Enabling oral novel Taxanes-based Chemotherapy with Lipophilic prodrug Self-nanoemulsifying drug delivery system.

Larotaxel (LTX) and SB-T-1214 (SBT), two new synthetic experimental toxoids, have shown broad-spectrum antitumor activity, especially against tumors that are resistant to other drugs. However, their poor solubility, membrane permeability, and first-pass effect limits their use in oral administration. We designed and synthesized two long-chain triglyceride-mimic prodrugs of LTX (LTXSSTG) and SBT (SBTSSTG), which are bridged by disulfide bonds and efficiently incorporated them into Self-nanoemulsifying drug delivery system (SNEDDS). These prodrugs can bypass hepatic metabolism by entering the blood through intestinal lymphatic transport, following a similar oral absorption pathway to dietary lipids. It was found that LTXSSTG and SBTSSTG significantly improved oral bioavailability (about 4.5-fold for LTX and 3.4-fold for SBT) compared to their solution forms. Moreover, with LTXSSTG and SBTSSTG incorporating reduction stimulus-responsive spacer were much more effective in suppressing tumor growth in vivo with eliminated adverse effects than solution form. To sum up, this strategy provides a new avenue to enhance oral delivery of new toxoids.

Association between total body muscle-fat ratio and risk of thyroid disorders: a cross-sectional study.

BACKGROUND: Thyroid disorders(TD) poses a significant health threat to Americans due to its high incidence rate. Obesity, a common factor linked to thyroid disorders, has garnered increasing attention. While Body mass index (BMI) is a widely used obesity index, it fails to account for the distribution of muscle and fat in the body. Recently, tMFR has emerged as a crucial obesity index in clinical research, warranting further investigation into its association with TD. OBJECTIVE: Exploring the association between tMFR and thyroid disorders. METHOD: A comprehensive survey and data analysis were conducted using the NHANES database to investigate the relationship between tMFR and the risk of TD. This study utilized multiple logistic regression, smooth curve fitting, and subgroup analysis across four periods from 2011 to 2018. RESULT: A total of 11,912 subjects were included in the study, showing a prevalence of 7.14% for TD. The research indicated that tMFR had an inverse correlation with the risk of TD in a comprehensive model (OR = 0.90, 95% CI 0.82 to 1.00). When tMFR was divided into quartiles (Q1-Q4), individuals in the highest quartile had a 28% lower risk of TD than those in Q1 (OR = 0.72, 95% CI 0.57 to 0.91). Analysis using smoothed curve fitting demonstrated a nonlinear relationship between tMFR and TD risk, with the inflection point for tMFR saturation effect identified as 1.5. Subgroup analysis further confirmed the strong association between tMFR and TD risk. Receiver operating characteristic (ROC) curve analysis indicated that tMFR exhibited superior predictive ability for TD relative to BMI. CONCLUSION: The study found a negative association between tMFR and the risk of TD; however, additional prospective studies are required to validate these findings.

Personality and Health-Related Quality of Life of Older Chinese Adults: Cross-Sectional Study and Moderated Mediation Model Analysis.

Background: Personality has an impact on the health-related quality of life (HRQoL) of older adults. However, the relationship and mechanisms of the 2 variables are controversial, and few studies have been conducted on older adults. Objective: The aim of this study was to explore the relationship between personality and HRQoL and the mediating and moderating roles of sleep quality and place of residence in this relationship. Methods: A total of 4123 adults 60 years and older were from the Psychology and Behavior Investigation of Chinese Residents survey. Participants were asked to complete the Big Five Inventory, the Brief version of the Pittsburgh Sleep Quality Index, and EQ-5D-5L. A backpropagation neural network was used to explore the order of factors contributing to HRQoL. Path analysis was performed to evaluate the mediation hypothesis. Results: As of August 31, 2022, we enrolled 4123 older adults 60 years and older. Neuroticism and extraversion were strong influencing factors of HRQoL (normalized importance >50%). The results of the mediation analysis suggested that neuroticism and extraversion may enhance and diminish, respectively, HRQoL (index: ß=-.262, P<.001; visual analog scale: ß=-.193, P<.001) by increasing and decreasing brief version of the Pittsburgh Sleep Quality Index scores (neuroticism: ß=.17, P<.001; extraversion: ß=-.069, P<.001). The multigroup analysis suggested a significant moderating effect of the place of residence (EQ-5D-5L index: P<.001; EQ-5D-5L visual analog scale: P<.001). No significant direct effect was observed between extraversion and EQ-5D-5L index in urban older residents (ß=.037, P=.73). Conclusions: This study sheds light on the potential mechanisms of personality and HRQoL among older Chinese adults and can help health care providers and relevant departments take reasonable measures to promote healthy aging.

