of the American Society of Nephrology was the most productive research journal. Johns Hopkins University is the most published organization. The United States is the global leader in the field and contributes the most to research. Research hotspots focus on epidemiological studies of frailty and frailty intervention. CONCLUSIONS: This study presents a comprehensive bibliometric analysis of CKD and frailty research. Key findings highlight the current focus on early screening and assessment of frailty in CKD patients, as well as physical function interventions in frail patients.

Dopaminergic versus anticholinergic treatment effects on physiologic complexity of hand tremor in Parkinson's disease: A randomized crossover study.

AIMS: Parkinsonian tremor (PT) is regulated by numerous neurophysiological components across multiple temporospatial scales. The dynamics of tremor fluctuation are thus highly complex. This study aimed to explore the effects of different medications on tremor complexity, and how the underlying factors contribute to such tremor complexity. METHODS: In this study, 66 participants received a 2-mg dose of benzhexol or a pre-determined dose of levodopa at two study visits in a randomized order. Before and after taking the medications, tremor fluctuation was recorded using surface electromyography electrodes and accelerometers in resting, posture, and weighting conditions with and without a concurrent cognitive task. Tremor complexity was quantified using multiscale entropy. RESULTS: Tremor complexity in resting (p = 0.002) and postural condition (p < 0.0001) was lower when participants were performing a cognitive task compared to a task-free condition. After taking levodopa and benzhexol, participants had increased (p = 0.02-0.03) and decreased (p = 0.03) tremor complexity compared to pre-medication state, respectively. Tremor complexity and its changes as induced by medications were significantly correlated with clinical ratings and their changes (ß = -0.23 to -0.39; p = 0.002-0.04), respectively. CONCLUSION: Tremor complexity may be a promising marker to capture the pathophysiology underlying the development of PT, aiding the characterization of the effects medications have on PT regulation.

Nomogram for predicting lymph node metastasis in patients with ovarian cancer using ultrasonography: a multicenter retrospective study.

BACKGROUND: Ovarian cancer is a common cancer among women globally, and the assessment of lymph node metastasis plays a crucial role in the treatment of this malignancy. The primary objective of our study was to identify the risk factors associated with lymph node metastasis in patients with ovarian cancer and develop a predictive model to aid in the selection of the appropriate surgical procedure and treatment strategy. METHODS: We conducted a retrospective analysis of data from patients with ovarian cancer across three different medical centers between April 2014 and August 2022. Logistic regression analysis was employed to establish a prediction model for lymph node metastasis in patients with ovarian cancer. We evaluated the performance of the model using receiver operating characteristic (ROC) curves, calibration plots, and decision analysis curves. RESULTS: Our analysis revealed that among the 368 patients in the training set, 101 patients (27.4%) had undergone lymph node metastasis. Maximum tumor diameter, multifocal tumor, and Ki67 level were identified as independent risk factors for lymph node metastasis. The area under the curve (AUC) of the ROC curve in the training set was 0.837 (95% confidence interval [CI]: 0.792-0.881); in the validation set this value was 0.814 (95% CI: 0.744-0.884). Calibration plots and decision analysis curves revealed good calibration and clinical application value. CONCLUSIONS: We successfully developed a model for predicting lymph node metastasis in patients with ovarian cancer, based on ultrasound examination results and clinical data. Our model accurately identified patients at high risk of lymph node metastasis and may guide the selection of appropriate treatment strategies. This model has the potential to significantly enhance the precision and efficacy of clinical management in patients with ovarian cancer.

Acute effect of levodopa on orthostatic hypotension and its association with motor responsiveness in Parkinson's disease: Results of acute levodopa challenge test.

