Multi-target analgesics with minimal side effects and high efficacy are a key research focus in addressing the global pain crisis. Using a molecular networking approach, five pairs of potent analgesic alkaloid enantiomers were isolated from the roots of Anacyclus pyrethrum (A. pyrethrum). Their structures were elucidated by comprehensive spectroscopic data analysis, including LR-HSQMBC and ¹H-¹⁵N HMBC, quantum ¹³C NMR DP4+ and ECD calculations, and single-crystal X-ray diffraction analysis. Anacyphrethines A (1) and B (2) are highly conjugated and polymethylated 6/6/6/6/5/7/5/5-fused octacyclic tetraazabic alkaloids possessing an unprecedented 8,14,18,24-tetraaza-octacyclo[16.8.2.1^1,23.0^4,28.0^5,17.0^9,16.0^11,15.0^21,27] nonacosane motif. Their biosynthetic pathways are proposed involving key aldol, hydroamination, and Schiff base reactions. All isolates showed potent analgesic effects in vivo. Even at a lower dose of 0.2 mg/kg, (±)-1 and (+)-1 still exhibited more potent analgesic activities than morphine. Interestingly, the racemic mixture (±)-1 showed stronger analgesic effect than either pure enantiomer alone at higher doses of 5 and 1 mg/kg; while, (±)-1 showed significant analgesic activities comparable to (+)-1 at lower doses of 0.2 and 0.04 mg/kg. (+)-1 had stronger analgesic effect than (-)-1 at five tested does. Further tests on 44 analgesic-related targets demonstrated that (+)-1 showed significant inhibitory effects against many ion channels such as TRPM8, Kv1.2, Kv1.3, and Ca_v2.1 with IC₅₀ values of 1.10 ± 0.26, 4.20 ± 0.07, 2.20 ± 0.24, and 10.40 ± 0.69 μmol/L, respectively, while (-)-1 primarily inhibited TRPC6, Kv1.2, and Kv1.3 ion channels with IC₅₀ values of 0.81 ± 0.05, 0.91 ± 0.04, and 1.50 ± 0.13 μmol/L, respectively, without affecting the opioid receptors, suggesting their non-opioid analgesic potentials. The molecular dockings provided structural guidance to develop potent non-opioid analgesics.

Acute liver failure (ALF) is a life-threatening condition associated with macrophage-mediated inflammatory responses. Effective therapies and drugs are still lacking to date. Here, we reveal that a derivative of xanthohumol, CAM12203, alleviates lipopolysaccharide (LPS) + d-galactosamine (D-GalN)-induced ALF through limiting macrophage-mediated inflammation, with the most significant impact on interleukin-1β (IL-1β) transcription. Through biotin labeling-mediated pull-down and LC-MS/MS analysis, diacylglycerol kinase ζ (DGKζ), a lipid-metabolizing kinase, is identified as the direct target of CAM12203. Mechanistically, DGKζ is induced in macrophages upon inflammatory stimuli and is upregulated observed on clinical liver failure samples. Its product phosphatidic acid (PA) boosts phospholipase C (PLC)-inositol 1,4,5-trisphosphate (IP₃)-Ca²⁺ signaling and subsequent janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) cascade, ultimately promoting IL-1β production and liver failure. DGKζ knockdown/ablation or inhibition significantly impairs the DGKζ-STAT3-IL-1β pathway along with ALF progression. Finally, CAM12203 is confirmed to be a new DGKζ inhibitor and acts against inflammation in a DGKζ-reliant manner. Taken together, CAM12203 inhibits IL-1β transcription in macrophages by binding to DGKζ and blocking the DGKζ-STAT3 axis, thereby exerting an ameliorative effect on ALF. These results not only highlight CAM12203 as a promising lead compound for ALF treatment, but also define DGKζ as a novel therapeutic target.