The impact of 25-hydroxyvitamin D and calcium on risk of age-related macular degeneration: a Mendelian randomization study.

BACKGROUND: The relationships between 25-hydroxyvitamin D [25(OH)D] and calcium and age-related macular degeneration (AMD) are unclear. OBJECTIVES: This study aimed to investigate the causal role of 25(OH)D concentrations, calcium concentrations, and dietary supplements use of vitamin D and calcium on risk of AMD and its subtypes. METHODS: Independent genetic variants associated with 25(OH)D and calcium concentrations were used as instrumental variables in published genome-wide association studies (GWASs) of European ancestry. The bidirectional 2-sample Mendelian randomization (MR) analyses were performed using summary-level data from the UK Biobank and FinnGen datasets. Sensitivity analyses were conducted to ensure the robustness of the MR results. The meta-analyses were conducted using both fixed-effect and random-effect models to provide comprehensive and reliable estimates. RESULTS: A standard deviation increase in calcium concentrations was linked to a 14%, 17%, and 13% reduction in the likelihood of developing AMD (95% confidence interval [CI]: 0.77, 0.97), wet AMD (95% CI: 0.73, 0.95), and dry AMD (95% CI: 0.75, 1.00), respectively. No significant causal relationships were detected between genetically predicted 25(OH)D concentrations and AMD and its subtypes (all P > 0.05). The combined analyses showed that higher calcium concentrations were associated with a reduced risk of overall AMD, with an odds ratio of 0.89 (95% CI: 0.81, 0.98). CONCLUSIONS: This study provides evidence supporting the causal relationship between calcium concentrations and risk of AMD and its subtypes, which may have important implications for the prevention, monitoring, and treatment of AMD.

Sheng-Jiang powder ameliorates NAFLD via regulating intestinal microbiota in mice.

Background: Intestinal microbiota have been demonstrated to be involved in the development of NAFLD, while the relationship between the severity of NAFLD and intestinal microbiota is still not fully elucidated. Sheng-Jiang Powder (SJP) showed exact efficacy in treating SFL and great potential in regulating intestinal microbiota, but the effects need to be further addressed in NASH and liver fibrosis. Objectives: To investigate the differences in intestinal microbiota of NAFLD with different severity and the effect of SJP on liver damage and intestinal microbiota. Design: NAFLD mice models with different severity were induced by high-fat diet (HFD) or choline-deficient, L-amino acid-defined high-fat diet (CDAHFD) feeding and then treated with SJP/normal saline. Methods: Biochemical blood tests, H&E/Masson/Oil Red O/IHC staining, Western blot, and 16SrDNA sequencing were performed to explore intestinal microbiota alteration in different NAFLD models and the effect of SJP on liver damage and intestinal microbiota. Results: Intestinal microbiota alteration was detected in all NAFLD mice. SJP induced increased expression of Pparγ and alleviated liver lipid deposition in all NAFLD mice. Microbiome analysis revealed obvious changes in intestinal microbiota composition, while SJP significantly elevated the relative abundance of Roseburia and Akkermansia, which were demonstrated to be beneficial for improving inflammation and intestinal barrier function. Conclusion: Our results demonstrated that SJP was effective in improving lipid metabolism in NAFLD mice, especially in mice with SFL. The potential mechanism may be associated with the regulation of intestinal microbiota.