OBJECTIVE: Levodopa administration can induce or worsen orthostatic hypotension (OH) in patients with Parkinson's disease (PD). Understanding of acute OH post levodopa (AOHPL) is important for rational drug use in PD patients. Primary objective of this study was to investigate the incidence of AOHPL in PD patients. The secondary objectives were a) hemodynamic character of AOHPL; b) risk factors of AOHPL; c) relationship between motor responsiveness and blood pressure (BP) change. METHODS: 490 PD inpatients underwent acute levodopa challenge test (LCT). Supine-to-standing test (STS) was done 4 times during LCT, including before levodopa and every hour post levodopa intake within 3 h. Patients were classified into two groups, AOHPL and non-AOHPL. A comprehensive set of clinical features scales was assessed, including both motor (e.g., motor response, wearing-off) and nonmotor symptoms (e.g., autonomic dysfunction, neuropsychology). RESULTS: 33.1% PD patients had OH before drug, 50.8% the same subjects had AOHPL during levodopa effectiveness. PD patients who had better response to levodopa likely to have lower standing mean artery pressure (MAP) and severer systolic BP drop after levodopa intake. BP increased when the motor performance worsened and vice versa. Beneficial response was a risk factors of AOHPL (OR = 1.624, P = 0.017). CONCLUSIONS: AOHPL was very common in PD patients. We suggested that PD patients with risk factors should monitor hemodynamic change during LCT to avoid AOHPL following the introduction or increase of oral levodopa. The fluctuations of BP were complicated and multifactorial, likely caused by the process of PD and levodopa both.

Daucosterol confers protection against T-2 toxin induced blood-brain barrier toxicity through the PGC-1α-mediated defensive response in vitro and in vivo.

T-2 toxin is a common environmental pollutant and contaminant in food and animal feed that represents a great challenge to human and animal' health throughout the world. Using natural compounds to prevent the detrimental effects of T-2 toxin represents an attractive strategy. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a critical regulator in various cellular processes. Recently, PGC-1α activation has been reported to confer protection against neurological injuries. We aimed to identify a potent PGC-1α activator from plants as a chemopreventive compound and to demonstrate the efficacy of the compound in attenuating T-2 toxin-induced blood-brain barrier (BBB) toxicity. We identified daucosterol, which binds directly to the 71-74 (-1100 to -1000 bp) position of the second promoter of human PGC-1α by hydrogen bonding. An in vitro and in vivo T-2 toxin induced BBB injury model revealed that this compound can protect against this injury by increasing transepithelial/transendothelial electrical resistance, reducing sodium fluorescein (NaF) infiltration and increasing the expression of tight junction-related proteins (zonula occludens-1 (ZO-1), occludin (OCLN), claudin-5 (CLDN5)) expression. In conclusion, we identified daucosterol as representing a novel of PGC-1α activators and illustrated the mechanism of specific binding site. Furthermore, we have demonstrated the feasibility of using natural compounds targeting PGC-1α as a therapeutic approach to protect humans from environmental insults that may occur daily such as lipopolysaccharide.

Development and Validation of Prediction Models for All-Cause Mortality and Cardiovascular Mortality in Patients on Hemodialysis: A Retrospective Cohort Study in China.

Purpose: This study aimed to develop two predictive nomograms for the assessment of long-term survival status in hemodialysis (HD) patients by examining the prognostic factors for all-cause mortality and cardiovascular (CVD) event mortality. Patients and methods: A total of 551 HD patients with an average age of over 60 were included in this study. The patients' medical records were collected from our hospital and randomly allocated to two cohorts: the training cohort (n=385) and the validation cohort (n=166). We employed multivariate Cox assessments and fine-gray proportional hazards models to explore the predictive factors for both all-cause mortality and cardiovascular event mortality risk in HD patients. Two nomograms were established based on predictive factors to forecast patients' likelihood of survival for 3, 5, and 8 years. The performance of both models was evaluated using the area under the curve (AUC), calibration plots, and decision curve analysis. Results: The nomogram for all-cause mortality prediction included seven factors: age ≥ 60, sex (male), history of diabetes and coronary artery disease, diastolic blood pressure, total triglycerides (TG), and total cholesterol (TC). The nomogram for cardiovascular event mortality prediction included three factors: history of diabetes and coronary artery disease, and total cholesterol (TC). Both models demonstrated good discrimination, with AUC values of 0.716, 0.722 and 0.725 for all-cause mortality at 3, 5, and 8 years, respectively, and 0.702, 0.695, and 0.677 for cardiovascular event mortality, respectively. The calibration plots indicated a good agreement between the predictions and the decision curve analysis demonstrated a favorable clinical utility of the nomograms. Conclusion: Our nomograms were well-calibrated and exhibited significant estimation efficiency, providing a valuable predictive tool to forecast prognosis in HD patients.

