[Research and development strategy of new traditional Chinese medicine drugs for syndromes based on human use experience].

Chinese drug registration laws and regulations have always reserved a place for the new traditional Chinese medicine(TCM) drugs for syndromes, but so far no such new drugs have been approved for registration. This paper expounded on the relevant policies, regulations, and technologies of new TCM drugs for syndromes in China and pointed out that the application of the animal model of TCM syndromes to carry out pharmacodynamics research and clinical efficacy evaluation criteria of TCM syndromes were the main technical difficulties in the research and development of new TCM drugs for syndromes. Not all syndromes are suitable for developing new drugs, and the indications for new TCM drugs should be constant syndromes. Among the three research and development models of simple syndrome, syndrome-unified disease, and combined disease and syndrome, the research and development model of combined disease and syndrome is recommended. Clinical positioning is the key to new TCM drugs for syndromes. It is encouraged to conduct high-quality human use experience studies to determine the clinical positioning of new TCM drugs for syndromes, as well as the target population, dose, course of treatment, and initial therapeutic and safety, and apply for exemption from non-clinical effectiveness studies. Clinical trials of new TCM drugs for syndromes should take the target symptoms or signs as the main efficacy index and the efficacy of TCM syndromes as the secondary efficacy index. Clinical research program design should implement the "patient-centered" concept and introduce clinical outcome evaluation indicators. In the clinical safety evaluation, special conditions such as characteristic syndromes and changes should be considered. With the construction of the human use experience technology system and the promotion of the TCM registration and evaluation evidence system featuring the "combination of TCM theory, human use experience, and clinical trials", it is believed that many high-quality new TCM drugs for syndromes will be developed in the future.

[Pharmaceutical changes and countermeasures for transformation of traditional Chinese medicine preparations in medical institutions into new drugs based on human use experience].

Traditional Chinese medicine(TCM) preparations in medical institutions, as a unique and important form of preparations in China, have a long history of human use and serve as a bridge between clinical experience prescriptions and new Chinese medicine preparations. The state encourages medical institutions to transform their preparations into new traditional Chinese medicines, emphasizing their role as "incubators". Since the proposal of the traditional Chinese medicine registration and evaluation evidence system with the integration of TCM theory, human use experience(HUE), and clinical experience, the idea of transforming preparations used in medical institutions into new drugs based on HUE has been increasingly valued by drug research and development organizations. In the transformation process, pharmaceutical changes should be concerned from multiple aspects. This paper discusses the pharmaceutical changes and countermeasures based on the transformation of traditional Chinese medicine preparations in medical institutions into new drugs based on HUE from the aspects of excipients, dosage forms, production technology, production scale, packaging materials and containers, production sites, and registration standards. It is emphasized that scientific decisions should be made according to the characteristics and clinical needs of drugs to ensure the stability of drug quality. The impacts of pharmaceutical changes on drug quality should be objectively assessed based on appropriate evaluation indexes and detection methods. The layout should be carried out in advance, and the key pharmaceutical information of the preparations should be kept stable, so as to underpin the transformation of traditional Chinese medicine preparations in medical institutions into new drugs based on HUE.

Oxidation of Biogenic U(IV) in the Presence of Bioreduced Clay Minerals and Organic Ligands.

Bioreduction of soluble U(VI) to sparingly soluble U(IV) is proposed as an effective approach to remediating uranium contamination. However, the stability of biogenic U(IV) in natural environments remains unclear. We conducted U(IV) reoxidation experiments following U(VI) bioreduction in the presence of ubiquitous clay minerals and organic ligands. Bioreduced Fe-rich nontronite (rNAu-2) and Fe-poor montmorillonite (rSWy-2) enhanced U(IV) oxidation through shuttling electrons between oxygen and U(IV). Ethylenediaminetetraacetic acid (EDTA), citrate, and siderophore desferrioxamine B (DFOB) promoted U(IV) oxidation via complexation with U(IV). In the presence of both rNAu-2 and EDTA, the rate of U(IV) oxidation was between those in the presence of rNAu-2 and EDTA, due to a clay/ligand-induced change of U(IV) speciation. However, the rate of U(IV) oxidation in other combinations of reduced clay and ligands was higher than their individual ones because both promoted U(IV) oxidation. Unexpectedly, the copresence of rNAu-2/rSWy-2 and DFOB inhibited U(IV) oxidation, possibly due to (1) blockage of the electron transport pathway by DFOB, (2) inability of DFOB-complexed Fe(III) to oxidize U(IV), and (3) stability of the U(IV)-DFOB complex in the clay interlayers. These findings provide novel insights into the stability of U(IV) in the environment and have important implications for the remediation of uranium contamination.

