A homoleptic Fe(iv) ketimide complex with a low-lying excited state.

The reaction of 4 equiv. of Li(N[double bond, length as m-dash]C( t Bu)Ph) with FeIICl2 results in isolation of [Li(Et2O)]2[FeII(N[double bond, length as m-dash]C( t Bu)Ph)4] (1), in good yields. The reaction of 1 with 1 equiv. of I2 leads to formation of [FeIV(N[double bond, length as m-dash]C( t Bu)Ph)4] (2), in moderate yields. 57Fe Mössbauer spectroscopy confirms the Fe(iv) oxidation state of 2, and X-ray crystallography reveals that 2 has a square planar coordination geometry along with several intramolecular H⋯C interactions. Furthermore, SQUID magnetometry indicates a small magnetic moment at room temperature, suggestive of an accessible S = 1 state. Both density functional theory and multiconfigurational calculations were done to elucidate the nature of the ground state. Consistent with the experimental results, the ground state was found to be an S = 0 state with an S = 1 excited state close in energy.

Influence of Chemical Structures on E-Beam Lithography Performance of Polysilsesquioxanes.

Hydrogenated silsesquioxane (HSQ) is a key inorganic electron beam resist, celebrated for its sub-10 nm resolution and etching resistance, but it faces challenges with stability and sensitivity. Our innovative study has comprehensively assessed the lithographic performance of three functionalized polysilsesquioxane (PSQ) resist series─olefins, halogenated alkanes, and alkanes─under electron beam lithography (EBL). We discovered that the addition of olefin groups, such as in the HMP-30 formulation with 30% propyl acrylate, remarkably increased the sensitivity to 0.6 µC/cm2. The inclusion of halogenated aromatic and hydrogen-substituted methyl groups further enhanced sensitivity and contrast, with HClBN-50 achieving a 22.9 nm resolution pattern. At the same time, the storage of PSQ resists was significantly improved compared to commercial HSQ with increasing alkane group content. Crucially, our research has unveiled the lithography reaction mechanism, highlighting how group encapsulation and steric hindrance influence PSQ performance. This insight is groundbreaking, offering a deeper understanding of the molecular structure-performance relationship and laying the groundwork for developing next-generation electron beam resists with superior sensitivity, resolution, and contrast for microelectronics manufacturing.

Efficacy of sexual stimulation in the treatment of distal ureteral stones: A meta-analysis.

Introduction: This study aimed to compare the clinical efficacy of sexual stimulation with that of placebo in the treatment of distal ureteral stones. Methods: We searched PubMed, Web of Science, Cochrane Library, and Google Scholar from January 1, 2000 to December 31, 2022 for studies comparing the efficacy of sexual stimulus with that of placebo for the treatment of distal ureteral stones. RevMan 5.3 software was used to pool the data. The study protocol was registered on PROSPERO (Registration Number: CRD42023432408). Results: A total of six randomized controlled trials comprising 535 cases of distal ureteral stones were included in this study. Among these, 273 cases were associated with sexual intercourse or masturbation 3-4 times a week, while 262 cases only received symptomatic treatment. The pooled results showed that the 2-week [risk ratios (RR) = 1.77, 95 % confidence interval (CI): 1.34, 2.33] and 4-week [RR = 1.48, 95 % CI: 1.29, 1.69] ureteral stone expulsion rates of the sexually stimulated group were significantly higher than those of the placebo group (ps < 0.01). Additionally, sexual stimulation was associated with a shorter ureteral stone expulsion time [weighted mean differences (WMD) = -3.74, 95 % CI: -6.27, -1.22, p < 0.01] and a decreased prevalence of renal colic attacks [WMD = -0.61, 95 % CI: -1.01, -0.22, p < 0.01] compared with those of the placebo group. Conclusion: Appropriate sexual stimulation can enhance the spontaneous expulsion of distal ureteral stones in patients presenting with tolerable pain.

Eudesmane-type sesquiterpenoids: Structural diversity and biological activity.

