The EPRS-ATF4-COLI pathway axis is a potential target for anaplastic thyroid carcinoma therapy.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is recognized as the most aggressive and malignant form of thyroid cancer, underscoring the critical need for effective therapeutic strategies to curb its progression and improve patient prognosis. Halofuginone (HF), a derivative of febrifugine, has displayed antitumor properties across various cancer types. However, there is a paucity of published research focused on the potential of HF to enhance the clinical efficacy of treating ATC. OBJECTIVE: In this study, we thoroughly investigated the antitumor effects and mechanisms of HF in ATC, aiming to discover lead compounds for treating ATC and reveal novel therapeutic targets for ATC tumors. METHODS: A series of assays, including CCK8, colony formation, tumor xenograft models, and ATC tumor organoid experiments, were conducted to evaluate the anticancer properties of HF both in vitro and in vivo. Techniques such as drug affinity responsive target stability (DARTS), western blot, immunofluorescence, and immunohistochemistry were employed to pinpoint HF target proteins within ATC. Furthermore, we harnessed the GEPIA and GEO databases and performed immunohistochemistry to validate the therapeutic potential of the glutamyl-prolyl-tRNA-synthetase (EPRS)- activating transcription factor 4 (ATF4)- type I collagen (COLI) pathway axis in the context of ATC. The study also incorporated RNA sequencing analysis, confocal imaging, and flow cytometry to delve into the molecular mechanisms of HF in ATC. RESULTS: HF exhibited a substantial inhibitory impact on cell proliferation in vitro and on tumor growth in vivo. The DARTS results highlighted HF's influence on EPRS within ATC cells, triggering an amino acid starvation response (AASR) by suppressing EPRS expression, consequently leading to a reduction in COLI expression in ATC cells. The introduction of proline mitigated the effect of HF on ATF4 and COLI expression, indicating that the EPRS-ATF4-COLI pathway axis was a focal target of HF in ATC. Analysis of the expression levels of the EPRS, ATF4, and COLI proteins in thyroid tumors, along with an examination of the relationship between COLI expression and thyroid tumor stage, revealed that HF significantly inhibited the growth of ATC tumor organoids, demonstrating the therapeutic potential of targeting the EPRS-ATF4-COLI pathway axis in ATC. RNA sequencing analysis revealed significant differences in the pathways associated with metastasis and apoptosis between control and HF-treated cells. Transwell assays and flow cytometry experiments provided evidence of the capacity of HF to impede cell migration and induce apoptosis in ATC cells. Furthermore, HF hindered cell metastasis by suppressing the epithelial-mesenchymal transition (EMT) pathway, acting through the inhibition of FAK-AKT-NF-κB/Wnt-ß-catenin signaling and restraining angiogenesis via the VEGF pathway. HF also promoted apoptosis through the mitochondrial apoptotic pathway. CONCLUSION: This study provided inaugural evidence suggesting that HF could emerge as a promising therapeutic agent for the treatment of ATC. The EPRS-ATF4-COLI pathway axis stood out as a prospective biomarker and therapeutic target for ATC.

Novel Isoalantolactone-Based Derivatives as Potent NLRP3 Inflammasome Inhibitors: Design, Synthesis, and Biological Characterization.

The NLRP3 inflammasome has been recognized as a promising therapeutic target in drug discovery for inflammatory diseases. Our initial research identified a natural sesquiterpene isoalantolactone (IAL) as the active scaffold targeting NLRP3 inflammasome. To improve its activity and metabolic stability, a total of 64 IAL derivatives were designed and synthesized. Among them, compound 49 emerged as the optimal lead, displaying the most potent inhibitory efficacy on nigericin-induced IL-1ß release in THP-1 cells, with an IC50 value of 0.29 µM, approximately 27-fold more potent than that of IAL (IC50: 7.86 µM), and exhibiting higher metabolic stability. Importantly, 49 remarkably improved DSS-induced ulcerative colitis in vivo. Mechanistically, we demonstrated that 49 covalently bound to cysteine 279 in the NACHT domain of NLRP3, thereby inhibiting the assembly and activation of NLRP3 inflammasome. These results provided compelling evidence to further advance the development of more potent NLRP3 inhibitors based on this scaffold.

Causal effect of gut microbiota of Defluviitaleaceae on the clinical pathway of "Influenza-Subacute Thyroiditis-Hypothyroidism".

