Polyphenols from hickory nut reduce the occurrence of atherosclerosis in mice by improving intestinal microbiota and inhibiting trimethylamine N-oxide production.

BACKGROUND: Trimethylamine N-oxide (TMAO), a metabolite produced by intestinal microbiota through metabolizing phosphatidylcholine, choline, l-carnitine and betaine in the diet, has been implicated in the pathogenesis of atherosclerosis (AS). Concurrently, dietary polyphenols have garnered attention for their potential to ameliorate obesity, diabetes and atherosclerosis primarily by modulating the intestinal microbial structure. Hickory (Carya cathayensis) nut, a polyphenol-rich food product favored for its palatability, emerges as a candidate for exploration. HYPOTHESIS/PURPOSE: The relationship between polyphenol of hickory nut and atherosclerosis prevention will be firstly clarified, providing theoretical basis for the discovery of natural products counteracting TMAO-induced AS process in hickory nut. STUDY DESIGN AND METHODS: Employing Enzyme-linked Immunosorbent Assay (ELISA) and histological examination of aortic samples, the effects of total polyphenol extract on obesity index, inflammatory index and pathological changes of atherosclerosis in C57BL/6 J mice fed with high-fat and high choline diet were evaluated. Further, the composition, abundance, and function of mouse gut microbiota were analyzed through 16srDNA sequencing. Concurrently, the levels of TMAO and the expression of key enzymes (CutC and FMO3) involved in its synthesis are quantified using ELISA, Western Blot and Real-Time Quantitative PCR (RT-qPCR). Additionally, targeted metabolomic profiling of the hickory nut polyphenol extract was conducted, accompanied by molecular docking simulations to predict interactions between candidate polyphenols and the CutC/FMO3 using Autodock Vina. Finally, the docking prediction were verified by microscale thermophoresis (MST) . RESULTS: Polyphenol extracts of hickory nut improved the index of obesity and inflammation, and alleviated the pathological changes of atherosclerosis in C57BL/6 J mice fed with high-fat and high-choline diet. Meanwhile, these polyphenol extracts also changed the composition and function of intestinal microbiota, and increased the abundance of microorganisms in mice. Notably, the abundance of intestinal microbiota endowed with CutC gene was significantly reduced, coherent with expression of CutC catalyzing TMA production. Moreover, polyphenol extracts also decreased the expression of FMO3 in the liver, contributing to the reduction of TMAO levels in serum. Furthermore, metabonomic profile analysis of these polyphenol extracts identified 647 kinds of polyphenols. Molecular docking predication further demonstrated that Casuariin and Cinnamtannin B2 had the most potential inhibition on the enzymatic activities of CutC or FMO3, respectively. Notably, MST analysis corroborated the potential for direct interaction between CutC enzyme and available polyphenols such as Corilagin, (-)-Gallocatechin gallate and Epigallocatechin gallate. CONCLUSION: Hickory polyphenol extract can mitigate HFD-induced AS by regulating intestinal microflora in murine models. In addition, TMA-FMO3-TMAO pathway may play a key role in this process. This research unveils, for the inaugural time, the complex interaction between hickory nut-derived polyphenols and gut microbial, providing novel insights into the role of dietary polyphenols in AS prevention.

Novel inhalation therapy in pulmonary fibrosis: principles, applications and prospects.

Pulmonary fibrosis (PF) threatens millions of people worldwide with its irreversible progression. Although the underlying pathogenesis of PF is not fully understood, there is evidence to suggest that the disease can be blocked at various stages. Inhalation therapy has been applied for lung diseases such as asthma and chronic obstructive pulmonary disease, and its application for treating PF is currently under consideration. New techniques in inhalation therapy, such as the application of microparticles and nanoparticles, traditional Chinese medicine monomers, gene therapy, inhibitors, or agonists of signaling pathways, extracellular vesicle interventions, and other specific drugs, are effective in treating PF. However, the safety and effectiveness of these therapeutic techniques are influenced by the properties of inhaled particles, biological and pathological barriers, and the type of inhalation device used. This review provides a comprehensive overview of the pharmacological, pharmaceutical, technical, preclinical, and clinical experimental aspects of novel inhalation therapy for treating PF and focus on therapeutic methods that significantly improve existing technologies or expand the range of drugs that can be administered via inhalation. Although inhalation therapy for PF has some limitations, the advantages are significant, and further research and innovation about new inhalation techniques and drugs are encouraged.

[Research progress in Astragali Radix and its active ingredients in treatment of lung cancer].