Prevention of the Lachnum polysaccharide and its selenium derivatives on cisplatin-induced acute kidney injury in mice.

To investigate the renal protective effects of the polysaccharide LEP-1a and derivatives of selenium (SeLEP-1a) from Lachnum YM38, cisplatin (CP) was used to establish an acute kidney model. LEP-1a and SeLEP-1a could effectively reverse the decrease in renal index and improved renal oxidative stress. LEP-1a and SeLEP-1a significantly reduced the contents of the inflammatory cytokines. They could inhibit the release of cyclooxygenase 2 (COX-2) and nitric oxide synthase (iNOS) and increase the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1). At the same time, the PCR results indicated that SeLEP-1a could significantly inhibit the mRNA expression levels of toll-like receptor 4 (TLR4), nuclear factor-kB (NF-κB) p65 and inhibitor of kappa B-alpha (IκBα). Western blot analysis showed that LEP-1a and SeLEP-1a significantly downregulated the expression levels of Bcl-2-associated X protein (Bax) and cleaved caspase-3 and upregulated phosphatidylinositol 3-kinase (p-PI3K), protein kinase B (p-Akt) and B-cell lymphoma 2 (Bcl-2) protein expression levels in the kidney. LEP-1a and SeLEP-1a could improve CP-induced acute kidney injury by regulating the oxidative stress response, NF-κB-mediated inflammation and the PI3K/Akt-mediated apoptosis signalling pathway.

Ameliorative effect of anisodamine (654-1/654-2) against myocardial dysfunction induced by septic shock via the NF-κB/NLRP-3 or the PI3K-AKT/NF-κB pathway.

BACKGROUND: Septic shock, an extremely dangerous condition that causes impairment of organ function, always largely contributes to mortality in intensive care units. The impact of septic shock-induced organ damage on morbidity and mortality is substantially influenced by myocardial dysfunction. However, it remains unclear whether and in what manner anisodamine (654-1/654-2) ameliorates myocardial dysfunction caused by septic shock. PURPOSE: This study is the pioneering investigation and validation about the protective efficacy of anisodamine (654-1/654-2) against LPS-induced myocardial dysfunction in septic shock rats. It also aims to explore the differences in the underlying molecular mechanisms of both drugs. METHODS: A septic shock model was established in SD rats by after tail vein administration of LPS. 64 rats were distributed into eight groups, such as LPS group, control group, LPS+654-1 group (1.25, 2.5, and 5 mg/kg), and LPS+654-2 group (1.25, 2.5, and 5 mg/kg). The hemodynamics, echocardiography, immunohistochemical analysis, TEM, TUNEL assay, and H&E staining were utilized to assess the septic shock model and myocardial function. Lactic acid, inflammatory markers (IL-1ß, IL-6, and TNF-α), endothelial injure markers (SDC-1, HS and TM) and myocardial injury markers (CK, c-TNT and NT-pro BNP) were assessed using ELISA or biochemical kits. Additionally, the mechanisms of 654-1/654-2 were analyzed using RNA-seq and bioinformatics, and validated using western blotting and RT-PCR. RESULTS: Administration of 654-1/654-2 significantly restored hemodynamics and improved myocardial and endothelial glycocalyx injury in septic shock rats. Furthermore, 654-1/654-2 dose-dependently reduced plasma levels of lactic acid, inflammatory cytokines, and markers of endothelial and myocardial injury. Analyses using RNA-seq, WB and RT-PCR techniques indicated that 654-1/654-2 could mitigate myocardial and endothelial injury by inhibiting the NF-κB and NLRP-3 pathways, and activating the PI3K-AKT pathway. CONCLUSIONS: These findings demonstrated that 654-1/654-2 could alleviate myocardial damage in septic shock rats. Specifically, 654-1 inhibited the NF-κB/NLRP-3 pathway, whereas 654-2 promoted the PI3K-AKT pathway and inhibited the NF-κB pathway, effectively mitigating the inflammatory response and cell apoptosis.

Chloroplast genome of Justicia procumbens: genomic features, comparative analysis, and phylogenetic relationships among Justicieae species.

