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Nonalcoholic fatty liver disease (NAFLD) is a major clinical and global public health issue, with no specific pharmacological treatment available. Currently, there is a lack of approved drugs for the clinical treatment of NAFLD. Large-leaf yellow tea polysaccharides (YTP) is a natural biomacromolecule with excellent prebiotic properties and significant therapeutic effects on multiple metabolic diseases. However, the specific mechanisms by which YTP regulates NAFLD remain unclear. This study aims to explore the prebiotic effects of YTP and the potential mechanisms by which it inhibits hepatic cholesterol accumulation in NAFLD mice. The effects of YTP on lipid accumulation were evaluated in NAFLD mice through obesity trait analysis and bile acids (BAs) metabolism assessment. Additionally, fecal microbiota transplantation (FMT) was performed, and high-throughput sequencing was employed to investigate the mechanisms underlying YTP's regulatory effects on gut microbiota and BA metabolism. Our study demonstrated that YTP altered the constitution of colonic BA, particularly increasing the levels of conjugated BA and non-12OH BA, which suppressed ileum FXR receptors and hepatic BA reabsorption, facilitated BA synthesis, and fecal BA excretion. The modifications were characterized by a decrease in the levels of FXR, FGF15, FGFR4, and ASBT proteins, and an increase in the levels of Cyp7a1 and Cyp27a1 proteins. YTP might affect enterohepatic circulation and by the activated the hepatic FXR-SHP pathway. Meanwhile, YTP reshaped the intestinal microbiome structure by decreasing BSH-producing genera and increasing taurine metabolism genera. The correlation analysis implied that Muribaculaceae, Pseudomonas, acterium_coprostanoligenes_group, Clostridiales, Lachnospiraceae_NK4A136_group, Delftia, Dubosiella, and Romboutsia were strongly correlated with specific BA monomers. YTP modulates bile salt hydrolase-related microbial genera to activate alternative bile acid synthesis pathways, thereby inhibiting NAFLD progression. These results suggest that YTP may serve as a potential probiotic formulation, offering a feasible dietary intervention for NAFLD. [ABSTRACT FROM AUTHOR]

• Hydroxy-α-sanshool induced liver injury in mice and had hepatotoxicity. • Hydroxy-α-sanshool induced liver lipid metabolism disorder, leading to abnormal accumulation of liver lipid. • Hydroxy-α-sanshool-induced hepatic lipid accumulation is associated with AMPK inactivation. • Hydroxy-α-sanshool induces lipid synthesis and mitochondrial dysfunction by inhibiting AMPK signaling pathway, leading to liver lipid metabolism disorders. With the increasing awareness of the safety of traditional Chinese medicine and food, as well as in-depth studies on the pharmacological activity and toxicity of Zanthoxylum armatum DC. (ZADC), it has been found that ZADC is hepatotoxic. However, the toxic substance basis and mechanism of action have not been fully elucidated. Hydroxy-α-sanshool (HAS) belongs to an amide compound in the fruits of ZADC, which may be hepatotoxic. However, the specific effects of HAS, including liver toxicity, are unclear. The objectives of this research was to determine how HAS affects hepatic lipid metabolism, identify the mechanism underlying the accumulation of liver lipids by HAS, and offer assurances on the safe administration of HAS. An in vivo experiment was performed by gavaging C57 BL/6 J mice with various dosages of HAS (5, 10, and 20 mg/kg). Biochemical indexes were measured, and histological analysis was performed to evaluate HAS hepatotoxicity. Hepatic lipid levels were determined using lipid indices and oil red O (ORO) staining. Intracellular lipid content were determined by biochemical analyses and ORO staining after treating HepG2 cells with different concentrations of HAS in vitro. Mitochondrial membrane potential, respiratory chain complex enzymes, and ATP levels were assessed by fluorescence labeling of mitochondria. The levels of proteins involved in lipogenesis and catabolism were determined using Western blotting. Mice in the HAS group had elevated alanine and aspartate aminotransferase blood levels as well as increased liver index compared with the controls. The pathological findings showed hepatocellular necrosis. Serum and liver levels of triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels were increased, whereas high-density lipoprotein cholesterol levels decreased. The ORO staining findings demonstrated elevated liver lipid levels. In vitro experiments demonstrated a notable elevation in triglyceride and total cholesterol levels in the HAS group. ATP, respiratory chain complex enzyme gene expression, mitochondrial membrane potential, and mitochondrial number were reduced in the HAS group. The levels of lipid synthesis-associated proteins (ACC, FASN, and SREBP-1c) were increased, and lipid catabolism-associated protein levels (PPARα and CPT1) and the p-AMPK/AMPK ratio were decreased in vivo and in vitro. HAS has hepatotoxic effects, which can induce fatty acid synthesis and mitochondrial function damage by inhibiting the AMPK signaling pathway, resulting in aberrant lipid increases. [Display omitted] [ABSTRACT FROM AUTHOR]