Sesquiterpenoids are integral constituents of terpenoid-bearing plants, comprising a diverse and abundant class of natural compounds, among which eudesmane-type sesquiterpenoids have bicyclic structures that feature the fusion of two six-membered carbon rings, thereby attracting considerable attention. They are widespread in nature, with multifaceted biological activities such as anti-inflammatory, anticancer, antimicrobial, antimalarial, and insecticidal activities, thus gaining focus in life science research. The discovery and identification of these active compounds have laid a foundation for unraveling their potential medicinal value. In this review, we comprehensively explore the natural eudesmane-type sesquiterpenoids isolated (totaling 391 compounds) between 2016 and 2022, elucidating their chemical structures, plant distribution patterns, and pertinent biological properties. Accordingly, the study serves not only as a framework for researchers to thoroughly comprehend these compounds but also as a robust reference for future endeavors aimed at exploring the pharmaceutical potential and prospective applications of these molecules.

Associations of Blood Cadmium Levels With Osteoarthritis Among US Adults in NHANES 2013-2018.

BACKGROUND: Osteoarthritis (OA) is a global public health problem, and limited information is available on the effects of Cd on OA. The purpose of this study is to explore the relationship between Cd and OA. METHOD: Weighted multivariable logistic regression model, trend test, restricted cubic spline, and stratified analysis were used to study the association between BCd and OA. RESULTS: In the two regression models of weighted multivariable logistic regression analysis, the correlation between BCd and OA was positive. Compared with the lowest quartile of BCd exposure, the highest quartile had a 2.03-fold (95% confidence interval, 1.67 to 2.47), displaying a dose-response relationship (P for trend <0.00001). The restrictive cubic spline shows a positive linear relationship between BCd and OA. CONCLUSION: There was a positive linear relationship between BCd and OA and a dose-response relationship.

Evolution, classification, structure, and functional diversification of steroid 5α-reductase family in eukaryotes.

Steroid 5α-reductase1/2 (SRD5A1/2) is an androgen protein that resembles the plant DET2 and is responsible for the conversion of testosterone to the more active dihydrotestosterone (DHT). Both proteins share functional homology and have a common ancestor. In mammals, the SRD5A1/2 can reduce a wide range of steroid substrates, such as testosterone, progesterone, and aldosterone, by reducing the Δ4 in ring A. The plant DET2 catalyzes the conversion of campesterol (CR) to campestanol (CN) by reducing the Δ5 in ring B during brassinosteroid (BRs) biosynthesis. We compared the evolution, structural, and functional homology of the SRD5A family and tried to identify the origin and functional diversification of duplicated genes in eukaryotes. We presented a detailed phylogeny that includes representative species from all eukaryotic groups. Our study indicated that protist is a common ancestor for all the subgroups of the SRD5A family. However, not all protists possess SRD5A1/2/DET2 or other homologs, suggesting that some protists may have lost these gene families during evolution. Lineage-specific duplication leads Caenorhabditis elegance to have three SRD5A1/2 genes but none was found in Drosophila melanogaster. We also identified a new subclass, DET2-like (DET2L), in plants that closely resemble SRD5A1/2/DET2. The hypothesized reductase DET2L showed no phenotypic enhancement when expressed in Arabidopsis det 2 mutants, suggesting its possible role in the reduction of polyprenol or other substrates.