Justicia procumbens L. is a traditional medicinal plant that is widely distributed in China. However, little is known about the genetic diversity and evolution of this genus, and no genomic studies have been carried out on J. procumbens previously. In this study, we aimed to assemble and annotate the first complete chloroplast genome (cpDNA) of J. procumbens and compare it with all previously published cpDNAs within the tribe Justicieae. Genome structure and comparative and phylogenetic analyses were performed. The 150,454 bp-long J. procumbens cpDNA has a circular and quadripartite structure consisting of a large single copy, a small single copy, and two inverted repeat regions. It contains 133 genes, of which 88 are protein-coding genes, 37 are tRNA genes, and eight are rRNA genes. Twenty-four simple sequence repeats (SSRs) and 81 repeat sequences were identified. Comparative analyses with other Justicieae species revealed that the non-coding regions of J. procumbens cpDNA showed greater variation than did the coding regions. Moreover, phylogenetic analysis based on 14 cpDNA sequences from Justicieae species showed that J. procumbens and J. flava were most closely related. This study provides valuable genetic information to support further research on the genetic diversity and evolutionary development of the tribe Justicieae.

Dormancy release of seeds of Podophyllum hexandrum Royle accompanied by changes in phytochemicals and inorganic elements.

Podophyllum hexandrum Royle is an alpine medicinal plant of considerable importance, and its seed dormancy severely inhibits population renewal. Although cold stratification can break dormancy to a certain extent, the migration and accumulation of phytochemicals and inorganic elements in the seeds during dormancy release and their functions remain unclear. Changes in phytochemicals and inorganic elements in different seed parts were analyzed during dormancy. The key differential phytochemicals and inorganic elements were screened and their association with dormancy release and their roles in dormancy release were explored. The results showed that dormancy release may have occurred following the decrease in palmitic acid and linoleic acid content in the seeds and the increase in 2,3-dihydro-3,5-dihydro-6-methyl-4 (h)-pyran-4-one content in the endosperm. Meanwhile, 6-propyltridecane and hexadecane in the seed coat may enhance the water permeability of seeds to speed up germination. Mg may migrate from the seed coat to the endosperm and seed embryos, whereas Co may migrate from the seed embryo to the seed coat. Ca, Mn, Mg, and Co are involved in various physiological metabolic processes, which may facilitate the dormancy release of P. hexandrum seeds. These findings have enhanced our understanding of the mechanisms of dormancy release in P. hexandrum seeds and can serve as a reference for the development of more effective dormancy-breaking techniques for the conservation of this endangered medicinal plant.

Genetically predicted plasma levels of amino acids and metabolic dysfunction-associated fatty liver disease risk: a Mendelian randomization study.

BACKGROUND: Emerging metabolomics-based studies suggested links between amino acid metabolism and metabolic dysfunction-associated fatty liver disease (MAFLD) risk; however, whether there exists an aetiological role of amino acid metabolism in MAFLD development remains unknown. The aim of the present study was to assess the causal relationship between circulating levels of amino acids and MAFLD risk. METHODS: We conducted a two-sample Mendelian randomization (MR) analysis using summary-level data from genome-wide association studies (GWAS) to evaluate the causal relationship between genetically predicted circulating levels of amino acids and the risk of MAFLD. In the discovery MR analysis, we used data from the largest MAFLD GWAS (8434 cases and 770,180 controls), while in the replication MR analysis, we used data from a GWAS on MAFLD (1483 cases and 17,781 controls) where MAFLD cases were diagnosed using liver biopsy. We used Wald ratios or inverse variance-weighted (IVW) methods in the MR main analysis and weighted median and MR-Egger regression analyses in sensitivity analyses. Furthermore, we performed a conservative MR analysis by restricting genetic instruments to those directly involved in amino acid metabolism pathways. RESULTS: We found that genetically predicted higher alanine (OR = 1.43, 95% CI 1.13-1.81) and lower glutamine (OR = 0.83, 95% CI 0.73-0.96) levels were associated with a higher risk of developing MAFLD based on the results from the MR main and conservative analysis. The results from MR sensitivity analyses and complementary analysis using liver proton density fat fraction as a continuous outcome proxying for MAFLD supported the main findings. CONCLUSIONS: Novel causal metabolites related to MAFLD development were uncovered through MR analysis, suggesting future potential for evaluating these metabolites as targets for MAFLD prevention or treatment.

Targeting endothelial cells with golden spice curcumin: A promising therapy for cardiometabolic multimorbidity.