Malignant breast cancer cells trigger the over-activation of osteoclast precursor cells, leading to bone loss and severe pain. Targeted inhibition of osteoclast differentiation has emerged as an important strategy for treating bone syndromes induced by breast cancer. The objective is to discover natural osteoclast inhibitor to treat osteoclastogenesis and bone destruction induced by breast cancer, and clarify the specific mechanisms. Recepteur d'origine Nantais (RON) protein was employed to search the natural osteoclast inhibitor for breast cancer-induced osteoclastogenesis by molecular docking, molecular dynamics simulation and cellular thermal shift assay (CETSA). In the in vitro experiment, breast cancer MDA-MB-231 cell-conditioned medium (MDA-MB-231 CM) was used to induce osteoclastogenesis in murine bone marrow-derived macrophages (BMMs), aiming to elucidate the effects and mechanisms of the natural osteoclast inhibitor. In the in vivo model, MDA-MB-231 cells was injected into the mouse tibia to evaluate the therapeutic effect of drug on breast cancer-induced bone destruction. We discovered a significant increase in the expression of RON during MDA-MB-231 CM-induced osteoclast differentiation in vitro. Molecular docking analysis found that oroxylin A (OA), a flavonoid derived from the Chinese medicine Scutellaria baicalensis Georgi , showed binding ability with RON, while its impact and mechanism on breast cancer-induced osteoclastogenesis and osteolysis remains unclear. Molecular dynamics simulation and CETSA further revealed that OA bound directly to the RON protein, and it also decreased RON expression in breast cancer CM-induced osteoclastogenesis. Correspondingly, OA suppressed the MDA-MB-231 CM-induced osteoclastogenesis and bone resorption in vitro. The downstream signals of RON including Src and NFATc1, as well as the osteoclast-specific genes, were downregulated by OA. Of interesting, the suppressive effect of OA on osteoclastogenesis induced by MDA-MB-231 CM was abolished after RON was knocked down by the specific RON-siRNA, this further confirmed that OA showed inhibitory effects on osteoclasts through targeting RON. In addition, we found that OA attenuated MDA-MB-231 cell-induced osteolysis and reduced the number of osteoclasts in vivo. Our results indicate that OA acts as a natural RON inhibitor to suppress breast cancer-induced osteoclastogenesis and osteolysis. This provides new strategy for treating breast cancer-induced bone destruction and related syndromes. [Display omitted] [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction is key to the pathogenesis of vascular dementia (VaD). Sirtuin-3 (SIRT3), an essential member of the sirtuins family, has been proven to be a critical sirtuin in regulating mitochondrial function. The phenolic glucoside gastrodin (GAS), a bioactive ingredient from Gastrodiae Rhizome (known in Chinese as Tian ma) demonstrates significant neuroprotective properties against central nervous system disorders; however, the precise mechanisms through which GAS modulates VaD remain elusive. This study aims to investigate whether GAS confers a protective role against VaD, and to figure out the underlying molecular mechanisms. A bilateral common carotid artery occlusion (BCCAO)-mediated chronic cerebral hypoperfusion (CCH) VaD rat model and a hypoxia model using HT22 cells were employed to investigate pharmacological properties of GAS in mitigating mitochondrial dysfunction. A SIRT3 agonist resveratrol (RES), a SIRT3 inhibitor 3-TYP and SIRT3-knockdown in vitro were used to explore the mechanism of GAS in association with SIRT3. The ability of SIRT3 to bind and deacetylate mitochondrial transcription factor A (TFAM) was detected by immunoprecipitation assay, and TFAM acetylation sites were further validated using mass spectrometry. GAS increased SIRT3 expression and ameliorated mitochondrial structure, mitochondrial respiration, mitochondrial dynamics along with upregulated TFAM, mitigating oxidative stress and senescence. Comparable results were noted with the SIRT3 agonist RES, indicating an impactful neuroprotection played by SIRT3. Specifically, the attenuation of SIRT3 expression through knockdown techniques or exposure to the SIRT3 inhibitor 3-TYP in HT22 cells markedly abrogated GAS-mediated mitochondrial rescuing function. Furthermore, our findings elucidate a novel facet: SIRT3 interacted with and deacetylated TFAM at the K5, K7, and K8 sites. Decreased SIRT3 is accompanied by hyper-acetylated TFAM. The present results were the first to demonstrate that the SIRT3/TFAM pathway is a protective target for reversing mitochondrial dysfunction in VaD. The findings suggest that GAS-mediated modulation of the SIRT3/TFAM pathway, a novel mechanism, could ameliorate CCH-induced VaD, offering a potentially beneficial therapeutic strategy for VaD. [Display omitted] [ABSTRACT FROM AUTHOR]

(Background): Cadmium is an environmental pollutant associated with several liver diseases. Baicalin and N-Acetylcysteine have antioxidant and hepatoprotective effects. (Purpose): However, it is unclear whether baicalin and N-Acetylcysteine can alleviate Cadmium -induced liver fibrosis by regulating metabolism, or whether they exert a synergistic effect. (Study design): We treated Cadmium-poisoned mice with baicalin, N-Acetylcysteine, or baicalin+ N -Acetylcysteine. We studied the effects of baicalin and N-Acetylcysteine on Cadmium-induced liver fibers and their specific mechanisms. (Methods): We used C57BL/6 J mice, and AML12, and HSC-6T cells to establish in vitro assays and in vivo models. (Results): Metabolomics was used to detect the effect of baicalin and N-Acetylcysteine on liver metabolism, which showed that compared with the control group, the Cadmium group had increased fatty acid and amino acid levels, with significantly reduced choline and acetylcholine contents. Baicalin and N-Acetylcysteine alleviated these Cadmium-induced metabolic changes. We further showed that choline alleviated Cadmium -induced liver inflammation and fibrosis. In addition, cadmium significantly promoted extracellular leakage of lactic acid, while choline alleviated the cadmium -induced destruction of the cell membrane structure and lactic acid leakage. Western blotting showed that cadmium significantly reduced mitochondrial transcription factor A (TFAM) and Choline Kinase α(CHKα2) levels, and baicalin and N-Acetylcysteine reversed this effect. Overexpression of Tfam in mouse liver and AML12 cells increased the expression of CHKα2 and the choline content, alleviating and cadmium-induced lactic acid leakage, liver inflammation, and fibrosis. (Conclusion): Overall, baicalin and N-Acetylcysteine alleviated cadmium-induced liver damage, inflammation, and fibrosis to a greater extent than either drug alone. TFAM represents a target for baicalin and N-Acetylcysteine, and alleviated cadmium-induced liver inflammation and fibrosis by regulating hepatic choline metabolism. [Display omitted] [ABSTRACT FROM AUTHOR]

In our previous study, we provided evidence that Astragalus mongholicus Bunge(AM) and its extracts possess a protective capability against radiation-induced damage, potentially mediated through the reduction of reactive oxygen species (ROS) and nitric oxide (NO). However, we were pleasantly surprised to discover during our experimentation that AM not only offers protection against radiation damage but also exhibits a radiation sensitization effect. This effect may be attributed to a specific small molecule present in AM known as ononin. Currently, radiation sensitizers are predominantly found in nitrazole drugs and nanomaterials, with no existing reports on the radiation sensitization properties of ononin, nor its underlying mechanism. This study aims to investigate the sensitization effect of the small molecule ononin derived from AM on lung cancer radiotherapy, elucidating its specific molecular mechanism of action. Additionally, the safety profile of combining astragalus small molecule ononin with radiation therapy will be evaluated. The effective concentration of ononin was determined through cell survival experiments, and the impact of ononin combined with varying doses of radiation on lung cancer cells was observed using CCK-8 and cell cloning experiments. The apoptotic effect of ononin combined with radiation on lung cancer cells was assessed using Hochester staining, flow cytometry, and WB assay. Additionally, WB and immunofluorescence analysis were conducted to investigate the influence of ononin on HIF-1α/VEGF pathway. Furthermore, Molecular Dynamics Simulation was employed to validate the targeted binding ability of ononin and HIF-1α. A lung cancer cell line was established to investigate the effects of knockdown and overexpression of HIF-1α. Subsequently, the experiment was repeated using tumor bearing nude mice and C57BL/6 mouse models in an in vivo study. Tumor volume was measured using a vernier caliper, while HE, immunohistochemistry, and immunofluorescence techniques were employed to observe the effects of ononin combined with radiation on tumor morphology, proliferation, and apoptosis. Additionally, Immunofluorescence was employed to examine the impact of ononin on HIF-1α/VEGF pathway in vivo , and its effect on liver function in mice was assessed through biochemistry analysis. At a concentration of 25 μM, ononin did not affect the proliferation of lung epithelial cells but inhibited the survival of lung cancer cells. In vitro experiments demonstrated that the combination of ononin and radiation could effectively inhibit the growth of lung cancer cells, induce apoptosis, and suppress the excessive activation of the Hypoxia inducible factor 1 alpha/Vascular endothelial growth factor pathway. In vivo experiments showed that the combination of ononin and radiation reduced the size and proliferation of lung cancer tumors, promoted cancer cell apoptosis, mitigated abnormal activation of the Hypoxia inducible factor 1 alpha pathway, and protected against liver function damage. This study provides evidence that the combination of AM and its small molecule ononin can enhance the sensitivity of lung cancer to radiation. Additionally, it has been observed that this combination can specifically target HIF-1α and exert its effects. Notably, ononin exhibits the unique ability to protect liver function from damage while simultaneously enhancing the tumor-killing effects of radiation, thereby demonstrating a synergistic and detoxifying role in tumor radiotherapy. These findings contribute to the establishment of a solid basis for the development of novel radiation sensitizers derived from traditional Chinese medicine. [ABSTRACT FROM AUTHOR]