OBJECTIVE To optimize the extraction process of Xuelian yishen formula. METHODS The contents of total flavone， echinacoside and acteoside， and extraction yield in Xuelian yishen formula were chosen as indexes， entropy weight method-analytic hierarchy process was adopted to determine the weight coefficient. Box-Behnken response surface methodology was used to optimize the extraction process of Xuelian yishen formula with extraction time， solid-liquid ratio and extraction times as factors， using comprehensive score of above indexes as index. RESULTS The optimal extraction process of Xuelian yishen formula was extraction time of 2 h， solid-liquid ratio of 1∶12， extracting for 3 times. Average comprehensive score of 3 validation tests was 96.40 points （RSD＝0.28%）， the deviation of which with predictive value was 0.98%. CONCLUSIONS The optimized extraction process is stable， feasible and reproducible， which can provide reference for the extraction process of Xuelian yishen formula.

Ten compounds were isolated from the water extract of Eriocaulon buergerianum by HP20, ODS, Sephadex LH-20 and MCI Gel CHP-20 column chromatographic methods. Their structures were identified by spectroscopic and chemical approaches as 6-methoxyquercetin-3-O-(2′′′-vanilloyl)-β-D-glucopyranosyl-(1→6)-β-D-glucopyranoside (1), syringaresinol-4′-O-β-D-glucopyranoside (2), rutin (3), 1-O-feruloylglycerol (4), 1,2-benzenediol (5), vomifoliol (6), β-D-(6-O-trans-feruloyl) fructofuranosyl-α-D-O-glucopyranosied (7), dihydroferulic acid (8), guanosine (9) and quercetin-3-O-β-gentiobioside (10). The compound 1 is a new compound, the compounds 2 and 4-10 were obtained from Eriocaulon genus for the first time, and the compound 3 was isolated from this plant for the first time. Molecular docking study showed that 1 is a potential inhibitor of TNF-α. The compound 1 was evaluated for their anti-inflammatory activities in vitro, and 1 showed significant inhibitory activity against TNF-α production in lipopolysaccharide (LPS)-induced RAW264.7 macrophage cells at the concentrations of 1, 10 and 100 μmol·L^-1.

Objective:Ultra-high performance liquid chromatography-quadrupole/orbitrap high resolution mass spectrometry （UHPLC-Q-Orbitrap-MS） was used to rapidly analyze and assign the chemical constituents of Naizilai granules. Method:An ACQUITY UPLC BEH Shield RP C₁₈ column （2.1 mm×100 mm， 1.7 µm） was selected for chromatographic analysis， the mobile phase was 0.1% formic acid aqueous solution （A） and acetonitrile （B） for gradient elution （0-3 min， 1%B； 3-16 min， 1%-11%B； 16-30 min， 11%-34%B； 30-37 min， 34%-52%B； 37-42 min， 52%-100%B； 42-44 min， 100%B）， flow rate was 0.3 mL·min^-1 and the column temperature was 35 ℃. Mass spectrometry data of Naizilai granules were collected in positive and negative ion modes， the chemical constituents of this preparation were speculated and identified according to the precise molecular weight， secondary fragmentation and other information， combined with reference substance and literature data. Result:A total of 175 compounds were identified and speculated， including 72 flavonoids， 77 organic acids， 15 sesquiterpenes， 6 coumarins and 5 other compounds. Among these identified chemical constituents， there were 154 from Artemisia rupestris， 64 from Hyssopus cuspidatus， 33 from Cordia dichotoma， 42 from Viola tianshanica， 56 from Lactuca sativa， 65 from Mentha haplocalyx， 78 from Matricaria chamomilla， 28 from Ziziphus jujuba， 7 of which were common components of these eight herbs. Conclusion:The established analytical method can realize the rapid and accurate identification of the chemical constituents in Naizilai granules， and basically covers the main constituents of each medicinal material in the formula， so as to provide a basis for improving the quality evaluation system of the preparation and lay a foundation for elucidating the pharmacodynamic mechanism.