Introduction: Hypothyroidism has been found to be influenced by gut microbiota. However, it remains unclear which a taxon of gut microbiota plays a key role in this function. Identifying the key bacteria affects hypothyroidism and through what mechanism will be helpful for the prevention of hypothyroidism through specific clinical pathways. Materials and methods: In Study A, 35 families and 130 genera of gut microbiota are used as exposures, with hypothyroidism as the outcome. The causal effect of the gut microbiota on hypothyroidism is estimated through two-sample Mendelian randomization. Combining the results of the two taxonomical levels, key taxa are selected, which in Study B are investigated for their causal association with multiple generally admitted causes of hypothyroidism and their more upstream factors. For validating and revealing the potential mechanism, enrichment analyses of the related genes and interacting transcription factors were performed. Results: In Study A, Defluviitaleaceae (OR: 0.043, 95% CI: 0.005-0.363, P = 0.018)/Defluviitaleaceae_UCG_011 (OR: 0.385, 95% CI: 0.172-0.865, P = 0.021) are significantly causally associated with hypothyroidism at both taxonomical levels. In Study B, Defluviitaleaceae family and Defluviitaleaceae_UCG_011 genus show the causal association with decreased thyroiditis (Family: OR: 0.174, 95% CI: 0.046-0.653, P = 0.029; Genus: OR: 0.139, 95% CI: 0.029-0.664, P = 0.043), decreased subacute thyroiditis (Family: OR: 0.028, 95% CI: 0.004-0.213, P = 0.007; Genus: OR: 0.018, 95% CI: 0.002-0.194, P = 0.013), decreased influenza (Family: OR: 0.818, 95% CI: 0.676-0.989, P = 0.038; Genus: OR: 0.792, 95% CI: 0.644-0.974, P = 0.027), and increased anti-influenza H3N2 IgG levels (Family: OR: 1.934, 95% CI: 1.123-3.332, P = 0.017; Genus: OR: 1.675, 95% CI: 0.953-2.943, P = 0.073). The results of the enrichment analysis are consistent with the findings and the suggested possible mechanisms. Conclusion: Defluviitaleaceae of the gut microbiota displays the probability of causally inhibiting the clinical pathway of "Influenza-Subacute Thyroiditis-Hypothyroidism" and acts as the potential probiotics to prevent influenza, subacute thyroiditis, and hypothyroidism.

NU6300 covalently reacts with cysteine-191 of gasdermin D to block its cleavage and palmitoylation.

Gasdermin D (GSDMD) serves as a vital mediator of inflammasome-driven pyroptosis. In our study, we have identified NU6300 as a specific GSDMD inhibitor that covalently interacts with cysteine-191 of GSDMD, effectively blocking its cleavage while not affecting earlier steps such as ASC oligomerization and caspase-1 processing in AIM2- and NLRC4-mediated inflammation. On the contrary, NU6300 robustly inhibits these earlier steps in NLRP3 inflammasome, confirming a unique feedback inhibition effect in the NLRP3-GSDMD pathway upon GSDMD targeting. Our study reveals a previously undefined mechanism of GSDMD inhibitors: NU6300 impairs the palmitoylation of both full-length and N-terminal GSDMD, impeding the membrane localization and oligomerization of N-terminal GSDMD. In vivo studies further demonstrate the efficacy of NU6300 in ameliorating dextran sodium sulfate-induced colitis and improving survival in lipopolysaccharide-induced sepsis. Overall, these findings highlight the potential of NU6300 as a promising lead compound for the treatment of inflammatory diseases.

Genes in Axonal Regeneration.

This review explores the molecular and genetic underpinnings of axonal regeneration and functional recovery post-nerve injury, emphasizing its significance in reversing neurological deficits. It presents a systematic exploration of the roles of various genes in axonal regrowth across peripheral and central nerve injuries. Initially, it highlights genes and gene families critical for axonal growth and guidance, delving into their roles in regeneration. It then examines the regenerative microenvironment, focusing on the role of glial cells in neural repair through dedifferentiation, proliferation, and migration. The concept of "traumatic microenvironments" within the central nervous system (CNS) and peripheral nervous system (PNS) is discussed, noting their impact on regenerative capacities and their importance in therapeutic strategy development. Additionally, the review delves into axonal transport mechanisms essential for accurate growth and reinnervation, integrating insights from proteomics, genome-wide screenings, and gene editing advancements. Conclusively, it synthesizes these insights to offer a comprehensive understanding of axonal regeneration's molecular orchestration, aiming to inform effective nerve injury therapies and contribute to regenerative neuroscience.