• C. nudiflora can inhibit the replication stage of H1N1. • C. can suppress the increase of inflammatory cytokines caused by H1N1 infection in mice, reducing lung damage. • C. nudiflora exhibits immunomodulatory effects on H1N1-infected mice. • C. nudiflora can regulate the toll-like receptor and STAT signaling pathway in H1N1-infected mice. In our preliminary research on screening traditional Chinese medicine extracts for anti-H1N1 activity, we discovered that the 75 % ethanol extract of Callicarpa nudiflora Hook. & Arn (C. nudiflora) exhibited promising anti-H1N1 infection activity. However, the underlying active components and mechanism of action remain to be elucidated. This experiment further explores the potential active components and mechanisms of action of C. nudiflora against H1N1. In this study, the composition of the C. nudiflora was determined using UPLC-Q-Orbitrap-MS/MS. The inhibitory effect of C. nudiflora on H1N1 was investigated using a Madin-Darby canine kidney (MDCK) cell model infected with H1N1, and the protective effect of C. nudiflora on H1N1-infected mice was examined using a Balb/c mouse model infected with H1N1. The potential mechanisms of action were demonstrated at the mRNA and protein levels. A total of 21 compounds were detected in C. nudiflora , which was found to act on the replication stages of H1N1. Moreover, C. nudiflora improved the survival rate of H1N1-infected mice, enhanced the organ index, alleviated the trend of weight loss, reduced lung viral load, mitigated lung tissue damage, and regulated CD4/CD8 and Th1/Th2 immune balance. Molecular mechanism studies revealed that C. nudiflora can regulate the expression of key genes in the toll-like receptor and STAT signaling pathway. C. nudiflora can inhibit H1N1 replication. It also can exert a regulatory effect on the immune response of H1N1-infected mice, and mitigate inflammatory damage by modulating the expression of key genes in the toll-like receptor and STAT signaling pathways, indicating its potential for development as an anti-H1N1 drug. [ABSTRACT FROM AUTHOR]

• EOFAZ attenuates the development of AS in HFD ApoE−/− mice. • EOFAZ reduces the ubiquitination degradation of PPARγ and directly bound to PPARγ increased its stability. • EOFAZ inhibits the formation of MFCs by augmenting cholesterol efflux through the activation of the PPARγ-LXRα-ABCA1/G1 pathway. • EOFAZ reduces MFCs formation, ameliorates lipid metabolism and the inflammatory microenvironment via activating PPARγ signaling, ultimately synergistically retarding AS development. Atherosclerosis (AS) is a progressive chronic disease. Currently, cardiovascular diseases (CVDs) caused by AS is responsible for the global increased mortality. Yanshanjiang as miao herb in Guizhou of China is the dried and ripe fruit of Fructus Alpinia zerumbet. Accumulated evidences have confirmed that Yanshanjiang could ameliorate CVDs, including AS. Nevertheless, its effect and mechanism on AS are still largely unknown. To investigate the role of essential oil from Fructus Alpinia zerumbet (EOFAZ) on AS, and the potential mechanism. A high-fat diet (HFD) ApoE−/− mice model of AS and a oxLDL-induced model of macrophage-derived foam cells (MFCs) were reproduced to investigate the pharmacological properties of EOFAZ on AS in vivo and foam cell formation in vitro , respectively. The underlying mechanisms of EOFAZ were investigated using Network pharmacology and molecular docking. EOFAZ effect on PPARγ protein stability was measured using a cellular thermal shift assay (CETSA). Pharmacological agonists and inhibitors and gene interventions were employed for clarifying EOFAZ's potential mechanism. EOFAZ attenuated AS progression in HFD ApoE−/− mice. This attenuation was manifested by the reduced aortic intima plaque development, increased collagen content in aortic plaques, notable improvement in lipid profiles, and decreased levels of inflammatory factors. Moreover, EOFAZ inhibited the formation of MFCs by enhancing cholesterol efflux through activiting the PPARγ-LXRα-ABCA1/G1 pathway. Interestingly, the pharmacological knockdown of PPARγ impaired the beneficial effects of EOFAZ on MFCs. Additionally, our results indicated that EOFAZ reduced the ubiquitination degradation of PPARγ, and the chemical composition of EOFAZ directly bound to the PPARγ protein, thereby increasing its stability. Finally, PPARγ knockdown mitigated the protective effects of EOFAZ on AS in HFD ApoE−/− mice. These findings represent the first confirmation of EOFAZ's in vivo anti-atherosclerotic effects in ApoE−/− mice. Mechanistically, its chemical constituents can directly bind to PPARγ protein, enhancing its stability, while reducing PPARγ ubiquitination degradation, thereby inhibiting foam cell formation via activation of the PPARγ-LXRα-ABCA1/G1 pathway. Simultaneously, EOFAZ could ameliorates blood lipid metabolism and inflammatory microenvironment, thus synergistically exerting its anti-atherosclerotic effects. [Display omitted] [ABSTRACT FROM AUTHOR]