A new insight into the influence of pH on the adsorption at oil-water interface and emulsion stability of egg yolk protein.

This study investigated the impact of varied pH treatments on the structural, emulsification, and interfacial adsorption properties of egg yolk. The solubility of egg yolk proteins decreased and then increased in response to pH changes, with a minimum value (41.95 %) observed at pH 5.0. The alkaline condition (pH 9.0) significantly impacted the secondary/tertiary structure of egg yolk, with the yolk solution displaying the lowest surface tension value (15.98 mN/m). Emulsion stability was found to be optimal when egg yolk was used as the stabilizer at pH 9.0, which corresponded to the more flexible diastolic structure, smaller emulsion droplets, increased viscoelasticity, and enhanced resistance to creaming. At pH 9.0, proteins exhibited a maximum solubility (90.79 %) due to their unfolded conformation, yet the protein adsorption content at the oil-water interface showed relatively low (54.21 %). At this time, electrostatic repulsion between the droplets and the spatial site barrier made by proteins that were unable to efficiently adsorb at the oil-water interface kept the emulsion stable. Moreover, it was found that different pH treatments could effectively regulate the relative adsorption contents of various protein subunits at the oil-water interface, and all proteins except livetin displayed good interfacial adsorption capacity at the oil-water interface.

Association between nut consumption and frailty in the elderly: a large sample cross-sectional study.

BACKGROUND: Limited literature has addressed the impact of nut consumption in mitigating frailty. This study aimed to investigate the association between nut consumption and frailty among Americans aged above 60 years, employing two 24-h dietary recalls for analysis. METHODS: The data sets of the National Health and Nutrition Examination Survey (NHANES) (2003-2018) and the Food Patterns Equivalents Database were utilised for a weighted multiple logistic regression model to evaluate the association between nut consumption and frailty in elderly adults. Furthermore, a restricted cubic spline model was employed to investigate the nonlinear relationship between nut intake and frailty. Besides, stratified and interaction analyses were conducted to explore the sensitivity of nut consumption in reducing the risk of frailty in diverse subgroups. RESULTS: The research study comprised 10,033 individuals aged 60 years or above, of whom 3591 were classified as frailty and 5302 consumed nuts. In the multivariate logistic regression analysis that adjusted for covariates, the weighted multivariate adjusted odds ratios demonstrated that the prevalence of frailty was lower in the nut intake group than in nonconsumers. The stratified analysis indicated that nearly all subgroups who consumed nuts had a significantly lower risk of frailty compared to nonconsumers, and an interaction was observed between nut intake and nonhypertensive populations. The optimal threshold for nut intake to decrease the risk of frailty was identified as 1.02 ounces. CONCLUSIONS: The study concluded that nut consumption has a constructive impact on averting frailty in elderly adults, particularly in nonhypertensive individuals. Nut intake of ~1.02 ounces per day is advantageous in improving the quality of life in elderly adults.

Effects of the synbiotic composed of mangiferin and Lactobacillus reuteri 1-12 on type 2 diabetes mellitus rats.