Association between ambient air pollution and dry eye symptoms among Chinese individuals during the COVID-19 pandemic: A national-based study.

PURPOSE: To examine the association between ambient air pollution and dry eye symptoms (DES) during the COVID-19 pandemic and explore whether air pollution had increased the risk of DES to a greater extent than other risk factors. METHODS: A nationwide cross-sectional survey was conducted from June 20, 2022 to August 31, 2022. The Ocular Surface Disease Index-6 (OSDI-6) questionnaire was used to assess the presence of DES. Logistic regression models were employed to analyze the associations between DES and air pollution variables, including air quality index (AQI), fine particulate matter (PM2.5), PM10, sulfur dioxide (SO2), carbon monoxide (CO), nitrogen dioxide (NO2), ozone (O3) and residing near industrial zones. We explored the interactions of air pollutants and other risk factors in the additive models by calculating the synergy index (SI). Standardized regression coefficients were calculated to compare the relative importance of risk factors for DES. RESULTS: A total of 21,909 participants were included in the analysis. Residing near industrial zones was significantly correlated with a higher risk of DES (Odds ratio (OR): 1.57, 95 % confidence interval (CI): 1.38-1.79). No significant associations were found between DES and air pollutants except SO2 (OR: 1.05, 95 % CI: 1.02-1.09, per standard deviation increment in SO2 concentration). The restricted cubic spline analyses revealed a linear concentration-response relationship between SO2 and DES. The interaction analyses suggested synergetic interactions of SO2 with depression and problematic internet use. Among the risk factors, depression, anxiety and problematic Internet use contributed more to the increased risk of DES. CONCLUSION: The association between ambient air pollutants and DES may have been mitigated during the pandemic due to increased time spent indoors. Despite this, our findings support the deleterious health impact of air pollutants. Future urban planning should plan industrial zones further away from residential areas.

Fine-tuning the activation behaviors of ternary modular cabazitaxel prodrugs for efficient and on-target oral anti-cancer therapy.

The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of reducing substances (e.g., ascorbic acid, glutathione, uric acid and tea polyphenols) in the systemic circulation. This may lead to toxicity, particularly in oral prodrugs that require more frequent and high-dose treatments. Fine-tuning the activation kinetics of these prodrugs is a promising prospect for more efficient on-target cancer therapies. In this study, disulfide, steric disulfide, and ester bonds were used to bridge cabazitaxel (CTX) to an intestinal lymph vessel-directed triglyceride (TG) module. Then, synthetic prodrugs were efficiently incorporated into self-nanoemulsifying drug delivery system (corn oil and Maisine CC were used as the oil phase and Cremophor EL as the surfactant). All three prodrugs had excellent gastric stability and intestinal permeability. The oral bioavailability of the disulfide bond-based prodrugs (CTX-(C)S-(C)S-TG and CTX-S-S-TG) was 11.5- and 19.1-fold higher than that of the CTX solution, respectively, demonstrating good oral delivery efficiency. However, the excessive reduction sensitivity of the disulfide bond resulted in lower plasma stability and safety of CTX-S-S-TG than that of CTX-(C)S-(C)S-TG. Moreover, introducing steric hindrance into disulfide bonds could also modulate drug release and cytotoxicity, significantly improving the anti-tumor activity even compared to that of intravenous CTX solution at half dosage while minimizing off-target adverse effects. Our findings provide insights into the design and fine-tuning of different disulfide bond-based linkers, which may help identify oral prodrugs with more potent therapeutic efficacy and safety for cancer therapy.

The protective effects of ligustrazine on ischemic stroke: a systematic review and meta-analysis of preclinical evidence and possible mechanisms.