• Shikonin reverses cancer-associated fibroblast (CAF)-induced gemcitabine resistance. • Shikonin impairs pancreatic cancer cell (PC)-induced reverse Warburg effect in CAFs. • Shikonin reduces lactate secretion from CAFs to fuel PC cells via inhibition of MCT4. Gemcitabine is a first-line chemotherapeutic agent for pancreatic cancer (PC); however, most patients who receive adjuvant gemcitabine rapidly develop resistance and recurrence. Cancer-associated fibroblasts (CAFs) are a crucial component of the tumor stroma that contribute to gemcitabine-resistance. There is thus an urgent need to find a novel therapeutic strategy to improve the efficacy of gemcitabine in PC cells under CAF-stimulation. To investigate if shikonin potentiates the therapeutic effects of gemcitabine in PC cells with CAF-induced drug resistance. PC cell-stimulated fibroblasts or primary CAFs derived from PC tissue were co-cultured with PC cells to evaluate the ability of shikonin to improve the chemotherapeutic effects of gemcitabine in vitro and in vivo. Glucose uptake assay, ATP content analysis, lactate measurement, real-time PCR, immunofluorescence staining, western blot, and plasmid transfection were used to investigate the underlying mechanism. CAFs were innately resistant to gemcitabine, but shikonin suppressed the PC cell-induced transactivation and proliferation of CAFs, reversed CAF-induced resistance, and restored the therapeutic efficacy of gemcitabine in the co-culture system. In addition, CAFs underwent a reverse Warburg effect when co-cultured with PC cells, represented by enhanced aerobic glycolytic metabolism, while shikonin reduced aerobic glycolysis in CAFs by reducing their glucose uptake, ATP concentration, lactate production and secretion, and glycolytic protein expression. Regarding the mechanism underlying these sensitizing effects, shikonin suppressed monocarboxylate transporter 4 (MCT4) expression and cellular membrane translocation to inhibit aerobic glycolysis in CAFs. Overexpression of MCT4 accordingly reversed the inhibitory effects of shikonin on PC cell-induced transactivation and aerobic glycolysis in CAFs, and reduced its sensitizing effects. Furthermore, shikonin promoted the effects of gemcitabine in reducing the growth of tumors derived from PC cells and CAF co-inoculation in BALB/C mice, with no significant systemic toxicity. These results indicate that shikonin reduced MCT4 expression and activation, resulting in inhibition of aerobic glycolysis in CAFs and overcoming CAF-induced gemcitabine resistance in PC. Shikonin is a promising chemosensitizing phytochemical agent when used in combination with gemcitabine for PC treatment. The results suggest that disrupting the metabolic coupling between cancer cells and stromal cells might provide an attractive strategy for improving gemcitabine efficacy. [Display omitted] [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma responds poorly to immune checkpoint inhibitors, such as PD-1 inhibitors, primarily due to the low infiltration capacity of TILs in the TME. Abnormal vasculature is an important factor which limiting the infiltration of TILs. According to recent research, targeting ELTD1 expression may improve TILs delivery to reverse immunosuppression and boost tumor responses to immunotherapy. Research has demonstrated that Tanshinone IIA (TSA) improves blood vessel normalization, but the precise mechanism is yet unknown. The purpose of this study is to investigate the molecular processes for TSA's pro-vascular normalization of HCC in vitro and in vivo. We established a mouse H22-luc in situ liver tumor model to evaluate the role of TSA vascular normalization and the immunosuppressive microenvironment. The role of ELTD1 in vascular and immune crosstalk was evaluated by bioinformatic analysis of the TCGA database. By creating a transwell co-culture cell model, the effects of TSA on enhancing tumor endothelial cell activities and ELTD1 intervention were evaluated. We investigated the effect of Tanshinone IIA (TSA), a major component of Salvia miltiorrhiza Bge., on the normalization of vasculature in situ HCC models. Our results demonstrated that TSA elicited vascular normalization in a hepatocellular carcinoma model in situ. In addition, the combination of TSA with anti-PD-1 significantly inhibited tumor development due to increased infiltration of immune cells in the tumor. Mechanistically, we demonstrated that TSA improved the immunosuppressive microenvironment by inhibiting tumor growth by suppressing ELTD1 expression, inhibiting downstream JAK1 and JAK2, promoting the expression of ZO-1, occlaudin, Claudin 5, and Col IV, and promoting vascular integrity and perfusion in situ. This study reveals a new mechanism between TSA and ELTD1 for vascular normalization, suggesting that therapeutic or pharmacological intervention with ELTD1 may enhance the efficacy of PD-1 inhibitors in HCC. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Nerigoside (NG), a cardenolide isolated from a commonfolk medicine, Nerium oleander Linn. (Apocynaceae), has not been explored for its biological effects. To date, cardenolides have received considerable attention in pharmacology studies due to their direct effects of apoptosis-induction or growth-inhibitory against tumor in vitro and in vivo. Whether and how NG exerts anticancer effects against colorectal cancer remains to be elucidated.Purpose: The aim of this study was to investigate the anticancer effect of NG in human colorectal cancer cells.Methods: To test anticancer effect, we compared potency of NG in two colorectal cancer cell lines, HT29 and SW620 by WST-1 and colony proliferation assays. And we investigated mechanism of anticancer activities by analyzing players in apoptotic and ERK/GSK3β/β-catenin signaling pathways in HT29 and SW620 cells treated with NG.Results: In this study, we showed that NG markedly suppressed the cell viability and colony formation of colorectal cancer cells HT29 and SW620, with no significant toxic effect on non-cancer cells NCM460. Annexin V-FITC/PI and CFSE labeling results revealed that NG suppressed cell proliferation in low concentration, along with reducing expression of PCNA, while NG induced apoptosis in high concentration,. Meanwhile, NG significantly arrested cell migration by reversal of EMT and cell cycle on G2/M. Then, we found that the ERK and GSK3β/β-catenin signaling pathway were noticeably blocked in CRC cells after treatment with NG. According to western blot, NG upregulated the expression of p-GSK3β/GSK3β and decreased especially the expression of β-catenin in nuclear. In addition, Wnt signaling and its target genes were suppressed in response to NG. Then, the Ser9 phosphorylation of GSK3β can be reduced / raised by GÖ 6983 / LiCl, respectively. Thus, we further confirmed that the GSK3β/β-catenin axis is involved in NG-prevented cell proliferation.Conclusion: NG inhibited the growth of colorectal cancer cells by suppressing ERK/GSK3β/β-catenin signaling pathway. And the GSK3β/β-catenin axis is involved in preventing cell proliferation and migration by NG-treatment. These results suggest that NG may be used to treat colorectal cancer, with better outcome by combining with GSK3β inhibitor to block Wnt pathway. [ABSTRACT FROM AUTHOR]