Cardiometabolic multimorbidity (CMM) is an increasingly significant global public health concern. It encompasses the coexistence of multiple cardiometabolic diseases, including hypertension, stroke, heart disease, atherosclerosis, and T2DM. A crucial component to the development of CMM is the disruption of endothelial homeostasis. Therefore, therapies targeting endothelial cells through multi-targeted and multi-pathway approaches hold promise for preventing and treatment of CMM. Curcumin, a widely used dietary supplement derived from the golden spice Carcuma longa, has demonstrated remarkable potential in treatment of CMM through its interaction with endothelial cells. Numerous studies have identified various molecular targets of curcumin (such as NF-κB/PI3K/AKT, MAPK/NF-κB/IL-1ß, HO-1, NOs, VEGF, ICAM-1 and ROS). These findings highlight the efficacy of curcumin as a therapeutic agent against CMM through the regulation of endothelial function. It is worth noting that there is a close relationship between the progression of CMM and endothelial damage, characterized by oxidative stress, inflammation, abnormal NO bioavailability and cell adhesion. This paper provides a comprehensive review of curcumin, including its availability, pharmacokinetics, pharmaceutics, and therapeutic application in treatment of CMM, as well as the challenges and future prospects for its clinical translation. In summary, curcumin shows promise as a potential treatment option for CMM, particularly due to its ability to target endothelial cells. It represents a novel and natural lead compound that may offer significant therapeutic benefits in the management of CMM.

Identifying the Potential of miRNAs in Houttuynia cordata-Derived Exosome-Like Nanoparticles Against Respiratory RNA Viruses.

Introduction: Pathogenic respiratory RNA viruses, including influenza A virus (IAV), respiratory syncytial virus (RSV), and SARS-CoV-2, are major causes of causes of acute respiratory infection globally. Plant-derived exosome-like nanoparticles containing miRNAs have shown substantial cross-kingdom regulatory effects on both viral and human transcripts. Houttuynia cordata (H. cordata), a traditional Chinese medicine frequently used to treat respiratory diseases. However, the role of H. cordata-derived exosome-like nanoparticles (HELNs) and the miRNA they encapsulated are unclear. Methods: HELNs were isolated from fresh underground roots (uHELNs) and above ground stems and leaves (aHELNs) using differential centrifugation. The HELNs were identified using transmission electron microscopy, nanoparticle tracking analysis, and zeta potential. Small RNA sequencing and RT-PCR were employed to determine the miRNA expression in uHELNs and aHELNs. All genomes were sourced from the NCBI database. Target prediction of viral genomes was performed using RNAhybrid, while human target prediction was conducted using both RNAhybrid and Miranda. Functional enrichment analysis was applied to the predicted human targets to explore the hub targets and their roles in antiviral effects. The accessibility of miRNA target sites was determined through the MFOLD web server, and customized dual-luciferase reporter assays were administered to validate the computational findings. Results: A total of 12 highly enriched miRNAs were identified in both uHELNs and aHELNs. Upon prediction and verification, miR858a and miR858b were shown to target the NP gene in H1N1, while miR166a-3p targeted the ORF1ab in SARS-CoV-2. However, no valid miRNA targets were found for RSV. Regarding human transcripts, miR168a-3p, miR168b-3p, and miR8175 were found to inhibit MAPK3 expression, and novel_mir2 could suppress both AKT1 and MAPK3 expression. Discussion: This study sheds light on the collaborative antiviral mechanism of miRNAs in HELNs across two species and explores the potential antiviral scopes of both H. cordata miRNAs and HELNs.

Alpinia katsumadai Hayata Volatile Oil Is Effective in Treating 5-Fluorouracil-Induced Mucositis by Regulating Gut Microbiota and Modulating the GC/GR Pathway and the mPGES-1/PGE2/EP4 Pathways.

This study was aimed to investigate the therapeutic effect and mechanism of AKHO on 5-fluorouracil (5-FU)-induced intestinal mucositis in mice. Mouse body weight, diarrhea score, and H&E staining were applied to judge the therapeutic effect of AKHO. 16S rDNA and nontargeted metabolomics have been used to study the mechanism. WB, ELISA, and immunohistochemistry were adopted to validate possible mechanisms. The results demonstrated that AKHO significantly reduced diarrhea scores and intestinal damage induced by 5-FU in mice. AKHO lowered the serum levels of LD and DAO, and upregulated the expressions of ZO-1 and occludin in the ileum. Also, AKHO upregulated the abundance of Lactobacillus in the gut and suppressed KEGG pathways such as cortisol synthesis and secretion and arachidonic acid metabolism. Further validation studies indicated that AKHO downregulated the expressions of prostaglandin E2 (PGE2), microsomal prostaglandin E synthase-1 (mPGES-1), and PGE2 receptor EP4, as well as upregulated the expression of glucocorticoid (GC) receptor (GR), leading to improved intestinal epithelial barrier function. Taken together, AKHO elicited protective effects against 5-FU-induced mucositis by regulating the expressions of tight junction proteins via modulation of GC/GR and mPGES-1/PGE2/EP4 pathway, providing novel insights into the utilization and development of this pharmaceutical/food resource.

Cascade catalysis-coordinated nanorobots toward synergistic cancer chemoimmunotherapy.

