Effects of Caloric Restriction and Intermittent Fasting and Their Combined Exercise on Cognitive Functioning: A Review.

PURPOSE OF REVIEW: The impact of dietary habits on cognitive function is increasingly gaining attention. The review is to discuss how caloric restriction (CR) and intermittent fasting (IF) can enhance cognitive function in healthy states through multiple pathways that interact with one another. Secondly, to explore the effects of CR and IF on cognitive function in conditions of neurodegenerative diseases, obesity diabetes and aging, as well as potential synergistic effects in combination with exercise to prevent cognitively related neurodegenerative diseases. RECENT FINDINGS: With age, the human brain ages and develops corresponding neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and epilepsy, which in turn trigger cognitive impairment. Recent research indicates that the impact of diet and exercise on cognitive function is increasingly gaining attention. The benefits of exercise for cognitive function and brain plasticity are numerous, and future research can examine the efficacy of particular dietary regimens during physical activity when combined with diet which can prevent cognitive decline.

A combination analysis based on bioinformatics tools reveals new signature genes related to maternal obesity and fetal programming.

Background: Maternal obesity significantly influences fetal development and health later in life; however, the molecular mechanisms behind it remain unclear. This study aims to investigate signature genes related to maternal obesity and fetal programming based on a genomic-wide transcriptional placental study using a combination of different bioinformatics tools. Methods: The dataset (GSE128381) was obtained from Gene Expression Omnibus (GEO). The data of 100 normal body mass index (BMI) and 27 obese mothers were included in the analysis. Differentially expressed genes (DEGs) were evaluated by limma package. Thereafter, functional enrichment analysis was implemented. Then, weighted gene co-expression network analysis (WGCNA) and the least absolute shrinkage and selection operator (LASSO) analysis were used to further screening of signature genes. Simple linear regression analysis was used to assess the correlation between signature genes and newborn birth weight. Gene set enrichment analysis (GSEA) was implemented to study signaling pathways related to signature genes. The expression of the signature genes was also explored in 48 overweight mothers in the same dataset. Results: A total of 167 DEGs were obtained, of which 122 were up-regulated while 45 were down-regulated. The dataset was then clustered into 11 modules by WGCNA, and the MEbrown was found as the most significant module related to maternal obesity and fetal programming (cor = 0.2, p = 0.03). The LASSO analysis showed that PTX3, NCF2, HOXB5, ABCA6, and C1orf162 are signature genes related to maternal obesity and fetal programming, which were increased in the placenta of obese mothers compared to those with normal BMI. The area under the curve (AUC) of the signature genes in the receiver operating characteristic curve (ROC) was 0.709, 0.660, 0.674, 0.667, and 0.717, respectively. Simple linear regression analysis showed that HOXB5 was associated with newborn birth weight. GSEA analysis revealed that these signature genes positively participate in various signaling pathways/functions in the placenta. Conclusion: PTX3, NCF2, HOXB5, ABCA6, and C1orf162 are novel signature genes related to maternal obesity and fetal programming, of which HOXB5 is implicated in newborn birth weight.

Systematic discovery of DNA-binding tandem repeat proteins.

Tandem repeat proteins (TRPs) are widely distributed and bind to a wide variety of ligands. DNA-binding TRPs such as zinc finger (ZNF) and transcription activator-like effector (TALE) play important roles in biology and biotechnology. In this study, we first conducted an extensive analysis of TRPs in public databases, and found that the enormous diversity of TRPs is largely unexplored. We then focused our efforts on identifying novel TRPs possessing DNA-binding capabilities. We established a protein language model for DNA-binding protein prediction (PLM-DBPPred), and predicted a large number of DNA-binding TRPs. A subset was then selected for experimental screening, leading to the identification of 11 novel DNA-binding TRPs, with six showing sequence specificity. Notably, members of the STAR (Short TALE-like Repeat proteins) family can be programmed to target specific 9 bp DNA sequences with high affinity. Leveraging this property, we generated artificial transcription factors using reprogrammed STAR proteins and achieved targeted activation of endogenous gene sets. Furthermore, the members of novel families such as MOON (Marine Organism-Originated DNA binding protein) and pTERF (prokaryotic mTERF-like protein) exhibit unique features and distinct DNA-binding characteristics, revealing interesting biological clues. Our study expands the diversity of DNA-binding TRPs, and demonstrates that a systematic approach greatly enhances the discovery of new biological insights and tools.