Lung cancer is the leading cause of cancer death, and its effective treatment is a difficult medical problem. Lung cancer belongs to the traditional Chinese medicine(TCM) disease categories of lung accumulation, lung amassment, and overstrain cough. Rich theoretical basis and practical experience have been accumulated in the TCM treatment of lung cancer. Astragali Radix is one of the representatives of Qi-tonifying drugs. It mainly treat the lung cancer with the syndrome of Qi deficiency and pathogen stagnation, following the principle of reinforcing healthy Qi and eliminating patgogenic Qi. Astragali Radix exerts a variety of pharmacological activities in the treatment of lung cancer, including inhibiting tumor cell proliferation and promoting tumor cell apoptosis, inhibiting tumor invasion and migration, regulating the tumor microenvironment, suppressing tumor angiogenesis, modulating autophagy, inducing macrophage polarization, enhancing immunity, inhibiting immune escape, and reversing cisplatin resistance. The active ingredients of Astragali Radix in treating lung cancer include polysaccharides, saponins, and flavonoids. This study reviewed the pharmacological activities and active ingredients of Astragali Radix in the treatment of lung cancer, providing a basis for the development and utilization of Astragali Radix resources and active ingredients and the research and development of anti-tumor drugs.

QiDiTangShen granules alleviates diabetic nephropathy podocyte injury: A network pharmacology study and experimental validation in vivo and vitro.

Background: QiDiTangShen granules (QDTS), a traditional Chinese medicine (TCM) compound prescription, have remarkable efficacy in diabetic nephropathy (DN) patients, and their pharmacological mechanism needs further exploration. Methods: According to the active ingredients and targets of the QDTS in the TCMSP database, the network pharmacology of QDTS was investigated. The potential active ingredients were chosen based on the oral bioavailability and the drug similarity index. At the same time, targets for DN-related disease were obtained from GeneCards, OMIM, PharmGKB, TTD, and DrugBank. The TCM-component-target network and the protein-protein interaction (PPI) network were constructed with the Cytoscape and STRING platforms, respectively, and then the core targets of DN were selected with CytoNCA. GO and KEGG enrichment analysis using R software. Molecular docking to identify the core targets of QDTS for DN. In vivo, db/db mice were treated as DN models, and the urine microalbuminuria, the pathological changes in the kidney and the protein expression levels of p-PI3K, p-Akt, JUN, nephrin and synaptopodin were detected by immunohistochemistry, immunofluorescence method and Western blotting. After QDTS was used in vitro, the protein expression of mouse podocyte clone-5 (MPC5) cells was detected by immunohistochemistry, immunofluorescence and Western blot. Results: Through network pharmacology analysis, 153 potential targets for DN in QDTS were identified, 19 of which were significant. The KEGG enrichment analysis indicated that QDTS might have therapeutic effects on IL-17, TNF, AGE-RAGE, PI3K-Akt, HIF-1, and EGFR through interfering with Akt1 and JUN. The main active ingredients in QDTS are quercetin, ß-sitosterol, stigmasterol and kaempferol. Both in vivo and in vitro studies showed that QDTS could decrease the urine microalbuminuria and renal pathology of db/db mice, and alleviate podocyte injuries through the PI3K/Akt signaling pathway. Conclusion: Through network pharmacology, in vivo and in vitro experiments, QDTS has been shown to improve the urine microalbuminuria and renal pathology in DN, and to reduce podocyte damage via the PI3K/Akt pathway.

Exploring the pathogenesis of depression and potential antidepressants through the integration of reverse network pharmacology, molecular docking, and molecular dynamics.

Depression is characterized by a significant and persistent decline in mood and is currently a major threat to physical and mental health. Traditional Chinese medicine can effectively treat depression with few adverse effects. Therefore, this study aimed to examine the use of reverse network pharmacology and computer simulations to identify effective ingredients and herbs for treating depression. Differentially expressed genes associated with depression were obtained from the Gene Expression Omnibus database, after which enrichment analyses were performed. A protein-protein interaction network was constructed using the STRING database to screen core targets. The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform database was used to screen ingredients related to these core targets, and the core ingredients were screened by constructing the "Targets-Ingredients-Herbs" network. Drug evaluation analysis was performed using the SwissADME and ADMETlab platforms, according to Lipinski Rule of 5. The binding between the targets and ingredients was simulated using molecular docking software. The binding stability was determined using molecular dynamics analysis. The "Ingredients-Herbs" network was constructed, and we annotated it for its characteristics and meridians. Finally, the selected herbs were classified to determine the formulation for treating depression in traditional Chinese medicine. The pathogenesis of depression was associated with changes in SPP1, Plasminogen activator inhibitor 1, CCNB1 protein, CCL3, and other genes. Computer simulations have verified the use of quercetin, luteolin, apigenin, and other ingredients as drugs for treating depression. Most of the top 10 herbs containing these ingredients were attributed to the liver meridian, and their taste was symplectic. Perilla Frutescen, Cyperi Rhizoma, and Linderae Radix, the main components of "Tianxiang Zhengqi Powder," can treat depression owing to Qi stagnation. Epimedium and Citicola, the main traditional Chinese herbs in "Wenshen Yiqi Decoction," have a positive effect on depression of the Yang asthenia type. Fructus Ligustri Lucidi and Ecliptae Herba are from the classic prescription "Erzhi Pills" and can treat depression of the Yin deficiency type. This study identified the key targets and effective medicinal herbs for treating depression. It provides herbal blend references for treating different types of depression according to the theory of traditional Chinese medicine.