Background: Swertia chirayita, has been commonly used under the name "Zang-yin-chen" for the treatment of liver infections, inflammation, abdominal pain, and bacterial infection in traditional Tibetan medicine. However, the bioactive components with anti-inflammatory activities and underlying mechanisms remain poorly evaluated.Study Design/methods: Repeated column chromatography yielded two main xanthones from petroleum ether (PE) and ethyl acetate fractions of whole plants of S. chirayita, and their structures were determined as bellidifolin (1) and swerchirin (2) on the basis of spectroscopic data and literature analysis. The anti-inflammatory activities and mechanisms of anti-inflammation of these two isolated xanthones were determined via enzyme-linked immunosorbent assay (ELISA) and western blot in lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophages in vitro.Results: Anti-inflammation assay demonstrated that 1 and 2 inhibit the production of the pro-inflammatory cytokines interleukin-6 (IL-6) and TNF-α in LPS-stimulated RAW 264.7 macrophages. Xanthone 1 also potently inhibited the production of prostaglandin E2 (PGE2) by suppressing the protein expression of cyclooxygenase-2 (COX-2) in LPS-stimulated RAW 264.7 macrophages. Western blot showed that the phosphorylation of c-Jun N-terminal kinases (JNK), extracellular signal-regulated kinase (ERK), and p38 MAPKs were remarkably attenuated by 1 in a concentration-dependent manner. Particularly, Compound 1 suppressed the phosphorylation of the inhibitor κB kinase-β (IKK-β), Akt, and p65 subunit of nuclear factor-kappaB (NF-κB).Conclusion: The potent suppressive effects of 1 from S. chirayita on inflammatory mediators by blocking the expression of COX-2 and phosphorylation of Akt, IKK-β, MAPK and NF-κB, activation in LPS-stimulated macrophages suggest that 1 can be a preventive therapeutic candidate for the management of inflammatory-mediated immune disorders. [ABSTRACT FROM AUTHOR]

Background: Berberine (BBR), a Chinese traditional herbal medicine, has many pharmacologic benefits such as anti-inflammation and anti-oxidation. It is widely used in clinical treatment of cardiovascular diseases such as hypertension. However, the mechanism of how BBR attenuates hypertension through affecting central neural system is not clear.Purpose: This study was designed to determine whether chronic infusion of BBR into the hypothalamic paraventricular nucleus (PVN) attenuates hypertension and sympathoexcitation via the ROS/Erk1/2/iNOS pathway.Methods: Two-kidney, one-clip (2K1C) renovascular hypertensive rats were randomly assigned and treated with bilateral PVN infusion of BBR (2μg/h) or vehicle (artificial cerebrospinal fluid) via osmotic minipumps for 28 days.Results: 2K1C rats showed higher mean arterial pressure (MAP) and PVN Fra-like activity, plasma levels of norepinephrine (NE), PVN levels of NOX2, NOX4, Erk1/2 and iNOS, and lower PVN levels of copper/zinc superoxide dismutase (Cu/Zn-SOD). Chronic infusion of BBR reduced MAP, PVN Fra-like activity and plasma levels of NE, reduced NOX2, NOX4, Erk1/2, iNOS and induced Cu/Zn-SOD in the PVN.Conclusions: These results suggest that BBR attenuates hypertension and sympathoexcitation via the ROS/Erk1/2/iNOS pathway in 2K1C renovascular hypertensive rats. [ABSTRACT FROM AUTHOR]

• pSmad3C+/− abates the hepatoprotective effect of AS-IV in heterozygous mice, the potential mechanism involves deactivating Nrf2/HO-1 pathway, as well as shifting pSmad3C/p21 tumour-suppressive to pSmad3L/PAI-1//c-Myc oncogenic. • Up-regulated pSmad3C using Smad3 EPSM plasmid in vitro intensify inhibitory effect of AS-IV on cell proliferation, migration, invasion and excessive production of ROS components followed by a shift of pSmad3L to pSmad3C and activation of Nrf2/HO-1 activity; similarly, opposite actions occur when upregulated pSmad3L. • Nrf2 conventional knockout abated AS-IV's carcinostatic effect by promoting pSmad3C/p21 to pSmad3L/PAI-1//c-Myc accompany with Nrf2 inactivation. • Nrf2 knockdown using a lentivirus-carried shRNA delivery system slacked the suppressive effects of AS-IV on cell phenotypes accompanied by conversion of pSmad3C to pSmad3L and inactivation of Nrf2/HO-1 signal. Complementarily, Nrf2 overexpression acquired a contrary result. • AS-IV exerts anti-hepatocarcinogenesis effect via the bidirectional crosstalk of pSmad3C/3 L and Nrf2/HO-1 signal. More importantly, taking the two into account, we put forward that the Nrf2-mediated pSmad3C/3 L transformation is the basis of AS-IV's anti-HCC therapy. Phosphorylated Smad3 isoforms are reversible and antagonistic, and the tumour-suppressive pSmad3C can shift to an oncogenic pSmad3L signal. In addition, Nrf2 has a two-way regulatory effect on tumours, protecting normal cells from carcinogens and promoting tumour cell survival in chemotherapeutics. Accordingly, we hypothesised that the transformation of pSmad3C/3L is the basis for Nrf2 to produce both pro- and/or anti-tumourigenic effects in hepatocarcinogenesis. Astragaloside IV (AS-IV), the major component of Astragalus membranaceus , exerts anti-fibrogenic and carcinogenic actions. Lately, AS-IV administration could delay the occurrence of primary liver cancer by persistently inhibiting the fibrogenesis and regulating pSmad3C/3 L and Nrf2/HO-1 pathways synchronously. However, effect of AS-IV on hepatocarcinogenesis implicated in the bidirectional cross-talking of pSmad3C/3 L and Nrf2/HO-1 signalling, especially which one contributes palpably than the other still remains unclear. This study aims to settle the above questions by using in vivo (pSmad3C+/− and Nrf2−/− mice) and in vitro (plasmid- or lentivirus- transfected HepG2 cells) models of HCC. The correlation of Nrf2 to pSmad3C/pSmad3L in HepG2 cells was analysed by Co-immunoprecipitation and dual-luciferase reporter assay. Pathological changes of Nrf2, pSmad3C, and pSmad3L in human HCC patients, pSmad3C+/- mice, and Nrf2−/- mice were gauged by immunohistochemical, haematoxylin and eosin staining, Masson, and immunofluorescence assays. Finally, western blot and qPCR were used to verify the bidirectional cross-talking of pSmad3C/3L and Nrf2/HO-1 signalling protein and mRNA in vivo and in vitro models of HCC. Histopathological manifestations and biochemical indicators revealed that pSmad3C+/- could abate the ameliorative effects of AS-IV on fibrogenic/carcinogenic mice with Nrf2/HO-1 deactivation and pSmad3C/p21 transform to pSmad3L/PAI-1//c-Myc. As expected, cell experiments confirmed that upregulating pSmad3C boosts the inhibitory activity of AS-IV on phenotypes (cell proliferation, migration and invasion), followed by a shift of pSmad3L to pSmad3C and activation of Nrf2/HO-1. Synchronously, experiments in Nrf2−/- mice and lentivirus-carried Nrf2shRNA cell echoed the results of pSmad3C knockdown. Complementarily, Nrf2 overexpression resulted in the opposite result. Furthermore, Nrf2/HO-1 contributes to AS-IV's anti-HCC effect palpably compared with pSmad3C/3L. These studies highlight that harnessing the bidirectional crosstalk pSmad3C/3 L and Nrf2/HO-1, especially Nrf2/HO-1 signalling, acts more effectively in AS-IV's anti-hepatocarcinogenesis, which may provide an important theoretical foundation for the use of AS-IV against HCC. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Intervertebral disc degeneration (IVDD) is a highly prevalent musculoskeletal disorder characterized by a local inflammatory response associated with the IL-1β/NLRP3 inflammasome positive feedback loop. Rice bran-derived gamma-oryzanol (Ory) as a sterol ferulate has attracted much attention due to its powerful anti-inflammatory, hypoglycemic and hypolipidemic health effects. As a clinical pharmaceutical for autonomic disorders, Ory's role in musculoskeletal degenerative disease remains unknown.Purpose: This study aims to validate the role of Ory in IVDD and explore the potential mechanism.Study Design: Establishing the in vitro and in vivo IVDD models to detect the protective effect and molecular mechanism of Ory.Method: The anti-ECM degradation, antioxidant and anti-NLRP3 inflammasome activation effects of Ory on IL-1β-stimulated nucleus pulposus (NP) cells were assessed by immunoblotting and immunofluorescence, etc. MRI, S-O staining and immunohistochemistry were performed to estimate the effects of Ory administration on acupuncture-mediated IVDD in rats at imaging and histological levels.Results: Ory treatment inhibited IL-1β-mediated ECM degradation, oxidative stress and NLRP3 inflammasome activation in NP cells. By interfering with NF-κB signaling and ROS overproduction, Ory interrupted IL-1β/NLRP3-inflammasome positive cycle. In vivo experiments showed that Ory delayed acupuncture-mediated IVDD development.Conclusion: Our results support the potential application of Ory as a therapeutic compound for IVDD. [ABSTRACT FROM AUTHOR]