Unveiling Gambogenic Acid as a Promising Antitumor Compound: A Review.

Gambogenic acid is a derivative of gambogic acid, a polyprenylated xanthone isolated from Garcinia hanburyi. Compared with the more widely studied gambogic acid, gambogenic acid has demonstrated advantages such as a more potent antitumor effect and less systemic toxicity than gambogic acid according to early investigations. Therefore, the present review summarizes the effectiveness and mechanisms of gambogenic acid in different cancers and highlights the mechanisms of action. In addition, drug delivery systems to improve the bioavailability of gambogenic acid and its pharmacokinetic profile are included. Gambogenic acid has been applied to treat a wide range of cancers, such as lung, liver, colorectal, breast, gastric, bladder, and prostate cancers. Gambogenic acid exerts its antitumor effects as a novel class of enhancer of zeste homolog 2 inhibitors. It prevents cancer cell proliferation by inducing apoptosis, ferroptosis, and necroptosis and controlling the cell cycle as well as autophagy. Gambogenic acid also hinders tumor cell invasion and metastasis by downregulating metastasis-related proteins. Moreover, gambogenic acid increases the sensitivity of cancer cells to chemotherapy and has shown effects on multidrug resistance in malignancy. This review adds insights for the prevention and treatment of cancers using gambogenic acid.

Exploring the Immunomodulatory Properties of Red Onion (Allium cepa L.) Skin: Isolation, Structural Elucidation, and Bioactivity Study of Novel Onion Chalcones Targeting the A2A Adenosine Receptor.

Onions are versatile and nutritious food widely used in various cuisines around the world. In our ongoing pursuit of bioactive substances with health benefits from red onion (Allium cepa L.) skin, a comprehensive chemical investigation was undertaken. Consequently, a total of 44 compounds, including three previously unidentified chalcones (1-3) were extracted from red onion skin. Of these isolates, chalcones 1-4 showed high affinity to A2A adenosine receptor (A2AAR), and chalcone 2 displayed the best binding affinity to A2AAR, with the IC50 value of 33.5 nM, good A2AAR selectivity against A1AR, A2BAR, and A3AR, and high potency in the cAMP functional assay (IC50 of 913.9 nM). Importantly, the IL-2 bioassay and the cell-mediated cytotoxicity assay demonstrated that chalcone 2 could boost T-cell activation. Furthermore, the binding mechanism of chalcone 2 with hA2AAR was elucidated by molecular docking. This work highlighted that the active chalcones in red onion might have the potential to be developed as A2AAR antagonists used in cancer immunotherapy.

Recent Progress and Prospects of Small Molecules for NLRP3 Inflammasome Inhibition.

NLRP3 inflammasome is a multiprotein complex involved in host immune response─which exerts various biological effects by mediating the maturation and secretion of IL-1ß and IL-18─and pyroptosis. However, its aberrant activation could cause amplification of inflammatory effects, thereby triggering a range of ailments, including Alzheimer's disease, Parkinson's disease, rheumatoid arthritis, gout, type 2 diabetes mellitus, and cancer. For the past few years, as an attractive anti-inflammatory target, NLRP3-targeting small-molecule inhibitors have been widely reported by both the academic and the industrial communities. In order to deeply understand the advancement of NLRP3 inflammasome inhibitors, we provide comprehensive insights and commentary on drugs currently under clinical investigation, as well as other NLRP3 inflammasome inhibitors from a chemical structure point of view, with an aim to provide new insights for the further development of clinical drugs for NLRP3 inflammasome-mediated diseases.

Discovery of Triazinone Derivatives as Novel, Specific, and Direct NLRP3 Inflammasome Inhibitors for the Treatment of DSS-Induced Ulcerative Colitis.

