查找使用阿拉丁产品的科研文献

LianZhiXiaoYan Formula alleviates LPS-induced chronic pneumonia via regulating metabolic reprogramming through SIRT3-SDH-SUCNR1 signaling pathway

Siyuan Liu,Jincheng Lv,Peng Peng,Xianshu Song,Pengyu Dai,Fangle Liu,Yufeng Yao,Chenchen Zhu,Chaozhan Lin

Ethnopharmacological relevance Recurrent or persistent respiratory tract infection may progress to chronic pneumonia or other debilitating sequelae in the absence of appropriate therapeutic interventions, seriously compromising the patients' quality of life. LianZhiXiaoYan Formula (LZXYF), a Chinese prescription composed of Chinese medical herbs Andrographis herba (ChuanXinLian) and Radix helicteris (ShanZhiMa), possesses efficiency of clearing heat and detoxifying, and shown a good therapeutic effect on respiratory infectious diseases, but its mechanism of action is not clear. Aim of the study Aim to evaluate the therapeutic efficacy of LZXYF in treatment of CP and investigate its molecular and physiological mechanisms. Materials and methods The therapeutic effects of LZXYF on CP was evaluated in an LPS-induced murine model by assessing the pulmonary function, lung histopathology, and biochemical indicators. To explore the mechanism of LZXYF, the lung metabolomics and the components of LZXYF distributed in lung were analyzed by UHPLC-Q-TOF-MS/MS. The impact of LZXYF on SIRT3-SDH-SCUNR1 pathway was investigated using RT-qPCR and Western blot, and the interaction between LZXYF and SIRT3 was verified via CETSA. LPS-induced LLC cell and succinate-induced RAW264.7 cell were employed to investigate the effect and mechanism of LZXYF on metabolic reprogramming and inflammation regulation, with selective inhibition of SIRT3 and SUCNR1, respectively. Results LZXYF treatment improved pulmonary function as demonstrated by increased Tidal volume, enhanced Minute ventilation, elevated Peak expiratory flow rate, and reduced Timed inspiration ( P < 0.05). Moreover, histopathological analysis revealed that LZXYF treatment attenuated emphysema and airway remodeling, concomitant with reduced the levels of TGF-β and HYP ( P < 0.01). Metabolomics demonstrated that LZXYF treatment restored 38 dysregulated metabolites in CP mice, primarily involving tryptophan, histidine, lysine and arginine metabolic pathways. Correlation analysis of 16 lung-distributed components and the 38 differential metabolites further indicated that LZXYF alleviated CP through SIRT3 signaling pathway mediated metabolic reprogramming. We further demonstrated that LZXYF could up-regulate SIRT3 to enhance the activities of SDH ( P < 0.01), a metabolic enzyme in TCA cycle, thereby regulating metabolic reprogramming and inhibiting the activation of SUCNR1 to prevent succinate-induced inflammation responses ( P < 0.01). Furthermore, we elucidated that the active components of LZXYF exerted ameliorated effects by up-regulating SIRT3 expression in LPS or 3-TYP induced LLC cell metabolic reprogramming, which revealed SIRT3 as a critical molecular target for LZXYF to improve metabolic reprogramming and suppress inflammatory responses induced by succinate. Conclusion LXZYF could ameliorate CP through up-regulating SIRT3, which enhances TCA cycle and suppresses succinate-mediated inflammation. This study provides new insight into the therapeutic potential of LZXYF for CP treatment.

Synthesis, bioactivity and molecular docking of novel coumarin-quinolinamide containing monocyclic monoterpenes as potential SDH inhibitors

Yuan Zhong,Cong Huang,Jing Zhang,Liang Zhong,Rong Zeng,Yuhuan Kuang,Xinyan Ye,Ziyin Xie,Ji Zhang,Zongde Wang,Shangxing Chen,Dayong Peng