Taohong Siwu decoction alleviates cognitive impairment by suppressing endoplasmic reticulum stress and apoptosis signaling pathway in vascular dementia rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Taohong Siwu Decoction (TSD), a classic traditional Chinese medicine formula, is used for the treatment of vascular diseases, including vascular dementia (VD). However, the mechanisms remain unclear. AIM OF STUDY: This study aimed to investigate whether TSD has a positive effect on cognitive impairment in VD rats and to confirm that the mechanism of action is related to the Endoplasmic Reticulum stress (ERs) and cell apoptosis signaling pathway. MATERIALS AND METHODS: A total of 40 male adult Sprague-Dawley rats were divided into four groups: sham-operated group (Sham), the two-vessel occlusion group (2VO), the 2VO treated with 4.5 g/kg/d TSD group (2VO + TSD-L), the 2VO treated with 13.5 g/kg/d TSD group (2VO + TSD-H). The rats underwent either 2VO surgery or sham surgery. Postoperative TSD treatment was given for 4 consecutive weeks. Behavioral tests were initiated at the end of gastrulation. Open-field test (OFT) was used to detect the activity level. The New Object Recognition test (NOR) was used to test long-term memory. The Morris water maze (MWM) test was used to examine the foundation of spatial learning and memory. As a final step, the hippocampus was taken for molecular testing. The protein levels of GRP78 (Bip), p-PERK, PERK, IRE1α, p-IRE1α, ATF6, eIF2α, p-eIF2α, ATF4, XBP1, Bcl-2 and Bax were determined by Western blot. Immunofluorescence visualizes molecular expression. RESULTS: In the OFT, residence time in the central area was significantly longer in both TSD treatment groups compared to the 2VO group. In the NOR, the recognition index was obviously elevated in both TSD treatment groups. The 2VO group had a significantly longer escape latency and fewer times in crossing the location of the platform compared with the Sham group in MWM. TSD treatment reversed this notion. Pathologically, staining observations confirmed that TSD inhibited hippocampal neuronal loss and alleviated the abnormal reduction of the Nissl body. In parallel, TUNEL staining illustrated that TSD decelerated neuronal apoptosis. Western Blot demonstrated that TSD reduces the expression of ERs and apoptotic proteins. CONCLUSION: In this study, the significant ameliorative effect on cognitive impairment of TSD has been determined by comparing the behavioral data of the 4 groups of rats. Furthermore, it was confirmed that this effect of TSD was achieved by suppressing the ERs-mediated apoptosis signaling pathway.

Title: Bona Fide Plant Steroid Receptors Are Innovated in Seed Plants and Angiosperms through Successive Whole Genome Duplication Events.

Whole genome duplication (WGD) events are widespread in plants and animals, thus their long-term evolutionary contribution has long been speculated, yet a specific contribution is difficult to verify. Here, we show that ɛ-WGD and ζ-WGD contribute to the origin and evolution of bona fide brassinosteroid (BR) signaling through the innovation of active BR biosynthetic enzymes and active BR receptors from their respective ancestors. We found that BR receptors BRI1 (BR Insensitive 1) and BRL1/3 (BRI1-likes 1/3) derived by ɛ-WGD and ζ-WGD, which occurred in the common ancestor of angiosperms and seed plants, respectively, while orphan BR receptor BRL2 first appeared in stomatophytes. Additionally, CYP85A enzymes synthesizing the bioactive BRs derived from a common ancestor of seed plants while its sister enzymes CYP90 synthesizing BR precursors presented in all land plants, implying possible ligand-receptor coevolution. Consistently, the island domains (IDs) responsible for BR perception in BR receptors were most divergent among different receptor branches, supporting ligand-driven evolution. As a result, BRI1 was the most diversified BR receptor in angiosperms. Importantly, relative to the BR biosynthetic DET2 gene presented in all land plants, BRL2, BRL1/3 and BRI1 had high expression in vascular plants ferns, gymnosperms and angiosperms, respectively. Notably, BRI1 is the most diversified BR receptor with the most abundant expression in angiosperms, suggesting potential positive selection. Therefore, WGDs initiate a neofunctionalization process diverged by ligand-perception and transcriptional expression, which might optimize both BR biosynthetic enzymes and BR receptors, likely contributing to the evolution of land plants, especially seed plants and angiosperms.

The role of FERMT2 in the tumor microenvironment and immunotherapy in pan-cancer using comprehensive single-cell and bulk sequencing.

FERMT2 has been identified as a participant in integrin-linked kinase signaling pathways, influencing epithelial-mesenchymal transition and thereby affecting tumor initiation, progression, and invasion. While the character of FERMT2 in the tumor microenvironment (TME) as well as its implications for immunotherapy remain unclear. Thus, we conducted a comprehensive analysis to assess the prognostic significance of FERMT2 using Kaplan-Meier analysis. In addition, we employed enrichment analysis to uncover potential underlying molecular mechanisms. Using "Immunedeconv" package, we evaluated the immune characteristics of FERMT2 within TME. Furthermore, we determined the expression levels of FERMT2 in various cell types within TME, based on single-cell sequencing data. To confirm the co-expression of FERMT2 and markers of cancer-associated fibroblasts (CAFs), we performed multiplex immunofluorescence staining on tissue paraffin sections across various cancer types. Our analysis disclosed a significant correlation between elevated FERMT2 expression and unfavorable prognosis in specific cancer types. Furthermore, we identified a strong correlation between FERMT2 expression and diverse immune-related factors, including immune checkpoint molecules, immune cell infiltration, microsatellite instability (MSI), and tumor mutational burden (TMB). Additionally, there was a significant correlation between FERMT2 expression and immune-related pathways, particularly those associated with activating, migrating, and promoting the growth of fibroblasts in diverse cancer types. Interestingly, we observed consistent co-expression of FERMT2 in both malignant tumor cells and stromal cells, particularly within CAFs. Notably, our findings also indicated that FERMT2, in particular, exhibited elevated expression levels within tumor tissues and co-expressed with α-SMA in CAFs based on the multiplex immunofluorescence staining results.