NLRP3 is an intracellular sensor protein that causes inflammasome formation and pyroptosis in response to a wide range of stimuli. Aberrant activation of NLRP3 inflammasome has been implicated in various chronic inflammatory diseases, making it a promising target for therapeutic intervention. In this work, a series of novel triazinone inhibitors of NLRP3 inflammasome were designed and synthesized. Compound L38 was identified for its excellent activity and acceptable metabolic stability among 41 compounds. Additionally, mechanism studies indicated that L38 inhibited NLRP3 inflammasome activation and pyroptosis by suppressing gasdermin D cleavage, ASC oligomerization, and NLRP3 inflammasome assembly while leaving mitochondrial ROS production, lysosome damage, and chloride/potassium efflux unaffected. Further investigation revealed that L38 could bind to the NACHT domain to exert inflammatory properties. Importantly, L38 exhibited positive therapeutic effects in DSS-induced ulcerative colitis mouse model. Taken together, this study presents a promising inhibitor of NLRP3 inflammasome deserving further investigation.

Diagnostic performance of ultrasound risk stratification systems on thyroid nodules cytologically classified as indeterminate: a systematic review and meta-analysis.

PURPOSE: Ultrasound (US) risk stratification systems (RSSs) are increasingly being utilized for the optimal management of thyroid nodules, including those with indeterminate cytology. The goal of this study was to evaluate the category-based diagnostic performance of US RSSs in identifying malignancy in indeterminate nodules. METHODS: This systematic review and meta-analysis was registered on PROSPERO (CRD42021266195). PubMed, EMBASE, and Web of Science were searched through December 1, 2022. Original articles reporting data on the performance of US RSSs for indeterminate nodules were included. The numbers of nodules classified as true negative, true positive, false negative, and false positive were extracted. RESULTS: Thirty-three studies evaluating 7,225 indeterminate thyroid nodules were included. The diagnostic accuracy was quantitatively synthesized using a Bayesian bivariate model based on the integrated nested Laplace approximation in R. For the intermediate- to high-risk category, the sensitivity levels of the American College of Radiology, the American Thyroid Association, the European Thyroid Association, the Korean Thyroid Association/Korean Society of Thyroid Radiology, and Kwak et al. were found to be 0.80, 0.72, 0.76, 0.96, and 0.97, respectively. The corresponding specificity measurements were 0.36, 0.50, 0.49, 0.28, and 0.17. Furthermore, for the high-risk category, the sensitivity values were 0.40, 0.46, 0.55, 0.47, and 0.10, while the specificity levels were 0.91, 0.90, 0.71, 0.91, and 0.99, respectively. CONCLUSION: The overall diagnostic performance of the US RSSs was moderate in the differentiation of indeterminate nodules.

Withaferin A: A Dietary Supplement with Promising Potential as an Anti-Tumor Therapeutic for Cancer Treatment - Pharmacology and Mechanisms.

Cancer, as the leading cause of death worldwide, poses a serious threat to human health, making the development of effective tumor treatments a significant challenge. Natural products continue to serve as crucial resources for drug discovery. Among them, Withaferin A (WA), the most active phytocompound extracted from the renowned dietary supplement Withania somnifera (L.) Dunal, exhibits remarkable anti-tumor efficacy. In this manuscript, we aim to comprehensively summarize the pharmacological characteristics of WA as a potential anti-tumor drug candidate, with the objective of contributing to its further development and the discovery of prospective drugs. Through an extensive review of literature from PubMed, Science Direct, and Web of Science, we have gathered substantial evidence showcasing WA's significant anti-tumor effects against a wide range of cancers in both in vitro and in vivo studies. Mechanistically, WA exerts its anti-tumor influence by inducing cell cycle arrest, apoptosis, autophagy, and ferroptosis. Additionally, it inhibits cell proliferation, cancer stem cells, tumor metastasis, and also suppresses epithelial-mesenchymal transition (EMT) and angiogenesis. Several studies have identified direct target proteins of WA, such as vimentin, Hsp90, annexin II and mFAM72A, while BCR-ABL, Mortalin (mtHsp70), Nrf2, and c-MYB are potential targets of WA. Notwithstanding its remarkable anti-tumor efficacy, there are some limitations associated with WA, including potential toxicity and poor oral bioavailability, which need to be addressed when considering it as an anti-tumor candidate agent. Nevertheless, I given its promising anti-tumor attributes, WA remains an encouraging candidate for future drug development. Unveiling the exact target and comprehensive mechanism of WA's action represents a crucial research direction to pursue in the future.