The impact of insomnia on brain networks topology in depressed patients: A resting-state fMRI study.

OBJECTIVE: Depression and insomnia frequently co-occur, but the neural mechanisms between patients with varying degrees of these conditions are not fully understood. The specific topological features and connectivity patterns of this co-morbidity have not been extensively studied. This study aimed to investigate the topological characteristics of topological characteristics and functional connectivity of brain networks in depressed patients with insomnia. METHODS: Resting-state functional magnetic resonance imaging data from 32 depressed patients with a high level of insomnia (D-HI), 35 depressed patients with a low level of insomnia (D-LI), and 81 healthy controls (HC) were used to investigate alterations in brain topological organization functional networks. Nodal and global properties were analyzed using graph-theoretic techniques, and network-based statistical analysis was employed to identify changes in brain network functional connectivity. RESULTS: Compared to the HC group, both the D-HI and D-LI groups showed an increase in the global efficiency (Eglob) values, local efficiency (Eloc) was decreased in the D-HI group, and Lambda and shortest path length (Lp) values were decreased in the D-LI group. At the nodal level, the right parietal nodal clustering coefficient (NCp) values were reduced in D-HI and D-LI groups compared to those in HC. The functional connectivity of brain networks in patients with D-HI mainly involves default mode network (DMN)-cingulo-opercular network (CON), DMN-visual network (VN), DMN-sensorimotor network (SMN), and DMN-cerebellar network (CN), while that in patients with D-LI mainly involves SMN-CON, SMN-SMN, SMN-VN, and SMN-CN. The values of the connection between the midinsula and postoccipital gyrus was negatively correlated with scores for early awakening in D-HI. CONCLUSION: These findings may contribute to our understanding of the underlying neuropsychological mechanisms in depressed patients with insomnia.

Biointerfacial supramolecular self-assembly of whey protein isolate nanofibrils on probiotic surface to enhance survival and application to 3D printing dysphagia foods.

Personalized three-dimensional (3D) printed foods rich in probiotics were investigated. Lactiplantibacillus plantarum (Lp), as a representative of probiotics, was used to investigate the 3D printing of probiotic-rich dysphagia foods. Here, whey protein isolate nanofibrils (WPNFs) were coated and anchored on bacterial surfaces via biointerfacial supramolecular self-assembly, providing protection against environmental stress and the 3D printing process. The optimized composite gels consisting of High acyl gellan gum (0.25 g), whey protein isolate (1.25 g), fructooligosaccharides (0.75 g), Lp-WPNFs-Glyceryl tributyrate emulsion (Φ = 40%, 3.75 mL) can realize 3D printing, and exhibit high resolution, and stable shape. The viable cell count is higher than 8.0 log CFU/g. They are particularly suitable for people with dysphagia and are classified as level 5-minced & moist in the international dysphagia diet standardization initiative framework. The results provide new insights into the development of WPNFs-coating on bacterial surfaces to deliver probiotics and 3D printed food rich in probiotics.

PLM_Sol: predicting protein solubility by benchmarking multiple protein language models with the updated Escherichia coli protein solubility dataset.