Succinate dehydrogenase inhibitors (SDHI) are widely used in plant antifungal agents. To break the barrier of resistance, a series of new coumarin-quinolinamide SDHI derivatives containing monocyclic monoterpenes were designed and synthesized using natural camphor or natural menthol as lead compounds, and their structures were characterized by FT-IR, 1 H NMR, 13 C NMR and HRMS. In vitro antifungal activity test results showed that the target compounds had inhibitory activity against most plant pathogenic fungi, especially against Rhizoctonia solani and Phytophthora nicotianae var. nicotianae , which was superior to other fungi. Among them, compounds 11t and 12t showed better inhibitory effects on Rhizoctonia solani than the commercial fungicide tricyclazole, with EC 50 of 16.90 mg/L and 27.09 mg/L, respectively. Based on this, the detached leaf assay was used to further explore the in vivo therapeutic and preventive effects of compounds 11t and 12t on rice sheath blight in plants. The results of the antifungal activity test in vivo showed that compound 11t was slightly better than the positive control, while compound 12t was close to the control effect of azoxystrobin. More importantly, the more bioactive compounds 11t and 12t did not affect the germination of cowpea seeds and also did not affect the growth of normal human hepatocytes and kidney cells. Molecular docking experiments showed that the introduction of the diethylamino group could promote the formation of hydrogen bonds between the hydrogen atom on the amide bond of the target compound and residue Tyr91, and compounds 11t and 12t had smaller free energy between the amino acid residue, which would enhance the antifungal activity of the compounds. These studies proved the potential value of this series of compounds for the study of novel amide-based SDHI fungicides.

SIRT5 Facilitates Liver Steatosis Progression via Promoting SDH Desuccinylation During High-Fat Diet Feeding

Zekun Liu,Jie Hu,Yinan Lin,Chuang Ge,Yuru Shao,Mengmeng Bao,Mengjie Liu,Shilin Jia,Yating Li,Xiaozhi Xu,Ruiyan Li,Qizhou Jiang,Fangrong Yan,Fei Xiao,Junmei Ye

Background and Aims Obesity is one of the main factors that causes liver steatosis. While the mechanism remains to be elucidated. Methods SIRT5 was knocked down in male C57/BL6 mice via tail vein injection of adenovirus, which were then fed either normal chow or a high-fat diet. Glucose and lipid content was detected in the serum, and the liver tissue was harvested for further analysis. We also used primary rat hepatocytes and a hepatocyte cell line L02 cells to explore the role of SIRT5 in regulating lipid overload-induced hepatocyte injury. Finally, rAAV-induced SDHC knockdown was applied to investigate the role of SDHC in HFD-induced liver steatosis. Results High-fat diet results in upregulation of SIRT5 and causes desuccinylation of mitochondrial proteins including SDH. Adenovirus-driven SIRT5 knockdown of SIRT5 induces alleviated high-fat diet-induced hepatic injury and preserves mitochondrial function. We also show that SIRT5 knockdown reduces oxidative stress of hepatocytes both in vivo and in vitro. Mechanistically, SIRT5 in hepatocytes facilitates the desuccinylation of mitochondrial proteins including SDH, reducing SDH activity, which results in mitochondrial dysfunction. Furthermore, SIRT5 specifically inhibits the expression of SDHC at the post-transcriptional level, and SDHC knockdown deteriorates lipid overload-induced hepatic lipotoxicity. Conclusion and Implications Our findings underscore the critical role of SIRT5 in the progress of liver steatosis and provide novel insights into the regulation of SDH by SIRT5-mediated desuccinylation that affects mitochondrial function. Moreover, our results suggest that targeting SIRT5 may offer a therapeutic strategy for liver steatosis.

Novel amide derivatives containing azetidine moiety as potential SDH inhibitors: Design, synthesis, and evaluation of bioactivity

Yong Zhang,Mei Zhu,Kun Hu,Xing Liu,Yue Zou,Jixiang Chen

Fluopyram is a highly effective agricultural fungicide targeting succinate dehydrogenase (SDH). Twenty-six novel amide derivatives containing azetidine were designed and synthesized with fluopyram as the lead, and their biological activities were tested. The results showed that some compounds had obvious antifungal activities against Phomopsis sp., among them, the EC 50 value of compound C24 was 5.7 mg/L, which was significantly better than fluopyram (105.4 mg/L). The curative and protective activities of compound C24 on kiwi fruit infected with Phomopsis sp. were 42.2 and 52.9 %, which were better than that of fluopyram (30.4 and 35.6 %) at 200 mg/L. Moreover, compound C24 exhibited excellent inhibitory against SDH. The results of scanning electron microscopy (SEM) indicated that the mycelium of Phomopsis sp. collapsed or even ruptured after compound C24 treatment. Meanwhile, molecular docking showed that compound C24 was deeply embedded into the SDH binding pocket, and the binding model was stabilized by a cation–π interaction with Cys-40, Tyr-58 and an H-bond with Lys-455 and Asn-452. Compound C24 can provide a valuable idea to find new succinate dehydrogenase inhibitors.