Background: Ginsenoside Re (Re) belongs to protopanaxatriol saponins and exists in Panax ginseng, Panax quinquefolium, Panax notoginseng, and other plants in the Araliaceae family. Re has recently become a research focus owing to its pharmacological activities and benefits to human bodies.Purpose: To summarize recent findings regarding the pharmacological effects and mechanisms of Re and highlight and predict the potential therapeutic effects and systematic mechanism of Re.Methods: Recent studies (2011-2021) on the pharmacological effects and mechanisms of Re were retrieved from Web of Science, PubMed, Google Scholar, Scopus, and Embase up to December 2021 using relevant keywords. Network pharmacology and bioinformatics analysis were used to predict the therapeutic effects and mechanisms of Re against potential diseases.Results: Re presented a wide range of therapeutic and biological activities, including neuroprotective, cardiovascular, antidepressant, antitumorigenic, and others effects. The related pharmacological mechanisms of Re include the regulation of cholinergic and antioxidant systems in the brain; the induction of tumor cell apoptosis; the inhibition of tau protein hyperphosphorylation and oxidative stress; the activation of p38MAPK, ERK1/2, and JNK signals; the improvement of lipid metabolism; and the reduction of endothelial cell dysfunction.Conclusion: This paper summarizes comprehensively the current research progress of Re and provides new research insights into the therapeutic effects and mechanisms of Re against potential diseases. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy drugs especially anthracyclines are widely used in the treatment of hematological malignancies and solid tumors. However, their clinical application is limited by dose-dependent and irreversible heart injury, which increases the risk of congestive heart failure and heart-related mortality.Purpose: This study aims to investigate the effect and mechanism of the natural flavonoid isoorientin (ISO) combined with doxorubicin (DOX) on the proliferation of tumor cells and improve the survival rate of DOX-injured cardiomyocytes.Study Design/methods: Cardiomyocyte H9c2 and a variety of tumor cells were used to evaluate the protective effect of ISO on DOX-induced myocardial injury and enhance the anticancer effects of DOX. DOX chemotherapy-injured mice were used to evaluate the cardioprotective effect of ISO.Results: The antiproliferation of DOX on Hela, HepG2, HT-29, and A549 cells could be increased synergistically when cotreated with ISO in vitro. ISO could also improve the survival rate of DOX-injured cardiomyocytes by reducing reactive oxygen species, maintaining mitochondrial function, and inhibiting apoptosis. In mice receiving DOX, a protective effect on myocardial tissue, which was reflected by improved survival state of mice receiving chemotherapy, was observed. The ECG, myocardial zymogram data, HE staining, and TEM observation of myocardial tissue sections showed that ISO had a dose-dependent protective effect on the mouse hearts injured by DOX. Network pharmacology and cardiomyocyte proteomics were used to seek for related target proteins to reveal the protective mechanism of ISO on mouse models, and some potential targets (including caspase-3, EGFR, MAPK1, ESR1, CDC42, STAT1, JAK2, LCK, and CDK2) were generated. Western blotting was further used to verify that ISO upregulated Nrf2 and TGF-β3 by downregulating the phosphorylation levels of JNK and p38 proteins on the MAPK pathway and the Akt and Stat3 expression levels. The downregulation of cleaved caspase-3 and upregulation of Bcl-xl by ISO further confirmed its inhibition on caspase-dependent cardiomyocyte apoptosis.Conclusion: ISO could be a potential synergistic anticancer agent with a favorable property of reducing the cardiotoxicity for DOX, and the effect mechanism could refer to the inhibition of ISO on MAPK and caspase-dependent apoptosis pathways. [ABSTRACT FROM AUTHOR]

Abstract: Daphnane-type diterpenoids (DDs) are the main types of plant diterpene orthoesters known and have remarkable biological activities. However, the in vivo toxicity and pharmacokinetic profile of DDs remains unkonwn. The aim of this study was to investigate the toxicity and pharmacokinetic profile of DDs from Genkwa Flos (Thymelaeaceae). The toxicity of diterpenoids was evaluated after oral administration of total diterpenoids extract from Genkwa Flos to rats, and the blood concentration of diterpenoids was analyzed by ultra performance liquid chromatography tandem triple-quadrupole mass spectrometry (UPLC–TQ-MS). The diterpenoids were confirmed to be the toxic components of Genkwa Flos. The pharmacokinetic profile of these diterpenoids was quite different due to their different structures. Although the contents of yuanhuafine and yuanhuapine were low in the extract, the blood concentrations were extremely high. In contrary, the contents of genkwanine F and Wikstroemia factor M1 in the extract were much higher, but they could not be detected in the blood. This result implied that yuanhuafine and yuanhuapine but not genkwanine F and Wikstroemia factor M1 were the potentail toxic components of Genkwa Flos in vivo. This paper shows for the first time the toxicity of diterpenoids from Genkwa Flos was correlated with their blood concentration and when DDs were used for medicinal purposes, their contents in herb as well as their blood concentrations should be considered. [Copyright &y& Elsevier]