Design, Synthesis, and Biological Evaluation of Novel P2X7 Receptor Antagonists for the Treatment of Septic Acute Kidney Injury.

Sepsis-associated acute kidney injury (AKI) is a serious clinical problem, without effective drugs. Abnormal activation of the purinergic P2X7 receptor (P2X7R) in septic kidneys makes its antagonist a promising therapeutic approach. Herein, a series of novel P2X7R antagonists were designed, synthesized, and structurally optimized. Based on in vitro potency in human/mouse P2X7R using HEK293 cells, hepatic microsomal stability, and pharmacokinetic and preliminary in vivo assessments, compound 14a was identified by respective human and mouse P2X7R IC50 values of 64.7 and 10.1 nM, together with favorable pharmacokinetic properties. Importantly, 14a dose-dependently alleviated kidney dysfunction and pathological injury in both lipopolysaccharide (LPS)- and cecal ligation/perforation (CLP)-induced septic AKI mice with a good safety profile. Mechanistically, 14a could suppress NLRP3 inflammasome activation to inhibit the expression of cleaved caspase-1, gasdermin D, IL-1ß, and IL-18 in the injured kidneys of septic mice. Collectively, these results highlighted that P2X7R antagonist 14a exerted a therapeutic potential against septic AKI.

Regulation of Schwann cell proliferation and migration via miR-195-5p-induced Crebl2 downregulation upon peripheral nerve damage.

Background: Schwann cells acquire a repair phenotype upon peripheral nerve injury (PNI), generating an optimal microenvironment that drives nerve repair. Multiple microRNAs (miRNAs) show differential expression in the damaged peripheral nerve, with critical regulatory functions in Schwann cell features. This study examined the time-dependent expression of miR-195-5p following PNI and demonstrated a marked dysregulation of miR-195-5p in the damaged sciatic nerve. Methods: CCK-8 and EdU assays were used to evaluate the effect of miR-195-5 on Schwann cell viability and proliferation. Schwann cell migration was tested using Transwell and wound healing assays. The miR-195-5p agomir injection experiment was used to evaluate the function of miR-195-5p in vivo. The potential regulators and effects of miR-195-5p were identified through bioinformatics evaluation. The relationship between miR-195-5p and its target was tested using double fluorescence reporter gene analysis. Results: In Schwann cells, high levels of miR-195-5p decreased viability and proliferation, while suppressed levels had the opposite effects. However, elevated miR-195-5p promoted Schwann cell migration determined by the Transwell and wound healing assays. In vivo injection of miR-195-5p agomir into rat sciatic nerves promote axon elongation after peripheral nerve injury by affecting Schwann cell distribution and myelin preservation. Bioinformatic assessment further revealed potential regulators and effectors for miR-195-5p, which were utilized to build a miR-195-5p-centered competing endogenous RNA network. Furthermore, miR-195-5p directly targeted cAMP response element binding protein-like 2 (Crebl2) mRNA via its 3'-untranslated region (3'-UTR) and downregulated Crebl2. Mechanistically, miR-195-5p modulated Schwann cell functions by repressing Crebl2. Conclusion: The above findings suggested a vital role for miR-195-5p/Crebl2 in the regulation of Schwann cell phenotype after sciatic nerve damage, which may contribute to peripheral nerve regeneration.

Mitochondrial dysfunction-targeting therapeutics of natural products in Parkinson's disease.

Parkinson's disease (PD), the second most common neurodegenerative disease worldwide, often occurs in middle-aged and elderly individuals. The pathogenesis of PD is complex and includes mitochondrial dysfunction, and oxidative stress. Recently, natural products with multiple structures and their bioactive components have become one of the most important resources for small molecule PD drug research targeting mitochondrial dysfunction. Multiple lines of studies have proven that natural products display ameliorative benefits in PD treatment by regulating mitochondrial dysfunction. Therefore, a comprehensive search of recent published articles between 2012 and 2022 in PubMed, Web of Science, Elesvier, Wliey and Springer was carried out, focusing on original publications related to natural products against PD by restoring mitochondrial dysfunction. This paper presented the mechanisms of various kinds of natural products on PD-related mitochondrial dysfunction regulation and provided evidence that natural products are promising to be developed as drugs for PD therapeutics.