Many synbiotics are effective for the prevention and treatment of type 2 diabetes mellitus (T2DM). In the treatment of T2DM, synbiotics often regulate the composition of intestinal flora, which autoinducer-2 (AI-2) may play an important role. Whether the changes of intestinal flora are related to AI-2 during synbiotics treatment of T2DM is a topic worth studying. We elucidated the effects of synbiotic composed of mangiferin and Lactobacillus reuteri 1-12 (SML) on T2DM rats. Male Spraque-Dawley rats were injected intraperitoneally with streptozotocin (STZ) and randomly grouped. After that, biochemical parameters, intestinal flora, fecal AI-2, and intestinal colonization of L. reuteri were detected. The results showed that SML had a hypoglycemic effect and mitigated the organ lesions of the liver and pancreas. Also, SML regulated biochemical parameters such as short chain fatty acids (SCFAs), lipopolysaccharides (LPS), intercellular cell adhesion molecule-1 (ICAM-1), and tumor necrosis factor-α (TNF-α). On the other hand, the proportion of probiotics, such as Lactobacillus acidophilus, L. reuteri, Bifidobacterium pseudolongum, Lactobacillus murinus, and Lactobacillus johnsonii, were elevated by the treatment of SML. In addition, SML promoted the colonization and proliferation of L. reuteri in the gut. Another thing to consider was that AI-2 was positively correlated with the total number of OTUs sequences and SML boosted AI-2 in the gut. Taken together, these results supported that SML may modulate intestinal flora through AI-2 to treat T2DM. This study provided a novel alternative strategy for the treatment of T2DM in future.

Compatibility of Polygonati Rhizoma and Angelicae Sinensis Radix enhance the alleviation of metabolic dysfunction-associated fatty liver disease by promoting fatty acid ß-oxidation.

Jiuzhuan Huangjing Pills (JHP) composed of Polygonati Rhizoma (PR) and Angelicae Sinensis Radix (ASR) remedied mitochondria to cure metabolic dysfunction-associated fatty liver disease (MAFLD). However, a comparison of the anti-MAFLD ability between JHP prescription and PR and ASR single-medicines in MAFLD has not been performed, and the action mechanisms and substances remain unknown. Our results show that JHP, PR and ASR decreased serum and liver lipid levels. The effects of JHP were stronger than those of PR and ASR. JHP, PR and ASR afforded protection to mitochondrial ultrastructure, and regulated oxidative stress and energy metabolism in mitochondria. JHP also regulated the expression of ß-oxidation genes, which were not regulated by PR and ASR. JHP-, PR- and ASR-derived components in mitochondrial extracts regulated oxidative stress, energy metabolism, and ß-oxidation gene expression and alleviated cellular steatosis. Four, six and eleven compounds were identified in mitochondrial extracts from PR-, ASR- and JHP-treated rats, respectively. The data suggest that JHP, PR and ASR alleviated MAFLD by remedying mitochondria, while the ability of JHP was stronger than that of PR and ASR, which was involved with the ß-oxidation promotion. The compounds identified may be the main ingredients in the three extracts active in MAFLD improvement.

Nicaraven protects against endotoxemia-induced inflammation and organ injury through modulation of AMPK/Sirt1 signaling in macrophages.

Endotoxemia is a disease characterized by systemic inflammatory responses and organ injury caused by lipopolysaccharide (LPS) infection, with high mortality. Nicaraven (AVS), a potent hydroxyl radical scavenger, has been proven to regulate the inflammatory response in tumors. To investigate the protective effects and mechanisms of AVS in endotoxemia, mice were injected intraperitoneally with LPS to induce endotoxemia. AVS treatment significantly decreased the levels of pro-inflammatory cytokines in the serum, reduced neutrophil infiltration, attenuated multiple organ injury, and increased the survival rate in LPS-challenged mice. In the LPS-induced inflammatory model of macrophages, AVS inhibited macrophage activation, suppressed nitric oxide (NO) production, and inhibited the expression and secretion of pro-inflammatory cytokines. Mechanistically, AVS treatment up-regulated silence information regulator transcript-1 (Sirt1) expression in a time- and dose-dependent manner. AVS treatment activated the AMP-dependent protein kinase (AMPK)/Sirt1 signaling pathway and suppressed the activation of nuclear factor kappa B (NF-κB) in macrophages exposed to LPS. However, the anti-inflammatory effects of AVS could be reversed by the AMPK, the Sirt1 inhibitor, or the histone deacetylase inhibitor. We confirmed that the AMPK inhibitor inhibited AVS-mediated AMPK/Sirt1 activation and NF-κB p65 acetylation. These results suggested that AVS alleviated endotoxemia by activating the AMPK/Sirt1 signaling pathway in macrophages.