Introduction: The objective of this study is to systematically evaluate the effect of ligustrazine on animal models of ischemic stroke and investigate its mechanism of action. Materials and Methods: The intervention of ligustrazine in ischemic diseases research on stroke model animals was searched in the Chinese National Knowledge Infrastructure (CNKI), Wanfang Database (Wanfang), VIP Database (VIP), Chinese Biomedical Literature Database (CBM), Cochrane Library, PubMed, Web of Science, and Embase databases. The quality of the included literature was evaluated using the Cochrane risk of bias tool. The evaluation included measures such as neurological deficit score (NDS), percentage of cerebral infarction volume, brain water content, inflammation-related factors, oxidative stress-related indicators, apoptosis indicators (caspase-3), and blood-brain barrier (BBB) permeability (Claudin-5). Results: A total of 32 studies were included in the analysis. The results indicated that ligustrazine significantly improved the neurological function scores of ischemic stroke animals compared to the control group (SMD = -1.84, 95% CI -2.14 to -1.55, P < 0.00001). It also reduced the percentage of cerebral infarction (SMD = -2.97, 95% CI -3.58 to -2.36, P < 0.00001) and brain water content (SMD = -2.37, 95% CI -3.63 to -1.12, P = 0.0002). In addition, ligustrazine can significantly improve various inflammatory factors such as TNF-α (SMD = -7.53, 95% CI -11.34 to -3.72, P = 0.0001), IL-1ß (SMD = -2.65, 95% CI -3.87 to -1.44, P < 0.0001), and IL-6 (SMD = -5.55, 95% CI -9.32 to -1.78, P = 0.004). It also positively affects oxidative stress-related indicators including SOD (SMD = 4.60, 95% CI 2.10 to 7.10, P = 0.0003), NOS (SMD = -1.52, 95% CI -2.98 to -0.06, P = 0.04), MDA (SMD = -5.31, 95% CI -8.48 to -2.14, P = 0.001), and NO (SMD = -5.33, 95% CI -8.82 to -1.84, P = 0.003). Furthermore, it shows positive effects on the apoptosis indicator caspase-3 (SMD = -5.21, 95% CI -7.47 to -2.94, P < 0.00001) and the expression level of the sex-related protein Claudin-5, which influences BBB permeability (SMD = 7.38, 95% CI 3.95 to 10.82, P < 0.0001). Conclusion: Ligustrazine has been shown to have a protective effect in animal models of cerebral ischemic injury. Its mechanism of action is believed to be associated with the reduction of inflammation and oxidative stress, the inhibition of apoptosis, and the repair of BBB permeability. However, further high-quality animal experiments are required to validate these findings.

Metal Halide Nanocrystals@Silica Aerogel Composite with Enhanced Dispersion Stability and Light Output for Efficient X-Ray Imaging in Harsh Environment.

Metal halide nanocrystals (MHNCs) embedded in a polymer matrix as flexible X-ray detector screens is an effective strategy with the advantages of low cost, facile preparation, and large area flexibility. However, MHNCs easily aggregate during preparation, recombination, under mechanical force, storage, or high operating temperature. Meanwhile, it shows an unmatched refractive index with polymer, resulting in low light yield. The related stability and properties of the device remain a huge unrevealed challenge. Herein, a composite screen (CZBM@AG-PS) by integrating MHNCs (Cs2ZnBr4: Mn2+ as an example) into silica aerogel (AG) and embedded in polystyrene (PS) is successfully developed. Further characterization points to the high porosity AG template that can effectively improve the dispersion of MHNCs in polymer detector screens, essentially decreasing nonradiative transition, Rayleigh scattering, and performance aging induced by aggregation in harsh environments. Furthermore, the higher light output and lower optical crosstalk are also achieved by a novel light propagation path based on the MHNCs/AG and AG/PS interfaces. Finally, the optimized CZBM@AG-PS screen shows much enhanced light yield, spatial resolution, and temperature stability. Significantly, the strategy is proven universal by the performance tests of other MHNCs embedded composite films for ultra-stable and efficient X-ray imaging.