Diagnostic performance of adult-based ultrasound risk stratification systems in pediatric thyroid nodules: a systematic review and meta-analysis.

Purpose: Ultrasound (US) is the first choice in the detection of thyroid nodules in pediatric and adult patients. The purpose of this study was to evaluate the diagnostic performance of adult-based US risk stratification systems (RSSs) when applied to the pediatric population. Methods: Medline, Embase, and Cochrane Library (CENTRAL) were searched up to 5 March 2023 for studies about the diagnostic performance of adult-based US RSS in pediatric patients. The pooled sensitivity, specificity, positive likelihood ratio (LR), negative LR, and diagnostic odds ratio (DOR) were calculated. The summary receiver operating characteristic (SROC) curves and area under the curve (AUC) were also analyzed. Results: The sensitivity was highest in American College of Radiology-Thyroid Imaging Reporting and Data System (ACR-TIRADS) category 4-5 and American Thyroid Association RSS high-intermediate risk (ATA), which was 0.84 [0.79, 0.88] and 0.84 [0.75, 0.90], respectively. The specificity was highest in ACR-TIRADS category 5 and Europe-TIRADS (EU-TIRADS) category 5, which was 0.93 [0.83, 0.97] and 0.93 [0.88, 0.98], respectively. The ACR-TIRADS, ATA, and EU-TIRADS showed moderate diagnostic performance in pediatric thyroid nodule patients. For Korea-TIRADS (K-TRADS) category 5, the summary sensitivity and specificity with a 95% CI were 0.64 [0.40, 0.83] and 0.84 [0.38, 0.99], respectively. Conclusions: In conclusion, the ACR-TIRADS, ATA, and EU-TIRADS have moderate diagnostic performance in pediatric thyroid nodule patients. The diagnostic efficacy of the K-TIRADS was not as high as expected. However, the diagnostic performance of Kwak-TIRADS was uncertain because of the small sample size and small number of studies included. More studies are needed to evaluate these adult-based RSSs in pediatric patients with thyroid nodules. RSSs specific for pediatric thyroid nodules and thyroid malignancies were necessary.

From lead to clinic: A review of the structural design of P2X7R antagonists.

P2X7R, which is a member of the purinergic P2 receptor family, is widely expressed in many immune cells, such as macrophages, lymphocytes, monocytes, and neutrophils. P2X7R is upregulated in response to proinflammatory stimulation, which is closely related to a variety of inflammatory diseases. The inhibition of P2X7 receptors has resulted in the elimination or reduction of symptoms in animal models of arthritis, depression, neuropathic pain, multiple sclerosis, and Alzheimer's disease. Therefore, the development of P2X7R antagonists is of great significance for the treatment of various inflammatory diseases. This review classifies the reported P2X7R antagonists according to their different cores, focuses on the structure-activity relationship (SAR) of the compounds, and analyzes some common substituents and strategies in the design of lead compounds, with the hope of providing valuable information for the development of new and efficient P2X7R antagonists.

Identification of the target protein and molecular mechanism of honokiol in anti-inflammatory action.

BACKGROUND: Searching the targets of natural products is very important for drug discovery and elucidating the mechanism of drug action and disease. Honokiol (HK), as the major active component of Magnolia officinalis Rehder & E.H.Wilson, has been widely used in medicine and cosmetics. Among its bioactivities, its anti-inflammatory activity is particularly impressive. However, the target protein of HK in anti-inflammatory action and its regulatory mechanism are unclear. PURPOSE: Here, we identified the target protein and molecular mechanism of the anti- inflammatory action of HK. METHODS: First, an LPS-induced septic shock model and DSS-induced ulcerative colitis model were used to assess the anti-inflammatory efficacy of HK. Second, the drug affinity responsive target stability, proteomics analysis, thermal shift assays and cellular thermal shift assays were used to identify and validate the target of HK. Finally, western blot, ELISA, LDH immunofluorescence staining, shRNA and LC/MS for L-leucine analysis were performed to determine the mechanism of the anti-inflammatory action of HK. RESULTS: This study revealed that HK significantly alleviated LPS-induced septic shock and DSS-induced ulcerative colitis in vivo, suggesting that HK has significant anti-inflammatory activity. HK treatment dramatically reduced IL-1ß release and caspase-1 activation at different time points, showing that HK could inhibit both NLRP3 inflammasome priming and activation processes in cells. HK also suppressed adaptor apoptosis speck-like protein oligomerization. Mechanistically, SLC3A2 was identified as a direct target of HK in THP-1 cells. HK downregulated SLC3A2 expression by promoting its degradation via proteasome-mediated proteolysis. Further study demonstrated that HK triggered SLC3A2 to suppress NLRP3 inflammasome activation by significantly reducing the content of L-leucine transported into cells and lysosomes to block the mTORC1 pathway. CONCLUSIONS: Our work identified HK as a promising anti-inflammatory drug candidate through the SLC3A2/L-leucine/mTORC1/NLRP3 pathways.