"Dual sensitive supramolecular curcumin nanoparticles" in "advanced yeast particles" mediate macrophage reprogramming, ROS scavenging and inflammation resolution for ulcerative colitis treatment.

Ulcerative colitis (UC) faces some barriers in oral therapy, such as how to safely deliver drugs to the colon and accumulate in the colon lesions. Hence, we report an advanced yeast particles system loaded with supramolecular nanoparticles with ROS scavenger (curcumin) to treat UC by reducing oxidative stress state and inflammatory response and accelerating the reprogramming of macrophages. In this study, the dual-sensitive materials are bonded on ß-cyclodextrin (ß-CD), the D-mannose (Man) is modified to adamantane (ADA), and then loaded with curcumin (CUR), to form a functional supramolecular nano-delivery system (Man-CUR NPs) through the host-guest interaction. To improve gastrointestinal stability and colonic accumulation of Man-CUR NPs, yeast cell wall microparticles (YPs) encapsulated Man-CUR NPs to form Man-CUR NYPs via electrostatic adsorption and vacuum extrusion technologies. As expected, the YPs showed the strong stability in complex gastrointestinal environment. In addition, the Man modified supramolecular nanoparticles demonstrated excellent targeting ability to macrophages in the in vitro cellular uptake study and the pH/ROS sensitive effect of Man-CUR NPs was confirmed by the pH/ROS-dual stimulation evaluation. They also enhanced lipopolysaccharide (LPS)-induced inflammatory model in macrophages through downregulation of pro-inflammatory factors, upregulation of anti-inflammatory factors, M2 macrophage polarization, and scavenging the excess ROS. Notably, in DSS-induced mice colitis model, Man-CUR NYPs can reduce the inflammatory responses by modulating TLR4/NF-κB signaling pathways, alleviate oxidative stress by Nrf2/HO-1 signaling pathway, promote macrophages reprogramming and improve the favorable recovery of the damaged colonic tissue. Taken together, this study not only provides strategy for "supramolecular curcumin nanoparticles with pH/ROS sensitive and multistage therapeutic effects" in "advanced yeast particles", but also provided strong theoretical support multi-effect therapy for UC.

Bovine colostrum to supplement the first feeding of very preterm infants: The PreColos randomized controlled trial.

BACKGROUND & AIMS: Gut immaturity leads to feeding difficulties in very preterm infants (<32 weeks gestation at birth). Maternal milk (MM) is the optimal diet but often absent or insufficient. We hypothesized that bovine colostrum (BC), rich in protein and bioactive components, improves enteral feeding progression, relative to preterm formula (PF), when supplemented to MM. Aim of the study is to determine whether BC supplementation to MM during the first 14 days of life shortens the time to full enteral feeding (120 mL/kg/d, TFF120). METHODS: This was a multicenter, randomized, controlled trial at seven hospitals in South China without access to human donor milk and with slow feeding progression. Infants were randomly assigned to receive BC or PF when MM was insufficient. Volume of BC was restricted by recommended protein intake (4-4.5 g/kg/d). Primary outcome was TFF120. Feeding intolerance, growth, morbidities and blood parameters were recorded to assess safety. RESULTS: A total of 350 infants were recruited. BC supplementation had no effect on TFF120 in intention-to-treat analysis [n (BC) = 171, n (PF) = 179; adjusted hazard ratio, aHR: 0.82 (95% CI: 0.64, 1.06); P = 0.13]. Body growth and morbidities did not differ, but more cases of periventricular leukomalacia were detected in the infants fed BC (5/155 vs. 0/181, P = 0.06). Blood chemistry and hematology data were similar between the intervention groups. CONCLUSIONS: BC supplementation during the first two weeks of life did not reduce TFF120 and had only marginal effects on clinical variables. Clinical effects of BC supplementation on very preterm infants in the first weeks of life may depend on feeding regimen and remaining milk diet. TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov: NCT03085277.

[Effect of deep needling "Tianshu" (ST25) on colonic motility in rats with slow transit constipation].