MLDA: Multi-Loss Domain Adaptor for Cross-Session and Cross-Emotion EEG-Based Individual Identification.

Traditional individual identification methods, such as face and fingerprint recognition, carry the risk of personal information leakage. The uniqueness and privacy of electroencephalograms (EEG) and the popularization of EEG acquisition devices have intensified research on EEG-based individual identification in recent years. However, most existing work uses EEG signals from a single session or emotion, ignoring large differences between domains. As EEG signals do not satisfy the traditional deep learning assumption that training and test sets are independently and identically distributed, it is difficult for trained models to maintain good classification performance for new sessions or new emotions. In this article, an individual identification method, called Multi-Loss Domain Adaptor (MLDA), is proposed to deal with the differences between marginal and conditional distributions elicited by different domains. The proposed method consists of four parts: a) Feature extractor, which uses deep neural networks to extract deep features from EEG data; b) Label predictor, which uses full-layer networks to predict subject labels; c) Marginal distribution adaptation, which uses maximum mean discrepancy (MMD) to reduce marginal distribution differences; d) Associative domain adaptation, which adapts to conditional distribution differences. Using the MLDA method, the cross-session and cross-emotion EEG-based individual identification problem is addressed by reducing the influence of time and emotion. Experimental results confirmed that the method outperforms other state-of-the-art approaches.

Chronic conditions and depressive symptoms in middle-aged and older Chinese adults: Roles of perceived social support and area of residence.

BACKGROUND: Many studies have shown that having noncommunicable chronic diseases (NCDs) is strongly associated with depressive symptoms in elderly people; however, the mechanisms of this association are not fully understood. This study aims to investigate whether perceived social support (PSS) mediates the effect of NCDs on depressive symptoms and whether these relationships differ depending on where middle-aged and elderly people live. METHODS: The study population was from the psychology and behavior investigation of Chinese residents (PBICR). A total of 8732 people aged 45 and older were included in the hypothetical modulated model. Perceived Social Support Scale (PSSS) and Patient Health Questionnaire-9 (PHQ-9) were used to evaluate PSS and depressive symptoms. RESULTS: NCDs were positively related to depressive symptoms (ß = 0.81, p < 0.01) and indirectly mediated through PSS (ß = 0.08). Residency moderated the relationship between NCDs and PSS (ß = -0.16, p < 0.01) and between NCDs and depressive symptoms (ß = 0.29, p < 0.01). Specifically, the effect of NCDs on PSS and depressive symptoms was greater in rural middle-aged and older adults. CONCLUSIONS: NCDs raise the risk of depressive symptoms in middle-aged and older Chinese, with PSS playing a partially protective role. In addition, the area of residence moderated the connection between the number of NCDs and PSS, NCDs, and depressive symptoms in middle-aged and older adults.

Histidine triad nucleotide-binding protein 2: From basic science to clinical implications.

Histidine triad nucleotide-binding protein 2 (HINT2) is a dimeric protein that belongs to the histidine triad protein superfamily, predominantly expressed in the liver, pancreas, and adrenal gland, and localised to the mitochondrion. HINT2 binds nucleotides and catalyses the hydrolysis of nucleotidyl substrates. Moreover, HINT2 has been identified as a key regulator of multiple biological processes, including mitochondria-dependent apoptosis, mitochondrial protein acetylation, and steroidogenesis. Genetic manipulation has provided new insights into the physiological roles of HINT2 in several processes, such as inhibition of cancer progression, regulation of hepatic lipid metabolism, and protective effects on the cardiovascular system. The current review outlines the background and functions of HINT2. In addition, it summarises research progress on the correlation between HINT2 and human malignancies, hepatic metabolic diseases, and cardiovascular diseases, with an attempt to provide new research directions emerging in this field and to unveil the therapeutic value of HINT2 as a target in the combat of human diseases.