Cancer has always been the biggest threat to human health, but the effect of traditional treatments such as surgery, chemotherapy, and radiotherapy is not satisfactory. Currently, nanomedicine-based chemoimmunotherapy can improve clinical results through unique synergistic effects. However, it is mainly enriched at tumor sites based on EPR effects, without an active delivery strategy and relatively low tumor targeting distribution. Therefore, nanorobots (Cu@MPS-GOD) with magnetic responsiveness and enzyme-like activity were prepared, which can enrich and move to the tumor site under the action of a 3D magnetic field, and cause tumor cell immunogenic death by cascade catalytic Fenton reactions. Meanwhile, Cu@MPS-GOD can also activate immune cells or induce cancer cells to expose surface antigens, trigger systemic anti-cancer immunity, and have a good inhibitory effect on a breast tumor model in mice with an inhibition rate of 59.3%. This work provides an attractive strategy to expand the therapeutic effect of cancer when chemical dynamic therapy is combined with immunotherapy, which has a potential clinical application prospect.

First report of leaf spot caused by Botrytis cinerea on Bletilla striata in Anhui province, China.

Bletilla striata (Thunb.) is a perennial herb plant of the orchidaceous family and is used as an ornamental plant in Europe and the United States. Furthermore, it is important as traditional Chinese medicine (TCM) in East Asian countries, such as China, Japan, Korea, Mongolia, and Myanmar (Gou et al. 2022). In April 2023, a severe disease similar to gray mold occurred in a B. striata plantation in Anqing, Anhui province, China (N30°27'15″, E116°18'32″), causing disease on about 20% of the plants in the field. Early symptoms were characterized by brown spots or stripes on the leaves of B. striata, and as the disease progressed, large brown irregular spots appeared. Eventually disease spots coalesced, covering the entire leaf surface and causing leaf death. A gray mildew layer was observed on the senescent leaves. To investigate the causal agent, 10 plants with typical symptoms were collected from the field. Leaf pieces (5 × 5 mm) from the border of infected areas were soaked in 75% ethanol for 10 seconds, and then transferred into 0.1% mercury bichloride for three min, rinsed three times with sterile water, and transferred to PDA at 25 °C for three days. Pure cultures were obtained by single spore isolation, and the resulting colonies were morphologically similar, indicating a single pathogen, of which the representative BSFC-7 was selected for further study. BSFC-7 colonies were initially white to gray-brown, and cottony aerial hyphae grew over the entire petri dish after five days of incubation. Grayish, branched conidiophores and their terminal unicellular conidia were observed under a microscope after additional two days at 25 °C. Conidia were colorless or gray, elliptical or oval, and 7.06-12.54 × 8.33-13.55 µm (n=30). Sclerotia appeared in BSFC-7 culture up to about two weeks and were black, hard, and round or irregularly shaped (0.81-4.32 × 0.97-5.68 mm, n=20). The morphological characteristics fit the description of Botrytis cinerea (Li et al. 2016). To further identify the species, genomic DNA of BSFC-7 was extracted. PCR analysis was performed with species-specific primer pairs C729+/C729- and two nuclear genes G3PDH and RPB2 with their corresponding primer pairs G3PDH-F/G3PDH-R and RPB2-F/RPB2-R (Rigotti et al. 2002; Aktaruzzaman et al. 2018). The sequences for all three PCR products of C729, G3PDH, and RPB2 (GenBank accession nos. OR287069, OR255923, and OR255924 respectively) exhibited 99 to 100% similarity with other B. cinerea isolates. In the pathogenicity test, detached leaves of B. striata were inoculated with the BSFC-7 isolate. The leaves were soaked in sodium hypochlorite (1%) for two min, washed with sterile distilled water, and then inoculated with 10 µl of conidial suspension (106 conidia/ml). Sterile water was used as control and samples were incubated at 25 °C. After three days, all leaves inoculated with conidia showed dark brown water-soaked lesions similar to those observed in the field, while the control leaves remained healthy. The pathogen was re-isolated from the affected leaves, fulfilling Koch's postulates. B. cinerea is a common pathogen on a wide range of host plant species worldwide and has been reported to infect B. striata in Yunnan province, China (Romanazzi and Feliziani 2014; Zhang et al. 2020). To our knowledge, this is the first report of B. cinerea causing leaf spots on B. striata in Anhui province, China. This study will provide a basis for controlling the prevalence and economic losses of gray mold on B. striata.

[Antidepressant mechanism of Shenling Kaixin Granules based on BDNF/TrkB/CREB pathway].