OBJECTIVE: To observe the effect of acupuncture of "Tianshu"(ST25) at different depths on colonic transportation function, expressions of colonic substance P (SP) and interstitial cells of Cajal (ICC) in rats with slow transit constipation (STC), so as to explore its mechanisms underlying improvement of STC．. METHODS: Fifty male Wistar rats were selected and randomly divided into control，STC model，conventional acupuncture，deep needling group 1 and deep needling group 2 groups，with 10 rats in each group．The STC model was established by gavage of 1 mg/mL compound diphenoxylate suspension (10 mg/kg), once every other day for 21 days, and rats of the control group were given the same dose of distilled water by gavage．EA (2 Hz, 2 mA) was applied to "Tianshu"(ST25), with the acupuncture needle inserted to a depth of 3 mm for rats of the conventional acupuncture group, 4.5 mm for those of deep needling group 1, and 10 mm for those of the deep needling group 2. The acupuncture needle was twirled for 1 min, then retained for 15 min each time, once a day for 15 consecutive days．Following modeling, rats of the 4 groups and the control group received gavage of active carbon 2 mL (100 g/L) for observing the excretion time of the first black stool grain to assess the intestinal transit function. The colonic myoelectric activities (frequency and amplitude) were recorded by using BIOPAC multichannel physiograph. The immunoactivity of SP and c-kit (a transmembrane protein kinase for identification of ICC) of colonic musculature was detected by immunohistochemistry. RESULTS: Compared with the control group，the time of excretion of the first black stool grain, and the amplitude of colonic electromyogram (EMG) were significantly increased (P<0.01), while the frequency of EMG, expressions of SP and c-kit (ICC) were significantly decreased in the model group (P<0.01). In contrast to the model group, both deep needling group 1 and 2 had a decrease in the time of excretion of the first black stool grain, and amplitude of intestinal EMG, and an increase of frequency of intestinal EMG, and immunoactivity of SP and c-kit (P<0.01). The effect of deep needling 2 is superior to that of deep needling 1 in reducing the time of excretion of the first black stool grain (P<0.05), lowering the amplitude of EMG of the gut smooth muscle (P<0.05) and in increasing the frequency of EMG (P<0.05) and the expressions of SP and c-kit (P<0.05). No significant changes were found in the levels of frequency and amplitude of EMG, and expressions of SP and c-kit after routine needling in comparison with the model group (P>0.05), except the excretion time of the first black stool grain (P<0.05). CONCLUSION: Deep needling at ST25 at depth of 4.5 mm and 10 mm，especially at depth of 10 mm，has a significant effect in promoting gut motility to ameliorate constipation in rats with STC, which may be related to its function in up-regulating the expressions of SP and ICC activity.

[Network visual data mining and analysis of literature on electroacupuncture treatment of post-stroke sequelae].

OBJECTIVE: To analyze the optimum stimulating parameters and acupoint combination law of electroacupuncture (EA) treatment of post-stroke sequelae (PSS) through the network visual data mining and analysis of the literature，so as to provide reference for clinical application. METHODS: The related articles of acupuncture treatment of PSS patients published from January 1, 2005 to December 31, 2021 were collected from databases of CNKI, Wanfang, Weipu（VIP), SinoMed, CHAOXING, DUXIU, PubMed, Ovid, Embase and Cochrane Library. After the articles were screened according to our formulated inclusion and exclusion criteria, a "Clinical Literature Database of EA Treatment of PSS" was established. The SPSS Modeler14.1 software was used for modeling (by using the parameters of EA, types of apoplexy sequelae, names of acupoints, methods of acupoint matching, acupoint-attributed meridians, etc.) and association rule analysis, and the Cytoscape 3.6.0 software was used for data network visualization analysis. RESULTS: A total of 354 articles were collected, including 13 types of PSS, among which the hemi-plegia accounts for the highest proportion (51.13%), followed by depression (17.51%) and dysphagia (14.97%). A total of 228 acupoints are used, with a total frequency-time of 1 690. Among the 8 PSS (hemiplegia, depression, dysphagia, cognitive impairment, urinary incontinence, urinary retention, speech disorders, constipation) with the frequency of application of acupoints greater than or equal to 3, 275 articles are involved, with the frequency of dense wave being the highest (123 times), followed by continuous waves (95 times). The stimulation frequency of EA appears 275 times, with the low frequency being the highest (188 times). For hemiplegia type of PSS, low frequency and continuous waves or dense waves are mostly used, and the high correlation acupoint groups are Zusanli(ST36)/Hegu(LI4), LI4/Quchi(LI11) and ST36/LI11. For depression, low frequency and dense waves are mostly used, and the high correlation acupoint groups are Baihui(GV20)/Yintang(EX-HN3), GV20/Shenting(GV24) and GV20/Neiguan(PC6). For swallowing disorder, the mostly used stimulation parameter is low frequency, and the high correlation acupoint groups are Lianquan(CV23)/ST36/Fenglong(ST40), Tongli(HT5)/Yifeng(TE17)/PC6/ST40, and TE17/HT5/PC6/LI4. CONCLUSION: EA therapy is frequently used in the treatment of PSS, for which ST36, LI4 and LI11 are most frequently used in the treatment of hemiplegia, with the stimulation parameters being low-frequency and continuous waves or dense waves. For depression, GV20, EX-HN3, GV24 and PC6 are used, with the stimulation parameters being low frequency and dense waves. For dysphagia, CV23, HT5, TE17, PC6, ST36, ST40 and LI4 are employed, with low frequency electrical stimulation.