Protein solubility plays a crucial role in various biotechnological, industrial, and biomedical applications. With the reduction in sequencing and gene synthesis costs, the adoption of high-throughput experimental screening coupled with tailored bioinformatic prediction has witnessed a rapidly growing trend for the development of novel functional enzymes of interest (EOI). High protein solubility rates are essential in this process and accurate prediction of solubility is a challenging task. As deep learning technology continues to evolve, attention-based protein language models (PLMs) can extract intrinsic information from protein sequences to a greater extent. Leveraging these models along with the increasing availability of protein solubility data inferred from structural database like the Protein Data Bank holds great potential to enhance the prediction of protein solubility. In this study, we curated an Updated Escherichia coli protein Solubility DataSet (UESolDS) and employed a combination of multiple PLMs and classification layers to predict protein solubility. The resulting best-performing model, named Protein Language Model-based protein Solubility prediction model (PLM_Sol), demonstrated significant improvements over previous reported models, achieving a notable 6.4% increase in accuracy, 9.0% increase in F1_score, and 11.1% increase in Matthews correlation coefficient score on the independent test set. Moreover, additional evaluation utilizing our in-house synthesized protein resource as test data, encompassing diverse types of enzymes, also showcased the good performance of PLM_Sol. Overall, PLM_Sol exhibited consistent and promising performance across both independent test set and experimental set, thereby making it well suited for facilitating large-scale EOI studies. PLM_Sol is available as a standalone program and as an easy-to-use model at https://zenodo.org/doi/10.5281/zenodo.10675340.

Specific detection of gut pathogens for one-pot chip based on RPA-CRISPR/Cas12a.

BACKGROUND: There are billions of bacteria in the intestine, most of which are harmless and play important roles in humans. Although only a very small number of bacteria can cause diseases, once the pathogenic bacteria are ingested into the body and multiply in large quantities, it can lead to inflammatory diseases in the intestines and even other organs. Although polymerase chain reaction can specifically detect bacterial nucleic acid. However, the demand for temperature cycling limits its portability. Therefore, it is hoped to establish a high-throughput, highly specific and portable detection platform for directly detecting nucleic acid of intestinal pathogens. RESULTS: Herein, a one-pot chip based on RPA-CRCISPR/Cas12a platform was developed. The chip is the same size as a glass slide and allows detection at the same temperature. Multiple samples could be detected simultaneously on the one chip, achieved high-throughput detection and improved the integration of detection. The specific recognition of CRISPR/Cas12a avoided the influence of non-specific amplification of RPA and enhanced the specificity of the analysis. At the same time, the one-pot chip avoided secondary contamination when the lid was opened during the analysis process. And the bacterial concentration showed good linearity at 102-108 cfu mL-1. The limit of detection could be as low as 0.43 cfu mL-1. This method has been successfully used to detect pollution samples. It can provide a reliable platform for early screening of gastrointestinal and other inflammatory diseases. SIGNIFICANCE: The one-pot chip based on the RPA-CRISPR/Cas12a platform established can directly detect the nucleic acid of intestinal pathogens, with portability and specificity. It is worth noting that the platform has good programmability, can be used for other target detection by changing crRNA and RPA primers, it can achieve multi sample detection on the one chip.

Tank-Mix Adjuvants Enhance Pesticide Efficacy by Improving Physicochemical Properties and Spraying Characteristics for Application to Cotton with Unmanned Aerial Vehicles.

Tank-mix adjuvants have been used to reduce spray drift and facilitate the efficacy of pesticides applied with unmanned aerial vehicles (UAVs). However, the effects of specific adjuvants on pesticide characteristics and the mechanism of action remain unclear. Herein, we analyzed the effects of three different types of tank-mix adjuvants (plant oil; mineral oil; and mixture of alcohol and ester) on the surface tension (ST), contact angle, wetting, permeation, evaporation, spray performance, and aphid-control effects of two types of pesticides. The mineral oil adjuvant Weichi (WCH) was highly effective in reducing the pesticide solution ST, improving the wetting and penetration ability, increasing droplet size, and promoting droplet deposition. The mixed alcohol and ester adjuvant Quanrun (QR) showed excellent wetting and antievaporation properties and promoted droplet deposition. A plant oil adjuvant (Beidatong) moderately improved wetting and penetration ability and reduced droplet drift. Field tests showed that the control efficiencies (CEs) of two pesticides were increased after the addition of adjuvants, even with 20% reductions in pesticide application. When the UAV was operated at 1.5 m, the CEs of two pesticides were increased from 65.39 and 66.63% to 73.11-76.52% and 77.91-88.31%, respectively. When operated at 2.5 m, the CEs were increased from 51.24 and 68.60% to 65.06-75.70% and 77.57-92.59%, respectively. Especially, the CEs of pesticides with WCH and QR increased obviously. Importantly, neither WCH nor QR inhibited hatching of the critical insect natural enemy ladybird beetle at concentrations used in the field. This study provides a framework for assessment of tank-mix adjuvants in aerial sprays and directly demonstrates the value of specific adjuvants in improving pesticide bioavailability and minimizing associated environmental pollution.