Plants of genus Cichorium are famous due to their therapeutic and medicinal properties. They are used as traditional medicine and edible food. To date, several scholars concentrated on compounds belonging to coumarins, flavonoids, sesquiterpenoids, triterpenoids, steroids, organic acids and other chemical constituents. Pharmacological effects such as photo-protective, hepatoprotective, anti-diabetic and lipid lowering, antioxidant, anti-inflammation, antifungal, antimalarial, increased bone mineral density, as well as vasorelaxant and antitumour activity were wildly reported. In this study, botanical resources, ethnopharmacological application, chemical constituents and bioactivities, as well as safety and toxicity of clinical applications of genus Cichorium were reviewed, which may provide a reliable basis for further development and utilization of Cichorium genetic resources.

Due to the diversity and complexity, the change of chemical components in medicinal plant according to the time, cultivated varieties or ecological condition is difficult to recognize using traditional phytochemistry method. In order to analyze the pharmacodynamics material basis in Uighur medicinal plant Artemisia rupestris L. in an effective and comprehensive way, a plant metabolomics approach was established based on liquid chromatography-tandem mass spectrometry (LC-MS/MS). This study firstly focused on the effect of extraction solvents,redissolve solvents and ultrasonic time on the untargeted metabolomics, then the optimal preparation condition was selected according to metabolites coverage. After methodology validation, the approach was applied to acquire metabolic information in root, stem, branchlet, leaf and flower of Artemisia rupestris L. The results showed that the metabolome in flower was obviously different with the other organs. Coupling with multivariate statistical analysis, a batch of differential metabolites were picked out, in which 61 flavonoids, 97 rupestonic acid derivatives, 7 chlorogenic acids and 15 other compounds were primarily recognized according to the characteristic fragmentation rules of specific structure type and database retrieval. Additionally,the distribution characteristics of the above 180 differential metabolites was illustrated by cluster heat map. In conclusion,this study provided important information about the rational utilization of effective parts from Artemisia rupestris L.,and offered a novel strategy for quality control,variety improvement and reasonable development of medicinal plants.

In traditional Chinese medicine, Nitraria sibirica Pall. (Nitrariaceae) is used to treat hypertension. This study determined the effects of the total alkaloids of the leaves of Nitraria sibirica (NSTA) on blood pressure and albuminuria in mice treated with angiotensin II and a high-salt diet (ANG/HS). Adult mice were divided into three groups: control; infused with angiotensin II and fed a diet containing 4% NaCl (ANG/HS; and ANG/HS plus injection of NSTA (1 mg·kg(-1)·d(-1), i.p.). After treatment of these regimens, daily water and food intake, kidney weight, blood pressure, urinary albumin excretion, renal concentrations of inflammatory markers, including soluble intercellular adhesion molecule-1 (sICAM-1) and monocyte chemoattractant protein-1 (MCP-1), and the expression of renal fibrosis markers were determined. Compared to the control group, the ANG/HS group had higher blood pressure and urinary albumin excretion. Treatment with NSTA in ANG/HS mice for three weeks significantly reduced blood pressure and urinary albumin excretion. ANG/HS treatment caused elevated levels of sICAM-1 and MCP-1, as well as increased fibrosis markers. Concurrent treatment with ANG/HS and NSTA attenuated the levels and expression of renal inflammatory and fibrosis markers. Treatment with NSTA effectively reduces hypertension-induced albuminuria through the reduction of renal inflammatory and fibrosis markers.
Albuminuria ; drug therapy ; metabolism ; physiopathology ; Alkaloids ; administration & dosage ; Angiotensin II ; metabolism ; Animals ; Blood Pressure ; drug effects ; Chemokine CCL2 ; metabolism ; Drugs, Chinese Herbal ; administration & dosage ; Humans ; Hypertension ; drug therapy ; metabolism ; physiopathology ; Magnoliopsida ; chemistry ; Male ; Mice ; Rats, Sprague-Dawley ; Sodium Chloride, Dietary ; adverse effects ; metabolism