To investigate the antidepressant mechanism of Shenling Kaixin Granules(SLKX) in treating chronic unpredictable mild stress(CUMS) model rats. Ninety male SD rats were randomly divided into control group, model group, Shugan Jieyu Capsules(110 mg·kg~(-1)) group and SLKX low-(90 mg·kg~(-1)), medium-(180 mg·kg~(-1)), and high-dose(360 mg·kg~(-1)) groups. Depression rat model was replicated by CUMS method. After treatment, the behavioral changes of rats were evaluated by sugar preference, open field, elevated cross maze and forced swimming experiments. The contents of interleukin 1 beta(IL-1ß), tumor necrosis factor α(TNF-α), brain-derived neurotrophic factor(BDNF) and 5-hydroxytryptamine(5-HT) in serum were determined by enzyme linked immunosorbent assay(ELISA), and the activities of superoxide dismutase(SOD) and catalase(CAT) in hippocampal CA1 region were also detected. Pathological changes in hippocampal CA1 region were detected by hematoxylin-eosin(HE) staining, and Western blot was used to determine the expression of nerve growth factor(NGF), BDNF, phospho-tyrosine kinase receptor(p-TrkB)/TrkB, phospho-cAMP-response element binding protein(p-CREB)/CREB, nuclear factor E2 related factor 2(Nrf2), heme oxygenase 1(HO-1), B-cell lymphoma-2(Bcl-2)/Bcl-2 associated X protein(Bax) and caspase-3 in hippocampal CA1 region. RESULTS:: showed that compared with the control group, the model group had decreased sugar preference, reduced number of entries and time spent in the center of open field and shortened total distance of movement, reduced number of entries and proportion of time spent in open arm, and increased number and time of immobility in forced swimming experiment. Additionally, the serum contents of IL-1ß and TNF-α and the expression of caspase-3 were higher, while the contents of BDNF and 5-HT, the activities of SOD and CAT in hippocampal CA1 region, the expressions of NGF, BDNF, p-TrkB/TrkB, p-CREB/CREB, HO-1 and Bcl-2/Bax, and the Nrf2 nuclear translocation were lower in model group than in control group. Compared with the conditions in model group, the sugar preference, the number of entries and time spent in the center of open, total distance of movement, and the number of entries and proportion of time spent in open arm in treatment groups were increased while the number and time of immobility in forced swimming experiment were decreased; the serum contents of IL-1ß and TNF-α and the expression of caspase-3 were down regulated, while the contents of BDNF and 5-HT, the activities of SOD and CAT in hippocampal CA1 region, the expressions of NGF, BDNF, p-TrkB/TrkB, p-CREB/CREB, HO-1, Bcl-2/Bax, and Nrf2 nuclear translocation were enhanced. In conclusion, SLKX might regulate the Nrf2 nucleus translocation by activating BDNF/TrkB/CREB pathway, lower oxidative stress damage in hippocampus, inhibit caspase-3 activity, and reduce apoptosis of hippocampal nerve cells, thereby playing an antidepressant role.

[Neuroprotective effect of ginsenoside Re on drosophila model of Parkinson's disease].

This study aims to explore the neuroprotective mechanism of ginsenoside Re(GS-Re) on drosophila model of Parkinson's disease(PD) induced by rotenone(Rot). To be specific, Rot was used to induce PD in drosophilas. Then the drosophilas were grouped and respectively treated(GS-Re: 0.1, 0.4, 1.6 mmol·L~(-1); L-dopa: 80 µmol·L~(-1)). Life span and crawling ability of drosophilas were determined. The brain antioxidant activity [content of catalase(CAT), malondialdehyde(MDA), reactive oxygen species(ROS), superoxide dismutase(SOD)], dopamine(DA) content, and mitochondrial function [content of adenosine triphosphate(ATP), NADH:ubiquinone oxidoreductase subunit B8(NDUFB8) Ⅰ activity, succinate dehydrogenase complex, subunit B(SDHB) Ⅱ activity] were detected by enzyme-linked immunosorbent assay(ELISA). The number of DA neurons in the brains of drosophilas was measured with the immunofluorescence method. The levels of NDUFB8 Ⅰ, SDHB Ⅱ, cytochrome C(Cyt C), nuclear factor-E2-related factor 2(Nrf2), heme oxygenase-1(HO-1), B-cell lymphoma/leukemia 2(Bcl-2)/Bcl-2-assaciated X protein(Bax), and cleaved caspase-3/caspase-3 in the brain were detected by Western blot. The results showed that model group [475 µmol·L~(-1) Rot(IC_(50))] demonstrated significantly low survival rate, obvious dyskinesia, small number of neurons and low DA content in the brain, high ROS level and MDA content, low content of SOD and CAT, significantly low ATP content, NDUFB8 Ⅰ activity, and SDHB Ⅱ activity, significantly low expression of NDUFB8 Ⅰ, SDHB Ⅱ, and Bcl-2/Bax, large amount of Cyt C released from mitochondria to cytoplasm, low nuclear transfer of Nrf2, and significantly high expression of cleaved caspase-3/caspase-3 compared with the control group. GS-Re(0.1, 0.4, and 1.6 mmol·L~(-1)) significantly improved the survival rate of PD drosophilas, alleviated the dyskinesia, increased DA content, reduced the loss of DA neurons, ROS level, and MDA content in brain, improved content of SOD and CAT and antioxidant activity in brain, maintained mitochondrial homeostasis(significantly increased ATP content and activity of NDUFB8 Ⅰ and SDHB Ⅱ, significantly up-regulated expression of NDUFB8 Ⅰ, SDHB Ⅱ, and Bcl-2/Bax), significantly reduced the expression of Cyt C, increased the nuclear transfer of Nrf2, and down-regulated the expression of cleaved caspase-3/caspase-3. In conclusion, GS-Re can significantly relieve the Rot-induced cerebral neurotoxicity in drosophilas. The mechanism may be that GS-Re activates Keap1-Nrf2-ARE signaling pathway by maintaining mitochondrial homeostasis, improves antioxidant capacity of brain neurons, then inhibits mitochondria-mediated caspase-3 signaling pathway, and the apoptosis of neuronal cells, thereby exerting the neuroprotective effect.