Gastrointestinal digestion of food proteins: Anticancer, antihypertensive, anti-obesity, and immunomodulatory mechanisms of the derived peptides.

Food proteins and their peptides play a significant role in the important biological processes and physiological functions of the body. The peptides show diverse biological benefits ranging from anticancer to antihypertensive, anti-obesity, and immunomodulatory, among others. In this review, an overview of food protein digestion in the gastrointestinal tract and the mechanisms involved was presented. As some proteins remain resistant and undigested, the multifarious factors (e.g. protein type and structure, microbial composition, pH levels and redox potential, host factors, etc.) affecting their colonic fermentation, the derived peptides, and amino acids that evade intestinal digestion are thus considered. The section that follows focuses on the mechanisms of the peptides with anticancer, antihypertensive, anti-obesity, and immunomodulatory effects. As further considerations were made, it is concluded that clinical studies targeting a clear understanding of the gastrointestinal stability, bioavailability, and safety of food-based peptides are still warranted.

A CTCF-binding site in the Mdm1-Il22-Ifng locus shapes cytokine expression profiles and plays a critical role in early Th1 cell fate specification.

Cytokine expression during T cell differentiation is a highly regulated process that involves long-range promoter-enhancer and CTCF-CTCF contacts at cytokine loci. Here, we investigated the impact of dynamic chromatin loop formation within the topologically associating domain (TAD) in regulating the expression of interferon gamma (IFN-γ) and interleukin-22 (IL-22); these cytokine loci are closely located in the genome and are associated with complex enhancer landscapes, which are selectively active in type 1 and type 3 lymphocytes. In situ Hi-C analyses revealed inducible TADs that insulated Ifng and Il22 enhancers during Th1 cell differentiation. Targeted deletion of a 17 bp boundary motif of these TADs imbalanced Th1- and Th17-associated immunity, both in vitro and in vivo, upon Toxoplasma gondii infection. In contrast, this boundary element was dispensable for cytokine regulation in natural killer cells. Our findings suggest that precise cytokine regulation relies on lineage- and developmental stage-specific interactions of 3D chromatin architectures and enhancer landscapes.

One-step high efficiency separation of prolyl endopeptidase from Aspergillus niger and its application.

Prolyl endopeptidase from Aspergillus niger (An-PEP) is an enzyme that recognizes C-terminal peptide bonds of amino acid chains and cleaves them by hydrolysis. An aqueous two-phase system (ATPS) was used to separate An-PEP from fermentation broth. Through single factor experiments, the ATPS containing 16 % (w/w) PEG2000 and 15 % (w/w) (NH4)2SO4 at pH 6.0 obtained the recovery of 79.74 ± 0.16 % and the purification coefficient of 7.64 ± 0.08. It was then used to produce soy protein isolate peptide (SPIP) by hydrolysis of soy protein isolate (SPI), and SPIP-Ferrous chelate (SPIP-Fe) was prepared with SPIP and Fe2+. The chelation conditions were optimized by RSM, as the chelation time was 30 min, chelation temperature was 25 °C, SPIP mass to VC mass was two to one and pH was 6.0. The obtained chelation rate was 82.56 ± 2.30 %. The change in the structures and functional features of SPIP before and after chelation were investigated. The FTIR and UV-Vis results indicated that the chelation of Fe2+ and SPIP depended mainly on the formation of amide bonds. The fluorescence, SEM and amino acid composition analysis results indicated that Fe2+ could induce and stabilize the surface conformation and change the amino acid distribution on the surfaces of SPIP. The chelation of SPIP and Fe2+ resulted in the enhancement of radical scavenging activities and ACE inhibitory activities. This work provided a new perspective for the further development of peptide-Fe chelates for iron supplement.