Clarification of the infection pattern of Xanthomonas citri subsp. citri on citrus fruit by artificial inoculation.

BACKGROUND: Citrus canker is a significant bacterial disease caused by Xanthomonas citri subsp. citri (Xcc) that severely impedes the healthy development of the citrus industry. Especially when citrus fruit is infected by Xcc, it will reduce or even lost its commercial value. However, due to the prolonged fruiting cycle and intricate structure, much less research progress had been made in canker disease on fruit than on leaf. In fact, limited understanding has been achieved on canker development and the response to Xcc infection in fruit. RESULTS: Herein, the progression of canker disease on sweet orange fruit was tracked in the field. Results indicated that typical lesions initially appear on the sepal, style residue, nectary disk, epicarp, and peduncle of young fruits after petal fall. The susceptibility of fruits to Xcc infection diminished as the fruit developed, with no new lesions forming at the ripening stage. The establishment of an efficient method for inoculating Xcc on fruit as well as the artificial inoculation throughout the fruit's developmental cycle clarified this infection pattern. Additionally, microscopic observations during the infection process revealed that Xcc invasion caused structural changes on the surface and cross-section of the fruit. CONCLUSIONS: An efficient system for inoculation on citrus fruit with Xcc was established, by which it can serve for the evaluation of citrus germplasm for canker disease resistance and systematic research on the interactions between Xcc and citrus fruits.

Aqueous Developable and CO2-Sourced Chemical Amplification Photoresist with High Performance.

Seeking high-performance photoresists is an important item for semiconductor industry due to the continuous miniaturization and intelligentization of integrated circuits. Polymer resin containing carbonate group has many desirable properties, such as high transmittance, acid sensitivity and chemical formulation, thus serving as promising photoresist material. In this work, a series of aqueous developable CO2-sourced polycarbonates (CO2-PCs) were produced via alternating copolymerization of CO2 and epoxides bearing acid-cleavable cyclic acetal groups in the presence of tetranuclear organoborane catalyst. The produced CO2-PCs were investigated as chemical amplification resists in deep ultraviolet (DUV) lithography. Under the catalysis of photogenerated acid, the acetal (ketal) groups in CO2-PC were hydrolysed into two equivalents of hydroxyl groups, which change the exposed area from hydrophobicity to hydrophilicity, thus enabling the exposed area to be developed with water. Through normalized remaining thickness analysis, the optimal CO2-derived resist achieved a remarkable sensitivity of 1.9 mJ/cm2, a contrast of 7.9, a favorable resolution (750 nm, half pitch), and a good etch resistance (38 % higher than poly(tert-butyl acrylate)). Such performances outperform commercial KrF and ArF chemical amplification resists (i.e., polyhydroxystyrene-derived and polymethacrylate-based resists), which endows broad application prospects in the field of DUV (KrF and ArF) and extreme ultraviolet (EUV) lithography for nanomanufacturing.