Design, Synthesis, and Antifungal Activity of N-(alkoxy)-Diphenyl Ether Carboxamide Derivates as Novel Succinate Dehydrogenase Inhibitors

Bo He,Yanhao Hu,Wang Chen,Xu He,Enpei Zhang,Mengxu Hu,Pu Zhang,Wei Yan,Yonghao Ye

Succinate dehydrogenase (SDH, EC 1.3.5.1) is one of the most promising targets for fungicide development and has attracted great attention worldwide. However, existing commercial fungicides targeting SDH have led to the increasingly prominent problem of pathogen resistance, so it is necessary to develop new fungicides. Herein, we used a structure-based molecular design strategy to design and synthesize a series of novel SDHI fungicides containing anN-(alkoxy)diphenyl ether carboxamide skeleton. The mycelial growth inhibition experiment showed that compoundM15exhibited a very good control effect against four plant pathogens, with inhibition rates of more than 60% at a dose of 50 μg/mL. A structure–activity relationship study found that N-O-benzyl-substituted derivatives showed better antifungal activity than others, especially the introduction of a halogen on the benzyl. Furthermore, the molecular docking results suggested that π–π interactions with Trp35 and hydrogen bonds with Tyr33 and Trp173 were crucial interaction sites when inhibitors bound to SDH. Morphological observation of mycelium revealed thatM15could inhibit the growth of mycelia. Moreover, in vivo and in vitro tests showed thatM15not only inhibited the enzyme activity of SDH but also effectively protected rice from damage due toR. solaniinfection, with a result close to that of the control at a concentration of 200 μg/mL. Thus, theN-(alkoxy)diphenyl ether carboxamide skeleton is a new starting point for the discovery of new SDH inhibitors and is worthy of further investigation.Keywords:succinate dehydrogenase (SDH);antifungal activity;fungicide;N-(alkoxy)diphenyl ether carboxamide

Application of a novel nanoemulsion adjuvant for rabies vaccine which stabilizes a Krebs cycle intermediate (SDH) in an animal model

Liu Ze,Li Zonglin,Wu Ya’Nan,Song Shaohui,Yang Huijuan,Cai Wei,Weidong Li,Guoyang Liao

Antifungal Activity and Mechanism of Camphor Derivatives against Rhizoctonia solani: A Promising Alternative Antifungal Agent for Rice Sheath Blight

Li Zhang,Yizhong Huang,Xinying Duan,Hongyan Si,Hai Luo,Shangxing Chen,Liheng Liu,Haohua He,Zongde Wang,Shengliang Liao

Rice sheath blight, caused by the fungus Rhizoctonia solani, poses a significant threat to rice cultivation globally. This study aimed to investigate the potential mechanisms of action of camphor derivatives against R. solani. Compound 4o exhibited superior fungicidal activities in vitro (EC50 = 6.16 mg/L), and in vivo curative effects (77.5%) at 500 mg/L were significantly (P < 0.01) higher than the positive control validamycin·bacillus (66.1%). Additionally, compound 4o exhibited low cytotoxicity and acute oral toxicity for adult worker honeybees of Apis mellifera L. Mechanistically, compound 4o disrupted mycelial morphology and microstructure, increased cell membrane permeability, and inhibited both PDH and SDH enzyme activities. Molecular docking and molecular dynamics analyses indicated a tight interaction of compound 4o with PDH and SDH active sites. In summary, compound 4o exhibited substantial antifungal efficacy against R. solani, serving as a promising lead compound for further optimization of antifungal agents.