Fructus gardeniae ameliorates anxiety-like behaviors induced by sleep deprivation via regulating hippocampal metabolomics and gut microbiota.

Fructus gardeniae (FG) is a traditional Chinese medicine and health food for thousands of years of application throughout Chinese history and is still widely used in clinical Chinese medicine. FG has a beneficial impact on anxiety, depression, insomnia, and psychiatric disorders; however, its mechanism of action requires further investigation. This study aimed to investigate the effects and mechanisms of FG on sleep deprivation (SD)-induced anxiety-like behavior in rats. A model of SD-induced anxiety-like behavior in rats was established by intraperitoneal injection of p-chlorophenylalanine (PCPA). This was accompanied by neuroinflammation and metabolic abnormalities in the hippocampus and disturbance of intestinal microbiota. However reduced SD-induced anxiety-like behavior and decreased levels of pro-inflammatory cytokines including TNF-α and IL-1ß were observed in the hippocampus of rats after 7 days of FG intervention. In addition, metabolomic analysis demonstrated that FG was able to modulate levels of phosphatidylserine 18, Phosphatidylinositol 18, sn-glycero-3-phosphocholine, deoxyguanylic acid, xylose, betaine and other metabolites in the hippocampus. The main metabolic pathways of hippocampal metabolites after FG intervention involve carbon metabolism, glycolysis/gluconeogenesis, pentose phosphate, and glycerophospholipid metabolism. 16S rRNA sequencing illustrated that FG ameliorated the dysbiosis of gut microbiota in anxious rats, mainly increased the abundance of Muribaculaceae and Lactobacillus, and decreased the abundance of Lachnospiraceae_NK4A136_group. In addition, the correlation analysis demonstrated that there was a close relationship between hippocampal metabolites and intestinal microbiota. In conclusion, FG improved the anxiety behavior and inhibited of neuroinflammation in sleep-deprived rats, and the mechanism may be related to the FG regulation of hippocampal metabolites and intestinal microflora composition.

Examining individual-level tri-exposure to greenspace and air/noise pollution using individual-level GPS-based real-time sensing data.

OBJECTIVE: Although exposure to air/noise pollution and greenspace has been found to significantly affect people's physical and mental health outcomes, there is still a lack of knowledge on what built-environment and socioeconomic factors are significantly associated with people's tri-exposure to air/noise pollution and greenspace. This study analyzes the associations between built-environment and socioeconomic factors and the tri-exposure to greenspace and air/noise pollution in Hong Kong. METHOD: Based on individual-level activity data, real-time GPS trajectories, and exposure data collected by portable sensors as well as remote sensing satellite imagery, we employ multinomial logistic regression to determine the socioeconomic and built-environment factors that are significantly associated with the type of participants' tri-exposure at the grid cell level. RESULTS: The results show that higher transit nodal accessibility, building density, building height and land-use mix are significantly associated with a higher likelihood of being disadvantaged in terms of tri-exposure to air/noise pollution and greenspace. While more advantageous tri-exposures are significantly related to higher median monthly household income and sky view factor. CONCLUSION: Old high-rise high-density neighborhoods are more likely to be triply disadvantaged with low greenspace exposure but high air pollution and noise pollution exposure. The findings provide policymakers with critical reference in terms of addressing the inequalities in the tri-exposure outcomes.