Probiotics combined with atorvastatin administration in the treatment of hyperlipidemia: A randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Hyperlipidemia is a common feature of chronic diseases. The aim of this work was designed to assess the role of probiotics (Lactobacillus casei Zhang, Bifidobactetium animalis subsp. lactis V9, and Lactobacillus plantarum P-8) in the treatment of hyperlipidemia. METHODS: Thirty three patients with hyperlipidemia were randomly divided into a probiotic group (n = 18) and a control group (n = 15). The probiotic group was administered probiotics (2 g once daily) and atorvastatin 20 mg (once daily), and the control group was administered a placebo (2 g once daily) and atorvastatin 20 mg (once daily). Serum and fecal samples were gathered for subsequent analyses. RESULTS: Time had a significant effect on the total cholesterol (TC), triglycerides (TG), and low-density lipoprotein-cholesterol (LDL-C) levels in the probiotic and control groups (P < .05). The gut microbial abundance in the probiotic group was markedly higher than that in the control group following 3-month probiotic treatment (P < .05). At the phylum level, probiotics exerted no notable effects on the relative abundance of Firmicutes, Bacteroidetes, and Actinobacteria but elevated that of Tenericutes and reduced Proteobacteria. At the genus level, probiotics increased the relative abundance of Bifidobacterium, Lactobacillus, and Akkermansia, and decreased that of Escherichia, Eggerthella, and Sutterella relative to the control group in months 1, 2, and 3 (P < .05). CONCLUSIONS: Probiotics optimize the gut microbiota structure and decrease the amount of harmful bacteria in patients with hyperlipidemia. Probiotics can influence the composition of gut microorganisms and increase their diversity and abundance in vivo. It is recommended to use probiotics combined with atorvastatin to treat patients with hyperlipidemia.

Insights into the Distinct Behaviors between Bifunctional and Binary Organoborane Catalysts through Terpolymerization of Epoxide, CO2, and Anhydride.

Alkyl borane compounds-mediated polymerizations have expanded to Lewis pair polymerization, free radical polymerization, ionic ring-opening polymerization, and polyhomologation. The bifunctional organoborane catalysts that contain the Lewis acid and ammonium or phosphonium salt in one molecule have demonstrated superior catalytic performance for ring-opening polymerization of epoxides and ring-opening copolymerization of epoxides and CO2 than their two-component analogues, i.e., the blend of organoborane and ammonium or phosphonium salt. To explore the origin of the differences of the one-component and two-component organoborane catalysts, here we conducted a systematic investigation on the catalytic performances of these two kinds of organoborane catalysts via terpolymerization of epoxide, carbon dioxide and anhydride. The resultant terpolymers produced independently by bifunctional and binary organoborane catalyst exhibited distinct microstructures, where a series of gradient polyester-polycarbonate terpolymers with varying polyester content were afforded using the bifunctional catalyst, while tapering diblock terpolymers were obtained using the binary system. The bifunctional catalyst enhances the competitiveness of CO2 insertion than anhydride, which leads to the premature incorporation of CO2 into the polymer chains and ultimately results in the formation of gradient terpolymers. DFT calculations revealed the role of electrostatic interaction and charge distribution caused by intramolecular synergistic effect for bifunctional organoborane catalyst.

Progress on the relationship between tumor suppressor PDCD4 and diseases based on the analysis of structural characteristics.

The tumor suppressor programmed cell death 4 (PDCD4) is downregulated in various tumor tissues indicating poor prognosis. PDCD4 is the first protein found to resist tumor transformation, invasion, and metastasis by inhibiting translation. The functions of PDCD4 dependent on its structures are affected by extracellular signals. It regulates tumor-related proteins through a variety of mechanisms, especially involved in two major signaling pathways, PI3K-Akt-mTOR and MAPK. By analyzing the relationship between the structures, functions and diseases of PDCD4, this review summarizes the roles of PDCD4 in several physiological processes and diseases such as apoptosis, autophagy, tumor, and inflammation in recent years, thereby providing insights for the study of the signaling pathways of PDCD4 and related proteins and the treatment of diseases targeting them.

Prelimbic cortex-nucleus accumbens core projection positively regulates itch and itch-related aversion.