To investigate the protective effects and possible mechanism of pomegranate flowers polyphenols (PFP) on liver function of rats with diabetes combining non-alcoholic fat liver diseases, diabetes combining nonalcoholic fat liver disease model rats were established with high calorie feeding and small dose intraperitoneal injection of streptozotocin (STZ). Model rats were randomly divided into: model group, metformin group, pomegranate flowers polyphenols low, medium and high dose group (75, 150 and 300 mg x kg(-1)). After four weeks treatment, the levels of FPG, blood fat profiles and serum insulin, ALT, AST levels, SOD and MDA in the liver and serum separately were analyzed with biochemical methods. Paraoxonase (PON1 and PON3) mRNA and protein expression in liver were checked by RT-PCR and immunohistochemical method. Pathological changes of the liver were observed. FPG, IRI, non-HDL-C and transaminase significantly reduced and HDL-C raised in the each PFP dose group; Furthermore, compared with model group, fat drops in liver cells significantly reduced, antioxidant ability enhanced, PON1 mRNA and protein expression level in liver increased significantly. The protective effects of PFP against diabetes combining non-alcoholic fat liver diseases rats might through the increase liver PON1 mRNA and protein expression further enhanced the body antioxidant capacity and reduced IRI so as to ameliorate the rat hepatic steatosis.
Alanine Transaminase ; blood ; Animals ; Aryldialkylphosphatase ; genetics ; metabolism ; Aspartate Aminotransferases ; blood ; Blood Glucose ; metabolism ; Diabetes Mellitus, Experimental ; metabolism ; pathology ; Fatty Liver ; metabolism ; pathology ; Flowers ; chemistry ; Insulin ; blood ; Liver ; metabolism ; pathology ; Male ; Malondialdehyde ; blood ; metabolism ; Non-alcoholic Fatty Liver Disease ; Plants, Medicinal ; chemistry ; Polyphenols ; isolation & purification ; pharmacology ; Punicaceae ; chemistry ; RNA, Messenger ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase ; blood ; metabolism

Protective effects of two different extracts of TSCA (total saponins from Cicer arietinum) were studied on kidney of T2DM rats. The diabetic model group was established with high calorie feeding and small dose injection of streptozotocin (STZ, 45 mg x kg(-1)). DM rats were randomly assigned to model group (feed with propylene glycol 1 mL/100 g), TSCA high dose group (300 mg x kg(-1)), TSCA low dose group (100 mg x kg(-1)) and normal control group (feed with propylene glycol 1 mL/100 g). After four weeks treatment with TSCA I and II, the levels of FPG FIns, BUN, Scr, ATII, ET-1, TXB2 and 6-keto-PGF1alpha in blood and the activities of SOD, GSH-PX and MDA in kidney were analyzed by biochemical methods. After four weeks treatment with TSCA II, the levels of FPG FIns, BUN, Scr, ATII and ET-1 were reduced significantly; and the ratios of TXB2 to 6-keto-PGF1alpha and SOD were effectively alleviated in TSCA II group. While there is no significant change on FPG and BUN in comparison to the rats treated with TSCA I, Scr, ATII, ET-I, GSH-PX and SOD were alleviated. The results suggest that TSCA II could be used to reduce FPG and FIns. According to the result of vasoactive substances index, TSCA II is more effective than TSCA I on renal protection of DM rats.
6-Ketoprostaglandin F1 alpha ; blood ; Angiotensin II ; blood ; Animals ; Blood Glucose ; metabolism ; Blood Urea Nitrogen ; Cicer ; chemistry ; Creatinine ; blood ; Diabetes Mellitus, Experimental ; blood ; metabolism ; Diabetes Mellitus, Type 2 ; blood ; metabolism ; Endothelin-1 ; blood ; Glutathione Peroxidase ; metabolism ; Hypoglycemic Agents ; isolation & purification ; pharmacology ; Insulin ; blood ; Kidney ; metabolism ; Male ; Malondialdehyde ; metabolism ; Plants, Medicinal ; chemistry ; Random Allocation ; Rats ; Rats, Wistar ; Saponins ; isolation & purification ; pharmacology ; Superoxide Dismutase ; metabolism ; Thromboxane B2 ; blood