Preparation and evaluation of an active modified oxygen/ carbon dioxide preservative for packaged fresh-cut durian

Guang Wu,Shuangdi Hou,Qingchun Yin,Li Guo,Hao Deng

In this study, a series of chitosan/copper nanocomposites (CS/Cu-NCs) served as catalyzers for VC to remove O 2 in food packages were successfully synthesized, characterized, and further utilized to prepare an active modified O 2 /CO 2 preservative. Transmission electron microscope, ultraviolet-visible, and infrared spectra confirmed CS/Cu-NCs #1–3 were successfully synthesized. Three components of the preservative were optimized, and the best formulation was: CS/Cu-NCs #2: VC: NaHCO 3 =0.5:1.5:0.15. It maintained relatively stable O 2 /CO 2 in the package at 10℃. Fresh-cut durian treated with 0 g (CK), 1.15 g (T1), 2.3 g (T2), and 3.45 g (T3) preservatives were stored at 10℃. Results showed that T1 group exhibited significantly ( P <0.05) higher firmness and VC content compared with CK at 12 d, indicating the best qualities. Key respiratory enzyme analyses verified that decreasing SDH, increasing G-6-PDH and 6-PGDH contributed mostly to the superior qualities of T1 group. This study could provide a prospective solution for packaged fresh-cut durian.

Design and Synthesis of Novel N-(Pyrazol-4-yl)benzamide Derivatives Featuring a Diphenylamine or Diphenyl Ether Scaffold as Potential Broad-Spectrum SDH Inhibitors

Bo Luo,Yanbing Wu,Xiaoyang Zhao,Huanxi Cui,Wenjing Niu,Zhanghan Gao,Xiaoyu Feng,Dan Li,Yi Zhao,Yuchen Tao,Xinyue Hu,Yinge Wang,Yihan Hu,Jianqi Chai

A series of novel N-(pyrazol-4-yl)benzamide derivatives featuring diphenylamine or diphenyl ether scaffolds was synthesized and evaluated for antifungal activities. Remarkably, compound 6i demonstrated potent broad-spectrum efficacy against five fungal species, particularly Sclerotinia sclerotiorum, with a half maximal effective concentration (EC50) value of 0.44 μg/mL, outperforming Boscalid (EC50 = 0.71 μg/mL) and nearing Fluxapyroxad (EC50 = 0.26 μg/mL). Additionally, compound 6i exhibited substantial protective effects against S. sclerotiorum on oilseed rape leaves, Rhizoctonia solani on rice leaves, and Valsa mali on apple fruits at 100 μg/mL. Scanning electron microscopy (SEM) analysis further confirmed that 6i could inflict significant damage to S. sclerotiorum hyphae. Further succinate dehydrogenase (SDH) enzymatic inhibition assays, molecular docking, and molecular dynamics (MD) simulations indicated that compound 6i could potentially act as a succinate dehydrogenase inhibitor (SDHI). These findings suggested that 6i held significant promise as an innovative broad-spectrum SDHI for crop protection, warranting further investigation.

Traits variation of acorns and cupules during maturation process in Quercus variabilis and Quercus aliena

Xiong Yang,Qian Zhang,Ning Yang,Muxi Chang,Yaoyao Ge,Huirong Zhou,Guolei Li

Quercus variabilis and Quercus aliena are two native tree species in China, which have similar habitats, and their regeneration mainly depends on acorn dispersal. This study analyzed the contents of water, soluble sugar, starch, soluble protein , and total phenolics in acorns and cupules during the whole development process to explore the difference between species. Thereinto, starch and total phenol occupied the dominant roles as their high contents. The acorn starch contents increased sharply during development in both species, but the contents in Q . variabilis were almost twice those of Q . aliena when mature. Similarly, high expression levels of starch synthase , soluble starch synthase 2 ( SSS2 ) were also found in the acorns of Q . variabilis . The total phenol contents in Q . variabilis acorns were high at the early stages, and decreased sharply to similar contents in Q . aliena when mature. Additionally, the cupules in Q . variabilis had high contents of total phenols during the whole development period. Similar trends were also found in the expression patterns of UGT84A13 and SDH . The high total phenols in acorns and cupules of Q . variabilis probably protect the acorns from Mechoris ursulus , as only Q . aliena suffered a severe pest infestation in the early development stages. This study not only clarifies the interspecific difference between storage and defense substances during the development process in acorns and cupules, but also deepens understanding the specialized mechanisms of plant–pest/animal interactions in Quercus .