Itch is one of the most common clinical symptoms in patients with diseases of the skin, liver, or kidney, and it strongly triggers aversive emotion and scratching behavior. Previous studies have confirmed the role of the prelimbic cortex (Prl) and the nucleus accumbens core (NAcC), which are reward and motivation regulatory centers, in the regulation of itch. However, it is currently unclear whether the Prl-NAcC projection, an important pathway connecting these two brain regions, is involved in the regulation of itch and its associated negative emotions. In this study, rat models of acute neck and cheek itch were established by subcutaneous injection of 5-HT, compound 48/80, or chloroquine. Immunofluorescence experiments determined that the number of c-Fos-immunopositive neurons in the Prl increased during acute itch. Chemogenetic inhibition of Prl glutamatergic neurons or Prl-NAcC glutamatergic projections can inhibit both histaminergic and nonhistaminergic itch-scratching behaviors and rectify the itch-related conditioned place aversion (CPA) behavior associated with nonhistaminergic itch. The Prl-NAcC projection may play an important role in the positive regulation of itch-scratching behavior by mediating the negative emotions related to itch.

KCTD5 regulates Ikaros degradation induced by chemotherapeutic drug etoposide in hematological cells.

Therapy-related leukemia carries a poor prognosis, and leukemia after chemotherapy is a growing risk in clinic, whose mechanism is still not well understood. Ikaros transcription factor is an important regulator in hematopoietic cells development and differentiation. In the absence of Ikaros, lymphoid cell differentiation is blocked at an extremely early stage, and myeloid cell differentiation is also significantly affected. In this work, we showed that chemotherapeutic drug etoposide reduced the protein levels of several isoforms of Ikaros including IK1, IK2 and IK4, but not IK6 or IK7, by accelerating protein degradation, in leukemic cells. To investigate the molecular mechanism of Ikaros degradation induced by etoposide, immunoprecipitation coupled with LC-MS/MS analysis was conducted to identify changes in protein interaction with Ikaros before and after etoposide treatment, which uncovered KCTD5 protein. Our further study demonstrates that KCTD5 is the key stabilizing factor of Ikaros and chemotherapeutic drug etoposide induces Ikaros protein degradation through decreasing the interaction of Ikaros with KCTD5. These results suggest that etoposide may induce leukemic transformation by downregulating Ikaros via KCTD5, and our work may provide insights to attenuate the negative impact of chemotherapy on hematopoiesis.

[Human Accumulation and Toxic Effects of Microplastics：A Critical Review].

The effect of microplastics on the ecological environment and human health has become a topical issue， and research on the risks and harmful effects of MPs on human health in particular has attracted widespread attention. Due to the characteristics of small size， low degradability， and easy migration， MPs continuously migrate from the environment to the human body， and their main exposure pathways are oral ingestion， inhalation， and dermal contact， with the main exposure media being food， drinking water， dust， personal care products， etc. MPs have been detected in organs， fluids， and excreta of digestive， respiratory， cardiovascular， reproductive systems， etc. The abundance range of MPs in the human body is 0-1 206.94 particles per gram. After entering the human body， MPs can cause cytotoxicity， mitochondrial toxicity， DNA damage， cell membrane damage， and other effects on human cells and organs， leading to serious consequences such as local inflammation， ecological imbalance， metabolic disorders， etc.， in various systems. Owing to their small specific surface area， they can also adsorb pollutants such as heavy metals， organic pollutants， antibiotics， pathogens， and harmful microorganisms， causing combined toxicity and immunotoxicity. In the end， we highlighted general deficiencies in existing studies and provided directions for future research on the influence of MPs on human health.

Analysis of disulfidptosis- and cuproptosis-related LncRNAs in modulating the immune microenvironment and chemosensitivity in colon adenocarcinoma.

The main objective was to establish a prognostic model utilising long non-coding RNAs associated with disulfidptosis and cuproptosis. The data for RNA-Sequence and clinicopathological information of Colon adenocarcinoma (COAD) were acquired from The Cancer Genome Atlas. A prognostic model was constructed using Cox regression and the Least Absolute Shrinkage and Selection Operator method. The model's predictive ability was assessed through principal component analysis, Kaplan-Meier analysis, nomogram etc. The ability of identifying the rates of overall survival, infiltration of immune cells, and chemosensitivity was also explored. In vitro experiments were conducted for the validation of differential expression and function of lncRNAs. A disulfidptosis and cuproptosis-related lncRNA prognostic model was constructed. The prognostic model exhibits excellent independent predictive capability for patient outcomes. Based on the authors' model, the high-risk group exhibited higher tumour mutation burdened worse survival. Besides, differences in immune cell infiltration and responsiveness to chemotherapeutic medications exist among patients with different risk scores. Furthermore, aberrant expressions in certain lncRNAs have been validated in HCT116 cells. In particular, FENDRR and SNHG7 could affect the proliferation and migration of colorectal cancer cells. Our study developed a novel prognostic signature, providing valuable insights into prognosis, immune infiltration, and chemosensitivity in COAD patients.