Prevalence of depressive symptoms and associated factors during the COVID-19 pandemic: A national-based study.

BACKGROUND: Previous studies have reported that the prevalence of depression and depressive symptoms was significantly higher than that before the COVID-19 pandemic. This study aimed to explore the prevalence of depressive symptoms and evaluate the importance of influencing factors through Back Propagation Neural Network (BPNN). METHODS: Data were sourced from the psychology and behavior investigation of Chinese residents (PBICR). A total of 21,916 individuals in China were included in the current study. Multiple logistic regression was applied to preliminarily identify potential risk factors for depressive symptoms. BPNN was used to explore the order of contributing factors of depressive symptoms. RESULTS: The prevalence of depressive symptoms among the general population during the COVID-19 pandemic was 57.57 %. The top five important variables were determined based on the BPNN rank of importance: subjective sleep quality (100.00 %), loneliness (77.30 %), subjective well-being (67.90 %), stress (65.00 %), problematic internet use (51.20 %). CONCLUSIONS: The prevalence of depressive symptoms in the general population was high during the COVID-19 pandemic. The BPNN model established has significant preventive and clinical meaning to identify depressive symptoms lay theoretical foundation for individualized and targeted psychological intervention in the future.

Enhancing Oral Performance of Paclitaxel Lipid-Mimic Prodrug via Modulating Type of Fatty Acids.

Owing to the serious clinical side effects of intravenous Taxol, an oral chemotherapeutic strategy is expected to be promising for paclitaxel (PTX) delivery. However, its poor solubility and permeability, high first-pass metabolism, and gastrointestinal toxicity need to be overcome. A triglyceride (TG)-like prodrug strategy facilitates oral drug delivery by bypassing liver metabolism. However, the effect of fatty acids (FAs) in sn-1,3 on the oral absorption of prodrugs remains unclear. Herein, a series of TG-mimetic prodrugs of PTX is explored with different carbon chain lengths and degrees of unsaturation of FAs at the sn-1,3 position in an attempt to enhance oral antitumor effect and to guide the design of TG-like prodrugs. Interestingly, the different FA lengths exhibit great influence on in vitro intestinal digestion behavior, lymph transport efficiency, and up to fourfold differences in plasma pharmacokinetics. The prodrug with long-chain FAs shows a more effective antitumor effect, whereas the degree of unsaturation has a negligible impact. The findings illustrate how FAs structures affect the oral delivery efficiency of TG-like PTX prodrugs and thus provide a theoretical basis for their rational design.

Incorporating a Lipophilic Disulfide-Bridged Linoleic Prodrug into a Self-Microemulsifying Drug Delivery System to Facilitate Oral Absorption of Paclitaxel.

The oral absorption of paclitaxel (PTX) is restricted by poor solubility in the gastrointestinal tract (GIT), low permeability, and high first-pass metabolism. Lipid carriers, such as a self-microemulsifying drug delivery system (SMEDDS), have been deemed as promising vehicles for promoting oral delivery of PTX. Herein, a lipophilic disulfide-bridged linoleic prodrug (PTX-S-S-LA) was synthesized and efficiently incorporated into SMEDDS to facilitate the oral absorption of PTX. This study mainly aims to evaluate the usefulness of the disulfide-bridged linoleic prodrug incorporated with SMEDDS and provides a new strategy for efficient oral delivery of PTX. The prodrug SMEDDS showed a markedly higher drug loading efficiency (3-fold) compared to that of parent PTX. PTX-S-S-LA SMEDDS significantly increased the drug partition (about 1.9-fold) in the intestinal micellar aqueous phase compared to PTX in the in vitro lipolysis study. Additionally, the gastrointestinal (GI) biodistribution study demonstrated that SMEDDS could enhance the GI biological adhesion and go through the lymphatic system to transport. Moreover, it was found that the reduction-sensitive prodrug (PTX-S-S-LA) has good stability in the GIT, leading to an improved antitumor efficiency without significant GI toxicity. Overall, the PTX-linoleic prodrug (PTX-S-S-LA) in combination with SMEDDS provides a promising way to enable effective oral delivery of PTX.