The Influence of Temperature Changes on the Rice Starch Structure and Digestive Characteristics: One and Two-Step Annealing.

This study investigated the effects of annealing on the structural and physicochemical properties of rice starch below the onset temperature (To) by 5 °C and 15 °C. The results revealed that annealing improved the gelatinization temperature of rice starch, decreased the swelling power, solubility, and paste viscosity of rice starch, and had no significant effects on the morphological structure and crystal configuration of rice starch. In one-step annealing, the annealing temperature of 60 °C is more conducive to the rearrangement of starch molecules, so its crystallinity, short-range ordered structure, and gelatinization temperature are higher than at 50 °C; however, its RDS, SDS, and RS contents will be increased. During the two-step annealing treatment, the temperature change is not conducive to the molecular chain rearrangement and to the formation of perfect crystalline structure, which increases the sensitivity of enzymes to starch, so the RDS content of starch increases significantly, while the RS content decreases.

Mapping knowledge structure and research trends of knee osteoarthritis with meniscus in two decades: A bibliometric analysis.

Background: Knee osteoarthritis (KOA) is a chronic degenerative disease that is closely related to the meniscus. Currently, no bibliometric studies have jointly analyzed KOA and the meniscus. This study aimed to provide a comprehensive analysis of the knowledge structure of KOA and the meniscus across two decades and to identify the emerging research trends from a bibliometric perspective. Methods: All articles reporting KOA and the meniscus from 2001 to 2021 were obtained from the Web of Science Core Collection. R software, CiteSpace, VOS Viewer, and Microsoft Excel were used to analyze the publications including the authors, cited authors, journals, cited journals, country of research, institutions, and research focus. These data were used to generate visual knowledge maps of the outputs. Results: A total of 3,218 articles were retrieved. Guermazi was identified as the author who had contributed the most to the field and Osteoarthritis and Cartilage was identified as the most productive research journal. The United States is the global leader in the field and the center for international cooperation with less international collaboration occurring in Eastern Asia. Boston University was the most prolific institution. According to the data, "articular-cartilage," "meniscectomy," "follow-up," "anterior cruciate ligament," and "cartilage" were identified as research hotspots in the field. "Consequences," "prognostic-factors," and "receptor" were predicted as future hot topics of research. Conclusions: This study is the first comprehensive bibliometric study to jointly analyze KOA and the meniscus. Our data enable a better understanding of research trends and identify research hotspots and gaps in knowledge across the field. Our findings provide practical information for researchers to better understand the key research areas and identify the research frontiers and future hot topics.

Cytochrome P450 enzymes mediated by DNA methylation is involved in deoxynivalenol-induced hepatoxicity in piglets.

Deoxynivalenol (DON) is an inevitable contaminant in animal feed and can lead to liver damage, then decreasing appetite and causing growth retardation in piglets. Although many molecular mechanisms are related to hepatoxicity caused by DON, few studies have been done on cytochrome P450 (CYP450) enzymes and DNA methylation. To explore the role of CYP450 enzymes and DNA methylation in DON-induced liver injury, male piglets were fed a control diet, or diet containing 1.0 or 3.0 mg/kg DON for 4 weeks. DON significantly raised the activity of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and glutamyl transpeptidase (GGT) (P < 0.01), leading to liver injury. In vivo study found that DON exposure increased the expression of CYP450 enzymes (such as CYP1A1, CYP2E1, CYP3A29) (P < 0.05), and disturbed the expression of nicotinamide N-methyltransferase (NNMT), galanin-like peptide (GALP) and insulin-like growth factor 1 (IGF-1) (P < 0.05), in which DNA methylation affected the expression of these genes. In vitro study (human normal hepatocytes L02) further proved that DON elevated the expression of CYP1A1, CYP2E1 and CYP3A4 (P < 0.05), and inhibited cell growth in a dose-dependent manner, resulting in cell necrosis. More importantly, knockdown of CYP1A1 or CYP2E1 could alleviate DON-induced growth inhibition by promoting IGF-1 expression. Taken together, increased CYP450 enzymes expression was one of the mechanisms of hepatoxicity and growth inhibition induced by DON, suggesting that the decrease of CYP450 enzymes can antagonize the hepatoxicity in animals, which provides some value for animal feed safety.

