pachymic-acid and Disease-Models--Animal

Articular cartilage degeneration is a characteristic pathological change of osteoarthritis (OA). Pachymic acid (PA) is an active ingredient found in Poria cocos. Previous studies have shown that PA has anti-inflammatory effects on a variety of diseases. However, the role of PA in OA and its underlying mechanisms has not been clearly elucidated. In this study, we investigated potential protective effect of PA on OA through cell experiments in vitro and animal experiments in vivo. PA inhibited interleukin-1β-induced inflammatory mediator production in chondrocytes, which includes nitric oxide, inducible nitric oxide synthase, prostaglandin E2, cyclooxygenase-2, tumor necrosis factor alpha and interleukin-6. Meanwhile, PA also reversed the up-regulation of matrix metalloproteinase-3 and thrombospondin motifs 5, and the down-regulation of collagen type II and aggrecan in IL-1β-treated chondrocytes. Mechanistically, our findings revealed that PA-mediated overexpression of SIRT6 inhibited the NF-κB signaling pathway. In vivo, PA contributes to improve cartilage damage in the mouse OA model. In summary, PA inhibited IL-1β-induced inflammation and extracellular matrix degeneration by promoting SIRT6 expression and inhibiting the NF-κB signaling pathway, which indicates that PA is beneficial for the treatment of OA.

Topics: Animals; Chondrocytes; Cyclooxygenase 2; Disease Models, Animal; Inflammation; Interleukin-1beta; Mice; NF-kappa B; Osteoarthritis; Sirtuins

Chronic kidney disease (CKD) is a major public health problem associated with high mortality. The therapeutic effects of pachymic in CKD management and its underlying mechanisms have not been studied. Therefore, we aimed to investigate the possible inhibitory effect of PA on renal Wnt/β-catenin signalling in CKD.. CKD was induced in rats by doxorubicin (DOX; 3.5 mg/kg i.p., twice weekly for 3 weeks). Rats were treated orally with PA (10 mg/kg/day), LOS (10 mg/kg/day) or their combination (PA + LOS) for 4 weeks starting after the last dose of DOX.. DOX-induced renal injury was characterized by high serum cystatin-C, and urine albumin/creatinine ratio, renal content of podocin and klotho were decreased. Tumour necrosis factor-α, interleukin-6, interleukin-1β, Wnt1, active β-catenin/total β-catenin ratio and fibronectin along with mRNA expression of RENIN, ACE and AT1 were increased in renal tissues. Treatment with either PA or LOS ameliorated all DOX-induced changes. The combined treatment was more effective in improving all changes than monotherapy.. These results suggest a new therapeutic benefit of PA in ameliorating CKD in rats through its up-regulatory effect on renal klotho thereby preventing Wnt/β-catenin reactivation and RAS gene expression. PA/LOS combination provided an additional inhibition of Wnt/β-catenin signalling and its downstream targets.

Topics: Animals; Cystatin C; Disease Models, Animal; Enzyme Inhibitors; Fibronectins; Gene Expression Regulation; Kidney Function Tests; Klotho Proteins; Phospholipases A; Rats; Renal Insufficiency, Chronic; Renin-Angiotensin System; Triterpenes; Wnt Signaling Pathway; Wolfiporia

Pulmonary hypertension (PH) is a severe pulmonary vascular disease that eventually leads to right ventricular failure and death. The purpose of this study was to investigate the mechanism by which pachymic acid (PA) pretreatment affects PH and pulmonary vascular remodeling in rats.. PH was induced via hypoxia exposure and administration of PA (5 mg/kg per day) in male Sprague-Dawley rats. Hemodynamic parameters were measured using a right ventricular floating catheter and pulmonary vascular morphometry was measured by hematoxylin-eosin (HE), α-SMA and Masson staining. MTT assays and EdU staining were used to detect cell proliferation, and apoptosis was analyzed by TUNEL staining. Western blotting and immunohistochemistry were used to detect the expression of proteins related to the Nrf2-Keap1-ARE pathway.. PA significantly alleviated hypoxic PH and reversed right ventricular hypertrophy and pulmonary vascular remodeling. In addition, PA effectively inhibited proliferation and promoted apoptosis in hypoxia-induced pulmonary artery smooth muscle cells (PASMCs). Moreover, PA pretreatment inhibited the expression of peroxy-related factor (MDA) and promoted the expression of antioxidant-related factors (GSH-PX and SOD). Furthermore, hypoxia inhibited the Nrf2-Keap1-ARE signaling pathway, while PA effectively activated this pathway. Most importantly, addition of the Nrf2 inhibitor ML385 reversed the inhibitory effects of PA on ROS generation, proliferation, and apoptosis tolerance in hypoxia-induced PASMCs.. Our study suggests that PA may reverse PH by regulating the Nrf2-Keap1-ARE signaling pathway.