Abstract: Dragon's blood is a bright red resin obtained from Dracaena cochinchinensis (Lour.) S.C.Chen (Yunnan, China). As a traditional Chinese medicinal herb, it has great traditional medicinal value and is used for wound healing and to stop bleeding. Its main biological activity comes from phenolic compounds. In this study, phenolic compounds were made into dropping pills and their protective effects were examined by establishing focal cerebral ischemia rats model used method of Middle Cerebral Artery Occlusion (MCAO), and by investigating indexes of neurological scores, infarct volume, cerebral index, cerebral water content and oxidation stress. Compared to model group, high, middle and low groups of Dragon's blood dropping pills could improve the neurological function significantly (p <0.01) and reduce cerebral infarct volume of focal cerebral ischemia rats remarkably (p <0.05–0.01). Meanwhile, each group could alleviate cerebral water content and cerebral index (p <0.05–0.01) and regulate oxidative stress of focal cerebral ischemia rats obviously (p <0.05–0.01). Activities of middle group corresponded with that treated with positive control drug. The results obtained here showed that Dragon's blood dropping pills had protective effects on focal cerebral ischemia rats. [Copyright &y& Elsevier]

Background: Dihydroquercetin (DHQ) is a flavonoid with strong anti-inflammatory and antioxidant effects. However, its protective activity against cigarette smoke-induced ferroptosis in the pathogenesis of chronic obstructive pulmonary disease and its underlying mechanisms remain unclear.Purpose: The present study was conducted to investigate the protective role of DHQ in the pathogenesis of COPD in vivo and in vitro.Methods: A cigarette smoke-induced COPD mouse model was established by cigarette smoke (CS) exposure combined with intraperitoneal injection of cigarette smoke extract (CSE). During the modeling process, the mice were intraperitoneally injected with DHQ daily. HBE cells were cultured with CSE with or without pretreatment with DHQ (40, 80 μM) or ML385 (10 μM). Cell viability was assessed by a cell counting kit 8 (CCK-8). The contents of malondialdehyde (MDA) and superoxide dismutase (SOD) were determined by MDA and SOD assay kits, respectively, and reactive oxygen species (ROS) generation was detected by DCFH-DA assays. Protein expression levels of solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPx4) and nuclear factor erythroid 2-related factor 2 (Nrf2) were measured by western blot. Lipid peroxidation was determined by C11-BODIPY staining. Transmission electron microscopy was used to observe the morphological features of the mitochondria.Results: Treatment with DHQ significantly elevated ferroptosis-related protein (SLC7A11 and GPx4) expression in vivo and in vitro. The mRNA levels of SLC7A11 and GPx4 were also increased after DHQ treatment. The excessive MDA and ROS production and depleted SOD activity induced by CSE were reversed by DHQ. DHQ notably reduced the increased lipid peroxidation induced by CSE in HBE cells. In addition, treatment with DHQ attenuated the morphological changes in the mitochondria caused by CSE. Moreover, we also found that DHQ increased the levels of Nrf2 in a concentration-dependent manner in the cigarette smoke-induced COPD mouse model and CSE-treated HBE cells. Additionally, after administering an Nrf2-specific inhibitor, ML385, to HBE cells, the elevated SLC7A11 and GPx4 mRNA and protein levels induced by DHQ were reversed. Moreover, ML385 treatment attenuated the protective effect of DHQ on lipid peroxidation.Conclusion: Our results show that treatment with DHQ significantly reverses the ferroptosis induced by cigarette smoke both in vivo and in vitro via a Nrf2-dependent signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Osteolytic diseases share symptoms such as bone loss, fracture and pain, which are caused by over-activated osteoclasts. Targeting osteoclast differentiation has emerged as a therapeutic strategy clinically. Dendrobine is an alkaloid isolated from Chinese herb Dendrobium nobile, with knowing effects of analgesia and anti-inflammation. The roles of dendrobine on osteoclasts and osteolysis remain unclear.Purpose: Herein, the possible roles of dendrobine in osteoclastogenesis, inflammatory osteolysis and the underlying mechanism were explored.Methods: Bone marrow-derived macrophages (BMMs) and RAW264.7 cells were employed to evaluate the roles of dendrobine on osteoclastogenesis, bone absorption and the underlying mechanism in vitro. LPS injection was used to cause inflammatory osteolysis in vivo.Results: Dendrobine repressed osteoclastogenesis, bone resorption induced by receptor activator of nuclear factor kappa B ligand (RANKL) in vitro. Mechanistically, dendrobine inhibited RANKL-upregulated intracellular (ROS), p-p38, c-Fos expression and nuclear factor of activated T cells (NFATc1) nuclear translocation. Osteoclastic genes were reduced, and among them matrix metalloproteinase 9 (MMP9) mRNA was dramatically blocked by dendrobine. Moreover, it substantially suppressed MMP9 protein expression during osteoclastogenesis in vitro. Accordingly, oral 20 mg/kg/day dendrobine was capable of preventing LPS-induced osteolysis with decreased osteoclasts in vivo.Conclusion: Taken together, dendrobine suppresses osteoclastogenesis through restraining ROS, p38-c-Fos and NFATc1-MMP9 in vitro, thus attenuates inflammatory osteolysis in vivo. This finding supports the discover of dendrobine as a novel osteoclast inhibitor for impeding bone erosion in the future. [ABSTRACT FROM AUTHOR]

Abstract: Systemic administration with bone marrow mesenchymal stem cells (BMSCs) is a promising approach to cure myocardial ischemia (MI), while the efficacy of cell transplantation is limited by the low engraftment of BMSCs. Tanshinone IIA (Tan IIA) has been reported many times for the treatment of MI. Therefore, the present study was performed to investigate whether Tan IIA could increase the migration of BMSCs to ischemic region and its potential mechanisms. In our study, we found that combination treatment with Tan IIA and BMSCs significantly alleviated the infarct size when compared with control group (31.46±3.00% vs. 46.95±6.51%, p <0.05). Results of real-time PCR showed that Tanshinone IIA (Tan IIA) did increase the migration of BMSCs to ischemic region in vivo, which was correlated with cardiac function recovery after MI. Furthermore, 2μM Tan IIA could enhance the migration capability of BMSCs in vitro (3.69-fold of control), and this enhancement could be blocked by AMD3100 (a CXC chemokine receptor 4 blocker). CXCR4, together with its specific receptor, stromal cell-derived factor-1 (SDF-1) plays a critical role in the stem cell recruitment. Our experiment indicated that Tan IIA could promote SDF-1α expression in the infarct area and enhance the CXCR4 expression of BMSCs in vitro. Therefore, we postulated that Tan IIA could increase the BMSCs migration via up-regulating SDF1/CXCR4 axis. [Copyright &y& Elsevier]