Brusatol: A potential sensitizing agent for cancer therapy from Brucea javanica.

Cancer is currently the most important problem endangering human health. As antitumor drugs have always been the most common methods for treating cancers, searching for new antitumor agents is of great significance. Brusatol, a quassinoid from the seeds of Brucea javanica, exhibits a potent tumor-suppressing effect with improved disease outcome. Studies have shown that brusatol not only shows potential tumor inhibition through multiple pharmacological effects, such as promoting apoptosis and inhibiting metastasis but also exhibits significant synergistic antitumor effects in combination with chemotherapeutic agents and overcoming chemical resistance in a wide range of cancer types. In this paper, the antitumor effects and mechanisms of brusatol were reviewed to provide evidence that brusatol has the exact antitumor efficacy of chemotherapeutic agents and show the potential of brusatol to be developed as a promising antitumor drug.

miR-328a-3p modulates the proliferative and migratory abilities of Schwann cells in peripheral nerves.

MicroRNAs (miRNAs) modulate Schwann cell phenotype. Here miR-328a-3p amounts after peripheral nerve damage were determined in injury stumps of the sciatic nerve in rats administered surgical crush. Quantitative real-time reverse transcription-polymerase chain reaction was performed to assess miR-328a-3p levels 0, 1, 4, 7 and 14 days post-sciatic nerve damage. The results showed miR-328a-3p was upregulated after nerve damage. CCK8 and EdU assays revealed elevated miR-328a-3p amounts suppressed Schwann cell viability and proliferation, respectively. Next, the migratory potential of cells was assessed by the Transwell chamber and wound healing assays. We found elevated miR-328a-3p amounts also suppressed Schwann cell migration. Conversely, low miR-328a-3p amounts promoted Schwann cell migration. The possible miR-328a-3p targets were predicted by bioinformatics. The 15 target genes retrieved provided insights into miR-328a-3p's effects on Schwann cells and expanded the understanding of miR-328a-3p's biological functions in the peripheral nervous system. Collectively, these findings revealed miR-328a-3p's effects on Schwann cells and provided further insights into the functions of miRNAs in peripheral nerves.

An epigenetic modifier enhances the generation of anti-phytopathogenic compounds from the endophytic fungus Chaetomium globosporum of Euphorbia humifusa.

Endophytic fungi are striking resources rich in bioactive structures with agrochemical significance. In order to maximize the opportunity of search for bioactive compounds, chemical epigenetic manipulation was introduced to enhance the structural diversity of the fungal products, and an UPLC-ESIMS and bioassay-guided separation was used to detect novel bioactive metabolites. Consequently, four previously undescribed compounds including two cyclopentenones (globosporins A and B) and two monoterpenoid indole alkaloids (globosporines C and D), as well as three known compounds, were isolated from the endophytic fungus Chaetomium globosporum of Euphorbia humifusa by exposure to a DNA methyltransferase inhibitor 5-azacytidine. Their structures including the absolute configurations were elucidated by the analysis of NMR spectroscopic data, HRESIMS, and TD-DFT-ECD calculations. The indole alkaloids (globosporines C and D) showed antimicrobial activities against three phytopathogenic microbes (Xanthomonas oryzae pv. oryzae, X. oryzae pv. oryzicola, and Pseudomonas syringae pv. lachrymans) with MICs in the range of 14-72 µg/mL. Mostly, globosporine D was proved to be potently anti-phytopathogenic against X. oryzae pv. oryzae in vitro and in vivo, which suggested that it has the potential to be developed as a candidate for the prevention of rice bacterial leaf blight. This work provides an efficient and environmentally friendly approach for expanding fungal products with agricultural importance.