Intelligent Jellyfish-type Janus Nanoreactor Targeting Synergistic Treatment of Bacterial Infections.

Infections caused by multidrug-resistant bacteria continue to pose a serious threat to human health, and therefore it is important to explore the availability of antimicrobial drugs and modalities. Herein, jellyfish-type irregular mesoporous iron oxide nanoreactors containing ciprofloxacin, Janus Fe3O4@mSiO2@Cip nanoparticles (JFmS@Cip NPs), were developed for pH-responsive synergistic antimicrobial therapy in a microacidic environment. Compared with the use of symmetric nanocarriers, the asymmetric decoration on both sides of the particles allows different components to act on bacteria, Fe3O4 NPs have good magnetic and peroxidase-like catalytic activity, and the antibiotic ciprofloxacin can kill bacteria efficiently. Notably, due to the synergistic effect between different components of Janus particles, in vitro antibacterial experiments showed that JFmS@Cip NPs can kill bacteria efficiently at low concentrations, reaching an antibacterial rate of 99.6%. JFmS@Cip NPs combine multiple antibacterial properties that can be used to improve the therapeutic efficacy of current nanomedicines against drug-resistant bacteria.

A Novel Targeted RIG-I Receptor 5'Triphosphate Double Strain RNA-Based Adjuvant Significantly Improves the Immunogenicity of the SARS-CoV-2 Delta-Omicron Chimeric RBD-Dimer Recombinant Protein Vaccine.

The rapid mutation and spread of SARS-CoV-2 variants recently, especially through the emerging variants Omicron BA5, BF7, XBB and BQ1, necessitate the development of universal vaccines to provide broad spectrum protection against variants. For the SARS-CoV-2 universal recombinant protein vaccines, an effective approach is necessary to design broad-spectrum antigens and combine them with novel adjuvants that can induce high immunogenicity. In this study, we designed a novel targeted retinoic acid-inducible gene-I (RIG-I) receptor 5'triphosphate double strain RNA (5'PPP dsRNA)-based vaccine adjuvant (named AT149) and combined it with the SARS-CoV-2 Delta and Omicron chimeric RBD-dimer recombinant protein (D-O RBD) to immunize mice. The results showed that AT149 activated the P65 NF-κB signaling pathway, which subsequently activated the interferon signal pathway by targeting the RIG-I receptor. The D-O RBD + AT149 and D-O RBD + aluminum hydroxide adjuvant (Al) + AT149 groups showed elevated levels of neutralizing antibodies against the authentic Delta variant, and Omicron subvariants, BA1, BA5, and BF7, pseudovirus BQ1.1, and XBB compared with D-O RBD + Al and D-O RBD + Al + CpG7909/Poly (I:C) groups at 14 d after the second immunization, respectively. In addition, D-O RBD + AT149 and D-O RBD + Al + AT149 groups presented higher levels of the T-cell-secreted IFN-γ immune response. Overall, we designed a novel targeted RIG-I receptor 5'PPP dsRNA-based vaccine adjuvant to significantly improve the immunogenicity and broad spectrum of the SARS-CoV-2 recombinant protein vaccine.

Thermographic evaluation of acupoints in lower limb region of individuals with osteoarthritis: A cross-sectional case-control study protocol.

PURPOSE: Acupuncture has been widely used in the treatment of knee osteoarthritis (KOA), but the selection of acupoints is indeterminate and lacks biological basis. The skin temperature of acupoints can reflect the state of local tissue and may be a potential factor for guiding acupoint selection. This study aims to compare the skin temperature of acupoints between KOA patients and the healthy population. STUDY DESIGN AND METHODS: This is a protocol for a cross-sectional case-control study with 170 KOA patients and 170 age- and gender-matched healthy individuals. Diagnosed patients aged 45 to 70 will be recruited in the KOA group. Participants in the healthy group will be matched with the KOA group based on mean age and gender distribution. Skin temperature of 11 acupoints (ST35, EX-LE5, GB33, GB34, EX-LE2, ST34, ST36, GB39, BL40, SP9, SP10) will be extracted from infrared thermography (IRT) images of the lower limbs. Other measurements will include demographic data (gender, age, ethnicity, education, height, weight, BMI) and disease-related data (numerical rating scale, pain sites, duration of pain, pain descriptors, pain activities). DISCUSSION: The results of this study will provide biological evidence for acupoint selection. This study is a precondition for follow-up studies, in which the value of optimized acupoint selection will be verified. TRIAL REGISTRATION: ChiCTR2200058867.