Plasma membrane flipping of Syntaxin-2 regulates its inhibitory action on insulin granule exocytosis.

Enhancing pancreatic ß-cell secretion is a primary therapeutic target for type-2 diabetes (T2D). Syntaxin-2 (Stx2) has just been identified to be an inhibitory SNARE for insulin granule exocytosis, holding potential as a treatment for T2D, yet its molecular underpinnings remain unclear. We show that excessive Stx2 recruitment to raft-like granule docking sites at higher binding affinity than pro-fusion syntaxin-1A effectively competes for and inhibits fusogenic SNARE machineries. Depletion of Stx2 in human ß-cells improves insulin secretion by enhancing trans-SNARE complex assembly and cis-SNARE disassembly. Using a genetically-encoded reporter, glucose stimulation is shown to induce Stx2 flipping across the plasma membrane, which relieves its suppression of cytoplasmic fusogenic SNARE complexes to promote insulin secretion. Targeting the flipping efficiency of Stx2 profoundly modulates secretion, which could restore the impaired insulin secretion in diabetes. Here, we show that Stx2 acts to assist this precise tuning of insulin secretion in ß-cells, including in diabetes.

Dao-Chi Powder Ameliorates Pancreatitis-Induced Intestinal and Cardiac Injuries via Regulating the Nrf2-HO-1-HMGB1 Signaling Pathway in Rats.

Dao-Chi powder (DCP) has been widely used in the treatment of inflammatory diseases in the clinical practice of traditional Chinese medicine, but has not been used in acute pancreatitis (AP). This study aimed to evaluate the effect of DCP on severe AP (SAP) and SAP-associated intestinal and cardiac injuries. To this end, an SAP animal model was established by retrograde injection of 3.5% taurocholic acid sodium salt into the biliopancreatic ducts of rats. Intragastric DCP (9.6 g/kg.BW) was administered 12 h after modeling. The pancreas, duodenum, colon, heart and blood samples were collected 36 h after the operation for histological and biochemical detection. The tissue distributions of the DCP components were determined and compared between the sham and the SAP groups. Moreover, molecular docking analysis was employed to investigate the interactions between the potential active components of DCP and its targets (Nrf2, HO-1, and HMGB1). Consequently, DCP treatment decreased the serum levels of amylase and the markers of gastrointestinal and cardiac injury, further alleviating the pathological damage in the pancreas, duodenum, colon, and heart of rats with SAP. Mechanistically, DCP rebalanced the pro-/anti-inflammatory cytokines and inhibited MPO activity and MDA levels in these tissues. Furthermore, Western blot and RT-PCR results showed that DCP intervention enhanced the expression of Nrf2 and HO-1 in the duodenum and colon of rats with SAP, while inhibiting the expression of HMGB1 in the duodenum and heart. HPLC-MS/MS analysis revealed that SAP promoted the distribution of ajugol and oleanolic acid to the duodenum, whereas it inhibited the distribution of liquiritigenin to the heart and ajugol to the colon. Molecular docking analysis confirmed that the six screened components of DCP had relatively good binding affinity with Nrf2, HO-1, and HMGB1. Among these, oleanolic acid had the highest affinity for HO-1. Altogether, DCP could alleviated SAP-induced intestinal and cardiac injuries via inhibiting the inflammatory responses and oxidative stress partially through regulating the Nrf2/HO-1/HMGB1 signaling pathway, thereby providing additional supportive evidence for the clinical treatment of SAP.

Conjunctive Analyses of BSA-Seq and BSR-Seq Unveil the Msß-GAL and MsJMT as Key Candidate Genes for Cytoplasmic Male Sterility in Alfalfa (Medicago sativa L.).