Neonicotinoids: mechanisms of systemic toxicity based on oxidative stress-mitochondrial damage.

Neonicotinoids are the most widely used pesticides in the world. However, research studies have shown that it can affect the cognitive abilities and health of non-target bees and other wild pollinators by inducing DNA damage, apoptosis and mitochondrial damage, injure to its central nervous system, and it is even developmentally neurotoxic to mammals and humans, with mitochondria being an important target of neonicotinoids. Therefore, this article reviews the role of mitochondrial morphology, calcium ions (Ca2+) homeostasis, respiratory function, apoptosis, and DNA damage in neonicotinoids-induced systemic toxicity. Additionally, it evaluates the protective effects of various active substances including vitamin C, N-acetylcysteine (NAC), curcumin (CUR), glutathione reduced (GSH), caffeic acid phenethyl ester (CAPE), resveratrol, and thymoquinone (TQ) on neonicotinoids-induced toxicity. This review manuscript found that mitochondria are important targets to neonicotinoids. Neonicotinoids can cause DNA damage, apoptosis, protein oxidation, and lipid peroxidation in non-target organisms by altering mitochondrial Ca2+ homeostasis, inhibiting mitochondrial respiration, and inducing reactive oxygen species (ROS) production. Several active substances (vitamin C, NAC, CUR, GSH, resveratrol, CAPE, and TQ) play a protective role against neonicotinoid-induced systemic toxicity by inhibiting ROS signaling pathways, apoptosis, and lipid peroxidation. This review manuscript emphasizes the importance and urgency of the development of neonicotinoid antidotes, emphasizes the prospect of the application of targeted mitochondrial antidotes, and prospects the development of neonicotinoid antidotes in order to provide some strategies for the prevention of neonicotinoid toxicity.

Ponicidin attenuates streptozotocin-induced diabetic nephropathy in rats via modulating hyperlipidemia, oxidative stress, and inflammatory markers.

The present research work was proposed to discover the beneficial roles of ponicidin against the streptozotocin (STZ)-induced diabetic nephropathy (DN) in rats via modulating the oxidative stress and inflammation. The DN was initiated to the Wistar rats via administering 45 mg/kg of STZ and then diabetic animals were supplemented with 50 mg/kg of ponicidin and 150 mg/kg of metformin (standard drug) for 8 weeks. The body weight and food intake of animals were checked every week. The glucose, insulin, and homeostasis model assessment- insulin resistance  (HOMA-IR) levels in the serum were assessed using kits. The levels of reactive oxygen species (ROS) accumulation, oxidative stress and antioxidant markers, and pro-inflammatory cytokines were examined using assay kits. The levels of lipid profiles and renal function markers were investigated using respective kits. The renal tissues were analyzed microscopically to detect the histological alterations. The ponicidin treatment effectively decreased the body weight, food intake, HOMA-IR, and HbAlc levels in the DN animals. The levels of ROS and MDA were decreased and superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) activities were improved by the ponicidin. The ponicidin also reduced the blood urea nitrogen (BUN), creatinine, lactate dehydrogenase (LDH), and kidney injury molecule (KIM-1) levels. The levels of low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), free fatty acid (FFA), and total cholesterol (TC) were decreased and the high-density lipoprotein (HDL) level was improved by the ponicidin treatment to the DN rats. The tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), nuclear factor-kappa B (NF-κB), and IL-6 levels were appreciably attenuated by the ponicidin. The ponicidin also ameliorated the DM-provoked histological alterations in the renal tissues. In conclusion, this study work evidenced that ponicidin has the therapeutic action in ameliorating the development of DN via averting oxidative stress, inflammation, and renal injury. It could be a promising therapeutic agent to treat DN in the future.