Food-derived bioactive peptides potentiating therapeutic intervention in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that affects the joints of the human body and is projected to have a prevalence age-standardized rate of 1.5 million new cases worldwide by 2030. Several conventional and non-conventional preventive and therapeutic interventions have been suggested but they have their side effects including nausea, abdominal pain, liver damage, ulcers, heightened blood pressure, coagulation, and bleeding. Interestingly, several food-derived peptides (FDPs) from both plant and animal sources are increasingly gaining a reputation for their potential in the management or therapy of RA with little or no side effects. In this review, the concept of inflammation, its major types (acute and chronic), and RA identified as a chronic type were discussed based on its pathogenesis and pathophysiology. The conventional treatment options for RA were briefly outlined as the backdrop of introducing the FDPs that potentiate therapeutic effects in the management of RA.

IL-2-free tumor-infiltrating lymphocyte therapy with PD-1 blockade demonstrates potent efficacy in advanced gynecologic cancer.

BACKGROUND: Tumor-infiltrating lymphocyte (TIL) therapy has been restricted by intensive lymphodepletion and high-dose intravenous interleukin-2 (IL-2) administration. To address these limitations, we conducted preclinical and clinical studies to evaluate the safety, antitumor activity, and pharmacokinetics of an innovative modified regimen in patients with advanced gynecologic cancer. METHODS: Patient-derived xenografts (PDX) were established from a local recurrent cervical cancer patient. TILs were expanded ex vivo from minced tumors without feeder cells in the modified TIL therapy regimen. Patients underwent low-dose cyclophosphamide lymphodepletion followed by TIL infusion without intravenous IL-2. The primary endpoint was safety; the secondary endpoints included objective response rate, duration of response, and T cell persistence. RESULTS: In matched patient-derived xenografts (PDX) models, homologous TILs efficiently reduced tumor size (p < 0.0001) and underwent IL-2 absence in vivo. In the clinical section, all enrolled patients received TIL infusion using a modified TIL therapy regimen successfully with a manageable safety profile. Five (36%, 95% CI 16.3-61.2) out of 14 evaluable patients experienced objective responses, and three complete responses were ongoing at 19.5, 15.4, and 5.2 months, respectively. Responders had longer overall survival (OS) than non-responders (p = 0.036). Infused TILs showed continuous proliferation and long-term persistence in all patients and showed greater proliferation in responders which was indicated by the Morisita overlap index (MOI) of TCR clonotypes between infused TILs and peripheral T cells on day 14 (p = 0.004) and day 30 (p = 0.004). Higher alteration of the CD8+/CD4+ ratio on day 14 indicated a longer OS (p = 0.010). CONCLUSIONS: Our modified TIL therapy regimen demonstrated manageable safety, and TILs could survive and proliferate without IL-2 intravenous administration, showing potent efficacy in patients with advanced gynecologic cancer. TRIAL REGISTRATION: NCT04766320, Jan 04, 2021.

PBAT-modified starch blended film extract induces in vitro toxicity in L-02 cells: induction of oxidative stress, inflammation, and modulation of AMPK pathway.

PBAT-modified starch blended film are thermoplastic biodegradable materials with good properties and a wide range of applications. In this study, L-02 cells were used as an in vitro toxicity evaluation system for risk assessment of PBAT-modified starch films with migration studies obtained in different food simulants. Determination of total migration and organic matter revealed that the results were in accordance with the standard except for the total organic matter under 95% (v/v) ethanol food simulant which exceeded the standard. The CCK-8 assay showed that these compounds affect the cell viability of L-02 cells. It was observed that the compounds made the cells express increased AST, ALT, TNF-α, IL-6, IL-1ß, and ROS, and decreased SOD, GSH, and ATP. In addition, we explored the effect of migration in PBAT-modified starch composites on protein and gene expression levels in L-02 cells using a transcriptomic approach and found that the AMPK signaling pathway was affected. The expression of AMPK signaling pathway-related proteins was detected by Western Blot, and the expression levels of p-AMPK/AMPK were found to be upregulated, and those of p-mTOR/mTOR, SIRT1, PGC-1α, NRF1 and TFAM were downregulated. The above data suggest that the compounds migrating into the PBAT-modified starch film when exposed to food may induce oxidative stress and inflammation in hepatocytes, and may cause damage to hepatocytes through the AMPK pathway.