Tongqiao Huoxue Decoction ameliorates traumatic brain injury-induced gastrointestinal dysfunction by regulating CD36/15-LO/NR4A1 signaling, which fails when CD36 and CX3CR1 are deficient.

AIMS: Gastrointestinal (GI) dysfunction, as a common peripheral-organ complication after traumatic brain injury (TBI), is primarily characterized by gut inflammation and damage to the intestinal mucosal barrier (IMB). Previous studies have confirmed that TongQiao HuoXue Decoction (TQHXD) has strong anti-inflammatory properties and protects against gut injury. However, few have reported on the therapeutic effects of TQHXD in a TBI-induced GI dysfunction model. We aimed to explore the effects of TQHXD on TBI-induced GI dysfunction and the underlying mechanism thereof. METHODS: We assessed the protective effects and possible mechanism of TQHXD in treating TBI-induced GI dysfunction via gene engineering, histological staining, immunofluorescence (IF), 16S ribosomal ribonucleic acid (rRNA) sequencing, real-time polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), Western blot (WB), and flow cytometry (FCM). RESULTS: TQHXD administration ameliorated TBI-induced GI dysfunction by modulating the abundance and structure of bacteria; reconstructing the destroyed epithelial and chemical barriers of the IMB; and improving M1/M2 macrophage, T-regulatory cell (Treg)/T helper 1 cell (Th1 ), as well as Th17 /Treg ratios to preserve homeostasis of the intestinal immune barrier. Notably, Cluster of Differentiation 36 (CD36)/15-lipoxygenase (15-LO)/nuclear receptor subfamily 4 group A member 1 (NR4A1) signaling was markedly stimulated in colonic tissue of TQHXD-treated mice. However, insufficiency of both CD36 and (C-X3-C motif) chemokine receptor 1 (CX3CR1) worsened GI dysfunction induced by TBI, which could not be rescued by TQHXD. CONCLUSION: TQHXD exerted therapeutic effects on TBI-induced GI dysfunction by regulating the intestinal biological, chemical, epithelial, and immune barriers of the IMB, and this effect resulted from the stimulation of CD36/NR4A1/15-LO signaling; however, it could not do so when CX3CR1 and CD36 were deficient. TQHXD might therefore be a potential drug candidate for treating TBI-induced GI dysfunction.

Selenium-enriched Bifidobacterium longum DD98 relieves irritable bowel syndrome induced by chronic unpredictable mild stress in mice.

Irritable bowel syndrome (IBS) is a functional intestinal disorder without clear pathological mechanisms. Classical treatments for IBS are not always effective and are usually accompanied by side effects. Selenium-enriched Bifidobacterium longum DD98 (Se-B. longum DD98) is a selenized probiotic strain which has shown many beneficial effects on the gastrointestinal tract, but its effects on IBS and the underlying mechanism are unclear. This study aims to investigate the relieving effects of Se-B. longum DD98 on chronic unpredictable mild stress (CUMS)-induced IBS in mice. The model mice were treated with saline, B. longum DD98, or Se-B. longum DD98 while receiving CUMS. The results suggest that Se-B. longum DD98 significantly relieved the intestinal symptoms of IBS mice and reduced intestinal permeability and inflammation. The depression and anxiety-like behaviors of IBS mice were also improved by Se-B. longum DD98. In addition, the expression of serotonin (5-HT), γ-aminobutyric acid (GABA), neuropeptide Y (NPY), and brain-derived neurotrophic factor (BDNF), which are indicators closely related to mood and brain-gut axis, were up-regulated in mice treated with Se-B. longum DD98. Furthermore, the 16S rRNA sequencing study showed that Se-B. longum DD98 effectively restored the relative abundance of intestinal microbes (e.g., Lactobacillus, Desulfovibrio, Akkermansia) and regulated the impaired diversity of gut microbiota in IBS mice. These results suggest that Se-B. longum DD98 positively acts on the brain-gut axis by improving intestinal functions and regulating mood-associated behaviors and indicators of IBS mice. Therefore, this Se-enriched probiotic strain could be considered a promising candidate for the alleviation of CUMS-induced IBS.