Design, synthesis, and nematicidal activity of novel 1,2,4-oxadiazole derivatives containing amide fragments

Ou Yuqin,Guo Xue,Zhang Qi,Zhang Wei,Gan Xiuhai

Plant-parasitic nematodes are seriously affecting agricultural production worldwide and there are few highly effective and low-risk nematicides to control nematode diseases. In order to discover new nematicides, a series of 1,2,4-oxadiazole derivatives containing amide fragments have been designed and synthesized with the principle of active substructure splicing. The nematicidal activity of the target compounds was evaluated in vitro and it indicated that compound C3 exhibited the most nematicidal activity against Bursaphelenchus xylophilus , Aphelenchoides bessey i, and Ditylenchus destructor with the LC 50 values of 37.2, 36.6, and 43.4 μg/mL, respectively, which were superior to positive agent tioxazafen. The preliminary mechanism results revealed that compound C3 not only inhibited the reproduction of B. xylophilus populations, but also affected the production of ROS and the accumulation of lipofuscin and lipids. Furthermore, compound C3 showed good inhibition of succinate dehydrogenase (SDH) with the IC 50 value of 45.5 µmol/L. Molecular docking indicated that compound C3 had excellent binding to amino acids around the SDH active pocket. This work indicated that 1,2,4-oxadiazole derivative containing amide fragment is a promising template for the discovery of new nematicides and compound C3 can be used as a potential nematicide candidate. Graphical abstract

Tanshinone IIA prevents LPS-induced inflammatory responses in mice via inactivation of succinate dehydrogenase in macrophages

Liu Qiu-yan,Zhuang Yu,Song Xian-rui,Niu Qun,Sun Qiu-shuang,Li Xiao-nan,Li Ning,Liu Bao-lin,Huang Fang,Qiu Zhi-xia

Metabolic reprogramming is associated with NLRP3 inflammasome activation in activated macrophages, contributing to inflammatory responses. Tanshinone IIA (Tan-IIA) is a major constituent from Salvia miltiorrhiza Bunge, which exhibits anti-inflammatory activity. In this study, we investigated the effects of Tan-IIA on inflammation in macrophages in focus on its regulation of metabolism and redox state. In lipopolysaccharides (LPS)-stimulated mouse bone marrow-derived macrophages (BMDMs), Tan-IIA (10 μM) significantly decreased succinate-boosted IL-1β and IL-6 production, accompanied by upregulation of IL-1RA and IL-10 release via inhibiting succinate dehydrogenase (SDH). Tan-IIA concentration dependently inhibited SDH activity with an estimated IC 50 of 4.47 μM in LPS-activated BMDMs. Tan-IIA decreased succinate accumulation, suppressed mitochondrial reactive oxygen species production, thus preventing hypoxia-inducible factor-1α (HIF-1α) induction. Consequently, Tan-IIA reduced glycolysis and protected the activity of Sirtuin2 (Sirt2), an NAD + -dependent protein deacetylase, by raising the ratio of NAD + /NADH in activated macrophages. The acetylation of α-tubulin was required for the assembly of NLRP3 inflammasome; Tan-IIA increased the binding of Sirt2 to α-tubulin, and thus reduced the acetylation of α-tubulin, thus impairing this process. Sirt2 knockdown or application of Sirt2 inhibitor AGK-2 (10 μM) neutralized the effects of Tan-IIA, suggesting that Tan-IIA inactivated NLRP3 inflammasome in a manner dependent on Sirt2 regulation. The anti-inflammatory effects of Tan-IIA were observed in mice subjected to LPS challenge: pre-administration of Tan-IIA (20 mg/kg, ip) significantly attenuated LPS-induced acute inflammatory responses, characterized by elevated IL-1β but reduced IL-10 levels in serum. The peritoneal macrophages isolated from the mice displayed similar metabolic regulation. In conclusion, Tan-IIA reduces HIF-1α induction via SDH inactivation, and preserves Sirt2 activity via downregulation of glycolysis, contributing to suppression of NLRP3 inflammasome activation. This study provides a new insight into the anti-inflammatory action of Tan-IIA from the respect of metabolic and redox regulation.