Abstract: Belamcanda chinensis (Iridaceae) belongs to the family of iridaceae and its rhizoma has been widely used for the treatment of throat ailment. Here we report a new pharmacological activity of B. chinensis leaf extract (BCL), that is, the hypoglycemic effect in normal and STZ-induced diabetic rats. Animals either healthy or STZ-induced diabetic show significantly lowered fasting blood glucose levels after treatment with BCL. The serum insulin concentration in normal rats is also enhanced. Additionally, the increase in blood glucose levels after administration of various carbohydrates in normal rats is significantly decreased and the oral glucose tolerance (OGTT) of STZ-induced diabetic rats is largely improved by BCL treatment. However, co-administration of BCL with Nifedipine, a Ca2+ ion channel blocker, or Nicorandil, an ATP-sensitive K+ ion channel opener thoroughly abolishes the hypoglycemic effect of BCL. HPLC analysis and compound identification showed that several isoflavone glycosides with antidiabetic activities were contained in BCL while pharmacological experiment showed that the polysaccharide fraction of BCL had no significant hypoglycemic effect on normal rats. Therefore, the isoflavone glycosides but not polysaccharides might be the active fraction of BCL in diabetes treatment. [Copyright &y& Elsevier]

Background: Parkinson's disease (PD) is one of the most common neurodegenerative motor disorders, and is characterized by the presence of Lewy bodies containing misfolded α-synuclein (α-syn) and by selective degeneration of midbrain dopamine neurons. Studies have shown that upregulation of ubiquitin-proteasome system (UPS) activity promotes the clearance of aggregation-prone proteins such as α-syn and Tau, so as to alleviate the neuropathology of neurodegenerative diseases.Purpose: To identify and investigate lycorine as a UPS enhancer able to decrease α-syn in transgenic PD models.Methods: Dot blot was used to screen α-syn-lowering compounds in an inducible α-syn overexpression cell model. Inducible wild-type (WT) and mutant α-syn-overexpressing PC12 cells, WT α-syn-overexpressing N2a cells and primary cultured neurons from A53T transgenic mice were used to evaluate the effects of lycorine on α-syn degradation in vitro. Heterozygous A53T transgenic mice were used to evaluate the effects of lycorine on α-syn degradation in vivo. mCherry-GFP-LC3 reporter was used to detect autophagy-dependent degradation. Ub-R-GFP and Ub-G76V-GFP reporters were used to detect UPS-dependent degradation. Proteasome activity was detected by fluorogenic substrate Suc-Leu-Leu-Val-Tyr-AMC (Suc-LLVY-AMC).Results: Lycorine significantly promoted clearance of over-expressed WT and mutant α-syn in neuronal cell lines and primary cultured neurons. More importantly, 15 days' intraperitoneal administration of lycorine effectively promoted the degradation of α-syn in the brains of A53T transgenic mice. Mechanistically, lycorine accelerated α-syn degradation by activating cAMP-dependent protein kinase (PKA) to promote proteasome activity.Conclusion: Lycorine is a novel α-syn-lowering compound that works through PKA-mediated UPS activation. This ability to lower α-syn implies that lycorine has the potential to be developed as a pharmaceutical for the treatment of neurodegenerative diseases, such as PD, associated with UPS impairment and protein aggregations. [ABSTRACT FROM AUTHOR]

Background: Osteoporosis is a threat to aged people who have excessive osteoclast activation and bone resorption, subsequently causing fracture and even disability. Inhibiting osteoclast differentiation and absorptive functions has become an efficient approach to treat osteoporosis, but osteoclast-targeting inhibitors available clinically remain rare. Kirenol (Kir), a bioactive diterpenoid derived from an antirheumatic Chinese herbal medicine Herba Siegesbeckiae, can treat collagen-induced arthritis in vivo and promote osteoblast differentiation in vitro, while the effects of Kir on osteoclasts are still unclear.Purpose: We explore the role of Kir on RANKL-induced osteoclastogenesis in vitro and bone loss in vivo.Methods: The in vitro effects of Kir on osteoclast differentiation, bone resorption and the underlying mechanisms were evaluated with bone marrow-derived macrophages (BMMs). In vivo experiments were performed using an ovariectomy (OVX)-induced osteoporosis model.Results: We found that Kir remarkably inhibited osteoclast generation and bone resorption in vitro. Mechanistically, Kir significantly inhibited F-actinring formation and repressed RANKL-induced NF-κB p65 activation and p-p38, p-ERK and c-Fos expression. Moreover, Kir inhibited both the expression and nuclear translocation of NFATc1. Ca2+ oscillation and caveolin-1 (Cav-1) were also reduced by Kir during osteoclastogenesis in vitro. Consistent with these findings, 2-10 mg/kg Kir attenuated OVX-induced osteoporosis in vivo as evidenced by decreased osteoclast numbers and downregulated Cav-1 and NFATc1 expression.Conclusions: Kir suppresses osteoclastogenesis and the Cav-1/NFATc1 signaling pathway both in vitro and in vivo and protects against OVX-induced osteoporosis. Our findings reveal Kir as a potential safe oral treatment for osteoporosis. [ABSTRACT FROM AUTHOR]

Background: Rhodioloside is a glucoside of tyrosol isolated from Rhodiola rosea. However, its regulating effect on hepatic dyslipidemia of atherogenic mice has rarely been studied.Purpose: The specific aims of current study included to clarify lipidomic perturbation in liver tissues of apolipoprotein E deficient (apoE-/-) mice fed with high-fat diet, and to examine the effects of rhodioloside against atherosclerosis and dyslipidemia.Study Design: The comparisons of hepatic lipidome were executed between wide type (WT) mice fed with normal diet (NDC) and apoE-/- mice fed with high-fat diet (Model), WT mice fed with high-fat diet (HFDC) versus the model mice, as well as the model mice versus rhodioloside-treated atherosclerotic mice.Methods: Ultra high performance liquid chromatography coupled with a Q exactive hybrid quadrupole-orbitrap mass spectrometry (UPLC-MS/MS) was employed to provide an unbiased and simultaneous measurement of individual lipid species in liver tissues.Results: Multivariate statistical analysis derived from LC-MS spectra revealed that high-fat diet and apoE deficiency caused a series of disturbances on glyerolipid metabolism, glycerophospholipid metabolism and sphingolipid metabolism. Rhodioloside administration showed atheroprotective effects on the apoE-/- mice with regulating the levels of 1 phosphatidylcholine, 2 phosphatidylserines, 5 alkyldiacylglycerols and 3 alkenyldiacylglycerols back to normal. In particular, PC (4:0/15:0) was positively associated with high-density lipoprotein cholesterol in blood, both of which could be ameliorated by rhodioloside.Conclusion: Our results identified the abnormal hepatic lipids in atherosclerosis progression that could efficiently improved by rhodioloside. These lipids contributed to biological understanding of atherogenic dyslipidemia in liver and could also served as sensitive indicators for drug target screening. [ABSTRACT FROM AUTHOR]