Identification of Protein Quality Markers in Toad Venom from Bufo gargarizans.

Toad venom is a traditional Chinese medicine with high medicinal value. The existing quality evaluation standards of toad venom have obvious limitations because of the lack of research on proteins. Thus, it is necessary to screen suitable quality markers and establish appropriate quality evaluation methods for toad venom proteins to guarantee their safety and efficacy in clinical applications. SDS-PAGE, HPLC, and cytotoxicity assays were used to analyze differences in protein components of toad venom from different areas. Functional proteins were screened as potential quality markers by proteomic and bioinformatic analyses. The protein components and small molecular components of toad venom were not correlated in content. Additionally, the protein component had strong cytotoxicity. Proteomics analysis showed that 13 antimicrobial proteins, four anti-inflammatory and analgesic proteins, and 20 antitumor proteins were differentially expressed extracellular proteins. A candidate list of functional proteins was coded as potential quality markers. Moreover, Lysozyme C-1, which has antimicrobial activity, and Neuropeptide B (NPB), which has anti-inflammatory and analgesic activity, were identified as potential quality markers for toad venom proteins. Quality markers can be used as the basis of quality studies of toad venom proteins and help to construct and improve safe, scientific, and comprehensive quality evaluation methods.

Retinol dehydrogenase 10 reduction mediated retinol metabolism disorder promotes diabetic cardiomyopathy in male mice.

Diabetic cardiomyopathy is a primary myocardial injury induced by diabetes with complex pathogenesis. In this study, we identify disordered cardiac retinol metabolism in type 2 diabetic male mice and patients characterized by retinol overload, all-trans retinoic acid deficiency. By supplementing type 2 diabetic male mice with retinol or all-trans retinoic acid, we demonstrate that both cardiac retinol overload and all-trans retinoic acid deficiency promote diabetic cardiomyopathy. Mechanistically, by constructing cardiomyocyte-specific conditional retinol dehydrogenase 10-knockout male mice and overexpressing retinol dehydrogenase 10 in male type 2 diabetic mice via adeno-associated virus, we verify that the reduction in cardiac retinol dehydrogenase 10 is the initiating factor for cardiac retinol metabolism disorder and results in diabetic cardiomyopathy through lipotoxicity and ferroptosis. Therefore, we suggest that the reduction of cardiac retinol dehydrogenase 10 and its mediated disorder of cardiac retinol metabolism is a new mechanism underlying diabetic cardiomyopathy.

Comprehensive Analysis of Secondary Metabolites of Four Medicinal Thyme Species Used in Folk Medicine and Their Antioxidant Activities In Vitro.

Thyme is a colloquial term for number of aromatic species belonging to the genus Thymus L., known for their expressed biological activities and therefore used worldwide for seasoning and in folk medicine. In the present paper, the content of the total polyphenols (TP), total flavonoids (TF), and antioxidant capacity were assessed in the extracts of four traditionally used thyme species. Moreover, a comprehensive metabolomic study of thyme bioactive compounds was performed, and the obtained data were processed using multivariate statistical tests. The results clearly demonstrated the positive correlation between the content of the TP, TF, and antioxidant activity, and TF was more significant than TP. The findings revealed that four selected thyme species contained 528 secondary metabolites, including 289 flavonoids and 146 phenolic acids. Thymus marschallianus had a higher concentration of active ingredients, which improve its antioxidant capacity. Differentially accumulated metabolites were formed by complex pathways such as flavonoid, flavone, flavonol, isoflavonoid, and anthocyanin biosynthesis. Correlation analysis showed that 59 metabolites (including 28 flavonoids, 18 phenolic acids, and 7 terpenoid compounds) were significantly correlated with obtained values of the antioxidant capacity. The results suggested that selected thyme species exhibit a great diversity in antioxidant-related components, whereas flavonoids may be responsible for the high antioxidant capacity of all studied thyme species. The present study greatly expands our understanding of the complex phytochemical profiles and related applications of selected medicinal plants.

Arctiin-encapsulated DSPE-PEG bubble-like nanoparticles inhibit alveolar epithelial type 2 cell senescence to alleviate pulmonary fibrosis via the p38/p53/p21 pathway.