8-shogaol derived from dietary ginger alleviated acute and inflammatory pain by targeting TRPV1.

Ginger, a well-known spice plant, has been used widely in medicinal preparations for pain relief. However, little is known about its analgesic components and the underlying mechanism. Here, we ascertained, the efficacy of ginger ingredient 8-Shogaol (8S), on inflammatory pain and tolerance induced by morphine, and probed the role of TRPV1 in its analgesic action using genetic and electrophysiology approaches. Results showed that 8S effectively reduced nociceptive behaviors of mice elicited by chemical stimuli, noxious heat as well as inflammation, and antagonized morphine analgesic tolerance independent on opioid receptor function. Genetic deletion of TRPV1 significantly abolished 8S' analgesia action. Further calcium imaging and patch-clamp recording showed that 8S could specifically activate TRPV1 in TRPV1-expressing HEK293T cells and dorsal root ganglion (DRG) neurons. The increase of [Ca2+]i in DRG was primarily mediated through TRPV1. Mutational and computation studies revealed the key binding sites for the interactions between 8S and TRPV1 included Leu515, Leu670, Ile573, Phe587, Tyr511, and Phe591. Further studies showed that TRPV1 activation evoked by 8S resulted in channel desensitization both in vitro and in vivo, as may be attributed to TRPV1 degradation or TRPV1 withdrawal from the cell surface. Collectively, this work provides the first evidence for the attractive analgesia of 8S in inflammatory pain and morphine analgesic tolerance mediated by targeting pain-sensing TRPV1 channel. 8S from dietary ginger has potential as a candidate drug for the treatment of inflammatory pain.

Dibutyl phthalate (DBP) promotes Epithelial-Mesenchymal Transition (EMT) to aggravate liver fibrosis into cirrhosis and portal hypertension (PHT) via ROS/TGF-ß1/Snail-1 signalling pathway in adult rats.

OBJECTIVE: The primary objective of this study was to investigate the toxicological impact of Dibutyl phthalate (DBP) on the process of liver fibrosis transitioning into cirrhosis and the subsequent development of portal hypertension (PHT) through the mechanism of epithelial-mesenchymal transition (EMT) mediated by the ROS/TGF-ß/Snail-1 signaling pathway. METHOD: Carbon tetrachloride (CCl4) (1 mg/kg) was introduced in adult rats by oral feeding in CCl4 and CCl4+DBP groups twice a week for 8 weeks, and twice for another 8 week in CCl4 group. DBP was introduced by oral feeding in the CCl4+DBP group twice over the following 8 weeks. We subsequently analyzed hemodynamics measurements and liver cirrhosis degree, hepatic inflammation and liver function in the different groups. EMT related genes expression in rats in the groups of Control, DBP, CCl4 and CCl4+DBP were measured by immunohistochemistry (IHC). Enzyme-linked immunosorbent Assay (ELISA), qRT-PCR, western blot were used to detect the EMT related proteins and mRNA gene expression levels in rats and primary hepatocytes (PHCs). Reactive oxygen species (ROS) were examined with a ROS detection kit. RESULTS: The results showed that the CCl4+DBP group had higher portal pressure (PP) and lower mean arterial pressure (MAP) than the other groups. Elevated collagen deposition, profibrotic factor, inflammation, EMT levels were detected in DBP and CCl4+DBP groups. ROS, TGF-ß1 and Snail-1 were highly expressed after DBP exposure in vitro. TGF-ß1 had the potential to regulate Snail-1, and both of them were subject to regulation by ROS. CONCLUSION: DBP could influence the progression of EMT through its toxicological effect by ROS/TGF-ß1/Snail-1 signalling pathway, causing cirrhosis and PHT in final. The findings of this research might contribute to a novel comprehension of the underlying toxicological mechanisms and animal model involved in the progression of cirrhosis and PHT, and potentially offered a promising therapeutic target for the treatment of the disease.