Knowing the molecular mechanism of male sterility in alfalfa is important to utilize the heterosis more effectively. However, the molecular mechanisms of male sterility in alfalfa are still unclear. In this study, the bulked segregant analysis (BSA) and bulked segregant RNA-seq (BSR) were performed with F2 separation progeny to study the molecular mechanism of male sterility in alfalfa. The BSA-seq analysis was located in a candidate region on chromosome 5 containing 626 candidate genes which were associated with male sterility in alfalfa, while the BSR-seq analysis filtered seven candidate DEGs related to male sterility, and these candidate genes including EF-Tu, ß-GAL, CESA, PHGDH, and JMT. The conjunctive analyses of BSR and BSA methods revealed that the genes of Msß-GAL and MsJMT are the common detected candidate genes involved in male sterility in alfalfa. Our research provides a theory basis for further study of the molecular mechanism of male sterility in alfalfa and significant information for the genetic breeding of Medicago sativa.

Emodin Ameliorates Acute Pancreatitis-Associated Lung Injury Through Inhibiting the Alveolar Macrophages Pyroptosis.

Objective: To investigate the protective effect of emodin in acute pancreatitis (AP)-associated lung injury and the underlying mechanisms. Methods: NaT-AP model in rats was constructed using 3.5% sodium taurocholate, and CER+LPS-AP model in mice was constructed using caerulein combined with Lipopolysaccharide. Animals were divided randomly into four groups: sham, AP, Ac-YVAD-CMK (caspase-1 specific inhibitor, AYC), and emodin groups. AP-associated lung injury was assessed with H&E staining, inflammatory cytokine levels, and myeloperoxidase activity. Alveolar macrophages (AMs) pyroptosis was evaluated by flow cytometry. In bronchoalveolar lavage fluid, the levels of lactate dehydrogenase and inflammatory cytokines were measured by enzyme-linked immunosorbent assay. Pyroptosis-related protein expressions were detected by Western Blot. Results: Emodin, similar to the positive control AYC, significantly alleviated pancreas and lung damage in rats and mice. Additionally, emodin mitigated the pyroptotic process of AMs by decreasing the level of inflammatory cytokines and lactate dehydrogenase. More importantly, the protein expressions of NLRP3, ASC, Caspase1 p10, GSDMD, and GSDMD-NT in AMs were significantly downregulated after emodin intervention. Conclusion: Emodin has a therapeutic effect on AP-associated lung injury, which may result from the inhibition of NLRP3/Caspase1/GSDMD-mediated AMs pyroptosis signaling pathways.

Long chain triglyceride-lipid formulation promotes the oral absorption of the lipidic prodrugs through coincident intestinal behaviors.

Oral administration of chemotherapy agents, such as docetaxel (DTX), is expected to reduce side effects significantly and increase dosing frequency. However, they often suffer from poor oral bioavailability, impeding their oral application. Dietary lipids such as triglycerides favor lymphatic transport nor vein system, bypassing the first-pass metabolism. Inspired by this concept, we developed a triglyceride-like prodrug of DTX (named as OATG) and explored the effect of lipid types on the OATG oral delivery. The plasma profile in rats revealed that long chain triglyceride (LCT)-based lipid formulations (LBLF) were more promising for OATG delivery than medium chain triglyceride (MCT) ones. The OATG LBLF elicited a markedly enhanced absorption compared with oral Taxotere or DTX LBLF, resulting in relative bioavailability 6.11 or 2.47-fold higher, respectively. The coincident intestinal behaviors of lipid excipients and TG-like prodrug facilitate the oral absorption of the prodrug. The effectiveness of the prodrug formulation was also examined in beagles with absolute bioavailability up to 41.08%, in sharp contrast to that of control DTX group (8%). Besides, the OATG oral formulation could be schedule-intensively administrated with no hypersensitivity, gastrointestinal and hematological toxicity. The current strategy provides an effective lipid formulation and a promising chance for chemotherapy at home.