Background: Idiopathic pulmonary fibrosis is a severe and deadly form of diffuse parenchymal lung disease and treatment options are few. Alveolar epithelial type 2 (AEC2) cell senescence is implicated in the pathogenies of IPF. A major bioactive compound from the traditional Chinese medicine Fructus arctii, arctiin (ARC) has robust anti-inflammatory, anti-senescence, and anti-fibrosis functions. However, the potential therapeutic effects of ARC on IPF and the underlying mechanisms involved are still unknown. Methods: First of all, ARC was identified as an active ingredient by network pharmacology analysis and enrichment analysis of F. arctii in treating IPF. We developed ARC-encapsulated DSPE-PEG bubble-like nanoparticles (ARC@DPBNPs) to increase ARC hydrophilicity and achieve high pulmonary delivery efficiency. C57BL/6 mice were used to establish a bleomycin (BLM)-induced pulmonary fibrosis model for assessing the treatment effect of ARC@DPBNPs on lung fibrosis and the anti-senescence properties of AEC2. Meanwhile, p38/p53 signaling in AEC2 was detected in IPF lungs, BLM-induced mice, and an A549 senescence model. The effects of ARC@DPBNPs on p38/p53/p21 were assessed in vivo and in vitro. Results: Pulmonary route of administration of ARC@DPBNPs protected mice against BLM-induced pulmonary fibrosis without causing significant damage to the heart, liver, spleen, or kidney. ARC@DPBNPs blocked BLM-induced AEC2 senescence in vivo and in vitro. The p38/p53/p21 signaling axis was significantly activated in the lung tissues of patients with IPF, senescent AEC2, and BLM-induced lung fibrosis. ARC@DPBNPs attenuated AEC2 senescence and pulmonary fibrosis by inhibiting the p38/p53/p21 pathway. Conclusion: Our data suggest that the p38/p53/p21 signaling axis plays a pivotal role in AEC2 senescence in pulmonary fibrosis. The p38/p53/p21 signaling axis inhibition by ARC@DPBNPs provides an innovative approach to treating pulmonary fibrosis in clinical settings.

Folic acid-modified lactoferrin nanoparticles coated with a laminarin layer loaded curcumin with dual-targeting for ulcerative colitis treatment.

Curcumin (CUR) is a promising natural compound in ulcerative colitis (UC) treatment, but limited by its low oral bioavailability and poor targeting ability. Therefore, given the targeting action of lactoferrin (LF) by binding to the LF receptors of intestinal epithelial cells (IECs) and of folic acid (FA) by binding to the FA receptors of macrophages, we developed an oral dual-targeting nanosystem. Laminarin (LA)-coated, FA-modified LF nanoparticles (NPs) were used to encapsulate CUR (LA/FA/CUR-NPs) with a food-grade, enzyme-sensitive, and dual-targeting capacity. For the generated NPs, LF improved the loading efficiency of CUR (95.08 %). The LA layer could improve the upper gastrointestinal tract stability of the NPs while improve drug release around colon lesion through ß-glucanase digestion. Based on the cellular uptake evaluation, FA/CUR-NPs were capable of specifically targeting colonic epithelial cells and macrophages through LF and FA ligands, respectively, to enhance the uptake efficiency. Moreover, based on the advantage of the dual-targeting strategy, oral administration of FA/CUR-NPs obviously reduced colitis symptoms by alleviating inflammation, accelerating colonic mucosal barrier repair and restoring the balance of the intestinal microbiota. This dual-targeted nanodesign corresponded to the multi-bioresponsibilities of CUR, thus offering a promising approach in UC treatment.

Analysis of Pharmacological Activities and Mechanisms of Essential Oil in Leaves of C. grandis 'Tomentosa' by GC-MS/MS and Network Pharmacology.

BACKGROUND: Citrus grandis 'Tomentosa,' a fruit epicarp of C. grandis 'Tomentosa' or C. grandis (L.) Osbeck is widely used in health food and medicine. Based on our survey results, there are also rich essential oils with bioactivities in leaves, but the chemical compounds in this part and relevant pharmacological activities have never been studied systematically. Therefore, this study was to preliminarily decipher the pharmacological activities and mechanisms of the essential oil in leaves of C. grandis 'Tomentosa' by an integrated network pharmacology approach. METHODS: Essential oil compositions from leaves ofC. grandis 'Tomentosa' were identified using GC-MS/MS. And then, the targets of these oil compositions were predicted and screened from TCMSP, SwissTargetPrediction, STITCH and SEA databases. STRING database was used to construct the protein-protein interaction networks, and the eligible protein targets were input into WebGestalt 2019 to carry out GO enrichment and KEGG pathway enrichment analysis. Based on the potential targets, disease enrichment information was obtained by TTD databases. Cytoscape software was used to construct the component-target-disease network diagrams. RESULTS: Finally, 61 essential oil chemical components were identified by GC-MS/MS, which correspond to 679 potential targets. Biological function analysis showed 12, 19, and 12 GO entries related to biological processes, cell components and molecular functions, respectively. 43 KEGG pathways were identified, of which the most significant categories were terpenoid backbone biosynthesis, TNF signaling pathway and leishmaniasis. The component-target-disease network diagram revealed that the essential oil compositions in leaves of C. grandis 'Tomentosa' could treat tumors, immune diseases, neurodegenerative diseases and respiratory diseases, which were highly related to CHRM1, PTGS2, CASP3, MAP2K1 and CDC25B. CONCLUSION: This study may provide new insight into C. grandis 'Tomentosa' or C. grandis (L.) Osbeck and may provide useful information for future utilization and development.