Lycium barbarum polysaccharides attenuate nonylphenol and octylphenol-induced oxidative stress and neurotransmitter disorders in PC-12 cells.

Nonylphenol (NP) and octylphenol (OP) are environmental contaminants with potential endocrine disrupting effects. However, there is limited research on the mechanisms and intervention of combined NP and OP exposure-induced neurotoxicity. This study aims to explore the cytotoxicity of combined NP and OP exposure and evaluate the potential of Lycium barbarum polysaccharides (LBP) in mitigating the aforementioned toxicity. In present study, LBP (62.5, 125 and 250 µg/mL) were applied to intervene rat adrenal pheochromocytoma (PC-12) cells treated with combined NP and OP (NP: OP = 4:1, w/w; 1, 2, 4 and 8 µg/mL). The results showed that NP and OP induced oxidative stress, disrupted the 5-hydroxytryptamine (5-HT) and cholinergic systems in PC-12 cells. Additionally, they activated the p38 protein kinase (p38) and suppressed the expression of silent information regulation type 1 (SIRT1), monoamine oxidase A (MAOA), phosphorylated cyclic-AMP response binding protein (p-CREB), brain-derived neurotrophic factor (BDNF) and phosphorylated tropomyosin-related kinase receptor type B (p-TrkB). However, N-acetyl-L-cysteine (NAC) treatment counteracted the changes of signalling molecule p38, SIRT1/MAOA and CREB/BDNF/TrkB pathways-related proteins induced by NP and OP. LBP pretreatment ameliorated combined NP and OP exposure-induced oxidative stress and neurotransmitter imbalances. Furthermore, the application of LBP and administration of a p38 inhibitor both reversed the alterations in the signaling molecule p38, as well as the proteins associated to the SIRT1/MAOA and CREB/BDNF/TrkB pathways. These results implied that LBP may have neuroprotective effects via p38-mediated SIRT1/MAOA and CREB/BDNF/TrkB pathways.

Determinants of mer Promoter Activity from Pseudomonas aeruginosa.

Since the MerR family is known for its special regulatory mechanism, we aimed to explore which factors determine the expression activity of the mer promoter. The Tn501/Tn21 mer promoter contains an abnormally long spacer (19 bp) between the -35 and -10 elements, which is essential for the unique DNA distortion mechanism. To further understand the role of base sequences in the mer promoter spacer, this study systematically engineered a series of mutant derivatives and used luminescent and fluorescent reporter genes to investigate the expression activity of these derivatives. The results reveal that the expression activity of the mer promoter is synergistically modulated by the spacer length (17 bp is optimal) and the region upstream of -10 (especially -13G). The spacing is regulated by MerR transcription factors through symmetrical sequences, and -13G presumably functions through interaction with the RNA polymerase sigma-70 subunit.

Anti-inflammatory probiotics HF05 and HF06 synergistically alleviate ulcerative colitis and secondary liver injury.