Recent advances in natural polysaccharides-based controlled release nanosystems for anti-cancer phototherapy.

Phototherapy, which relies on light to trigger phototherapeutic agents (PAs) to generate cytotoxic reactive oxygen species or hyperthermia, has received much attention in cancer treatment. However, traditional PAs have shortcomings such as low water solubility, easy aggregation-induced fluorescence quenching and low target site accumulation efficiency, which severely limit clinical anticancer applications. Naturally derived polysaccharides have attracted great attention in the scientific community in nano-drug delivery systems (NDDS) due to their abundant resources, biocompatibility, targeting ability, bioactivity and so on, which is expected to assist PAs to play a synergistic effect. This article reviews the recent progress of polysaccharides in the field of cancer phototherapy, including the advantages of polysaccharides as nanocarrier materials to deliver PAs; the main mechanism for the preparation of PAs-loaded polysaccharides nanoformulation; construction of polysaccharides-based NDDS for delivery of PAs and its functional modification strategy, hoping to further improve the therapeutic effect of phototherapy against cancer.

Supplementation of mitochondria from endometrial mesenchymal stem cells improves oocyte quality in aged mice.

Maternal ageing is one of the major causes of reduced ovarian reserve and low oocyte quality in elderly women. Decreased oocyte quality is the main cause of age-related infertility. Mitochondria are multifunctional energy stations that determine the oocyte quality. The mitochondria in aged oocytes display functional impairments with mtDNA damage, which leads to reduced competence and developmental potential of oocytes. To improve oocyte quality, mitochondrial supplementation is carried out as a potential therapeutic approach. However, the selection of suitable cells as the source of mitochondria remains controversial. We cultivated endometrial mesenchymal stem cells (EnMSCs) from aged mice and extracted mitochondria from EnMSCs. To improve the quality of oocytes, GV oocytes were supplemented with mitochondria via microinjection. And MII oocytes from aged mice were fertilized by intracytoplasmic sperm injection (ICSI), combining EnMSCs' mitochondrial microinjection. In this study, we found that the mitochondria derived from EnMSCs could significantly improve the quality of aged oocytes. Supplementation with EnMSC mitochondria significantly increased the blastocyst ratio of MII oocytes from aged mice after ICSI. We also found that the birth rate of mitochondria-injected ageing oocytes was significantly increased after embryo transplantation. Our study demonstrates that supplementation with EnMSC-derived mitochondria can improve the quality of oocytes and promote embryo development in ageing mice, which might provide a prospective strategy for clinical treatment.

Resource Utilization of Red Mud from the Solid Waste of Aluminum Industry Used in Geothermal Wells.

It is difficult for the commonly used Class G oil well cement to withstand the high-temperature environment of geothermal wells, and it is easy to deteriorate the mechanical properties and damage the integrity of the cement sheath. Industrial solid waste red mud can be used as supplementary cementing materials (SCMs) to improve its mechanical properties at high temperatures. In addition, compared to Class G oil well cement, high belite cement (HBC) has lower energy consumption and better mechanical properties at high temperatures. In this study, the mechanical properties of HBC as a gel material and quartz sand and red mud as SCMs were studied at high temperatures. The ratio of HBC to SCMs and the ratio of quartz sand to red mud in SCMs were optimized using the response surface method (RSM). The response surface was established using the three-level factorial design model, which fit well with the experimental data. The optimization results show that the best mass ratio of SCMs/HBC is 37.5% and that the best quality ratio of quartz sand/red mud is 9 under the curing conditions of 180 °C. However, the best mass ratio of SCMs/HBC is 49.3%, and the best quality ratio of quartz sand/red mud is 7 under 220 °C. With the addition of SCMs, the silicon-to-calcium ratio of HBC hydration products decreases, and high-temperature-stable xonotlite and tobermorite can be formed. After adding SCMs, the cement sample is denser without obvious cracks.