Given the limited efficacy and adverse effects associated with conventional drugs, probiotics are emerging as a promising therapeutic strategy for mitigating the chronic nature of ulcerative colitis (UC) and its consequential secondary liver injury (SLI). Limosilactobacillus fermentum HF06 and Lactiplatibacillus plantarum HF05 are strains we screened with excellent anti-inflammatory and probiotic properties in vitro. In this study, the intervention of HF06 and HF05 in combination (MIXL) was found to be more effective in alleviating intestinal inflammation and secondary liver injury in UC mice compared to supplementing with the two strains individually. Results demonstrated that MIXL effectively attenuated colon shortening and weight loss, downregulated the expression of pro-inflammatory cytokines TNF-α, IL-1ß, and IL-6 mRNA in the intestines, mitigated SLI, and augmented the enzymatic activities of SOD, CAT, and GSH-Px in the liver. MIXL enhances the intestinal barrier in UC mice, regulates the structure and composition of the gut microbiota, promotes the abundance of Lactobacillus, and suppresses the abundance of bacteria associated with inflammation and liver injury, including Clostridium_Sensu_Stricto_1, Escherichia, Shigella, Enterococcus, Corynebacterium, Desulfovibrio, and norank_f__Oscillospiraceae. This study demonstrated the synergistic effect of HF06 and HF05, providing a reliable foundation for the alleviation of UC.

Schisandrin B ameliorates adjuvant-induced arthritis in rats via modulation of inflammatory mediators, oxidative stress, and HIF-1α/VEGF pathway.

OBJECTIVES: Schisandrin B (Sch B) has been shown to possess anti-inflammatory and antioxidant properties, however, its antirheumatoid arthritis properties and potential mechanism remain unexplored. This study evaluated the potential of Sch B in adjuvant-induced arthritic (AIA) rats. METHODS: AIA was induced by injecting 0.1 ml of CFA into the paw of rats and the animals were administered with Sch B (50 mg/kg) for 28 days. The effects of Sch B were evaluated using arthritis severity, serum levels of oxido-inflammatory, and metabolic index parameters. KEY FINDINGS: Sch B eased arthritic symptoms by significantly reducing paw swelling and arthritic score and increased body weight gain. Moreover, Sch B alleviated the levels of oxido-inflammatory markers including interleukin-1 beta, interleukin-6, tumor necrosis factor alpha, nuclear factor kappa B, transforming growth factor ß1, inducible nitric oxide synthase and malonaldehyde, as well as increased the levels of superoxide dismutase, glutathione, and Nrf2. Sch B also remarkably restored the altered levels of triglyceride, aspartate aminotransferase, lactic acid, pyruvate, phosphoenolpyruvate carboxylase, glucose, hypoxia inducible factor-1 alpha, and vascular endothelial growth factor. In addition, Sch B markedly alleviated p65 expression in the treated AIA rats. CONCLUSION: This study suggests that Sch B alleviated AIA by reducing oxidative stress, inflammation, and angiogenesis.

Effects of 1,4-dihydropyridine derivatives on cell injury and mTOR of HepG2 and 3D-QSAR study.

1,4-dihydropyridine derivatives (1,4-DHPs) are a class of drugs used to treat cardiovascular diseases, but these drugs can cause liver injury. To reveal the toxicity characteristics of these compounds, we used a series of assays, including cell viability, enzyme activity detection, and western blotting, to investigate the toxicity of seven kinds of 1,4-DHPs (0-100 µM) on HepG2 cells and establish 3D-QSAR model based on relevant toxicity data. After HepG2 cells were treated with 1,4-DHPs for 24 h, high-dose (100 µM) 1,4-DHPs decreased cell viability to varying degrees, while ROS and MDA contents were significantly increased, and ATP content was reduced. Moreover, with the concentration of 100 µM 1,4-DHPs (Nimodipine, Nitrendipine, Cilnidipine, and Manidipine) were markedly inhibited the phosphorylation levels of mTOR protein. The results of the 3D-QSAR model showed that the non-cross validation coefficient (R2) and cross validation coefficient (Q2) of the model were 0.982 and 0.652, respectively. Combined with external validation and the Williams diagram, the model showed good predictability and application domain. Based on the CoMSIA 3D contour map, the introduction of large volume and hydrogen bond receptor groups on the carbonyl oxygen side chains of the 1,4-DHPs ring 3- and 5- was beneficial for reducing the toxicity of 1,4-DHPs. The results of this study could supplement information on the cytotoxicity of 1,4-DHPs, and could provide theoretical support for predicting the toxicity of 1,4-DHPs.