Topics: Animals; Antioxidant Response Elements; Disease Models, Animal; Hypertension, Pulmonary; Kelch-Like ECH-Associated Protein 1; Male; NF-E2-Related Factor 2; Phospholipase A2 Inhibitors; Rats; Rats, Sprague-Dawley; Signal Transduction; Triterpenes

Topics: Animals; Cardiomegaly; Disease Models, Animal; Disease Susceptibility; Doxorubicin; Gene Expression Regulation; Heart Failure; Heart Function Tests; Membrane Proteins; MicroRNAs; Myocytes, Cardiac; Rats; Ryanodine Receptor Calcium Release Channel; Signal Transduction; Triterpenes

Women with polycystic ovary syndrome (PCOS) are characterized by endocrine disorders accompanied by a decline in oocyte quality. In this study, we generated a PCOS mice model by hypodermic injection of dehydroepiandrosterone, and metformin was used as a positive control drug to study the effect of pachymic acid (PA) on endocrine and oocyte quality in PCOS mice. Compared with the model group, the mice treated with PA showed the following changes (slower weight gain, improved abnormal metabolism; increased development potential of GV oocytes, reduced number of abnormal MII oocytes, and damaged embryos; lower expression of ovarian-related genes in ovarian tissue and pro-inflammatory cytokines in adipose tissue). All these aspects show similar effects on metformin. Most notably, PA is superior to metformin in improving inflammation of adipose tissue and mitochondrial abnormalities. It is suggested that PA has the similar effect with metformin, which can improve the endocrine environment and oocyte quality of PCOS mice. These findings suggest that PA has the similar effect with metformin, which can improve the endocrine environment and oocyte quality of PCOS mice.

Topics: Animals; Dehydroepiandrosterone; Disease Models, Animal; Female; Metformin; Mice; Oocytes; Ovary; Polycystic Ovary Syndrome; Triterpenes

We have previously shown that pachymic acid (PA) inhibited tumorigenesis of gastric cancer (GC) cells. However, the exact mechanism underlying the radiation response of GC was still elusive. To evaluate the effects of PA treatment on radiation response of GC cell lines both in vitro and in vivo, a colony formation assay and xenograft mouse model were employed. Changes in Bax and HIF1[Formula: see text] expressions were assessed in GC cells following PA treatment. Luciferase reporter and chromatin immune-precipitation assays were carried out to investigate the regulation of Bax through HIF1[Formula: see text]. Stable HIF1[Formula: see text] knockdown was introduced into GC cells to further study the mechanism underlying PA-enhanced response to radiation both in vitro and in vivo. PA greatly enhanced the sensitivity of GC cells to radiation in vitro and in vivo, upregulated Bax expression and inhibited hypoxia. Bax expression was under hypoxia inhibition, and PA increased Bax expression through repressing HIF1[Formula: see text]. Stable HIF1[Formula: see text] overexpression in GC cells abolished the sensitizing effect of PA on GC cells to radiation both in vitro and in vivo. PA functions as a radiation sensitizing compound in GC. PA treatment induces the expression of pro-apoptotic factor Bax by inhibiting hypoxia/HIF1[Formula: see text], supporting the therapeutic potential of PA in radiation therapy against GC.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Cell Line, Tumor; Disease Models, Animal; Female; Gene Expression; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Mice, Inbred BALB C; Mice, Nude; Phytotherapy; Radiation-Sensitizing Agents; Stomach Neoplasms; Triterpenes; Up-Regulation; Wolfiporia

The purpose of this study was to elucidate the possible beneficial effects of pachymic acid (PA) on acute lung injury (ALI) in a rat model of sepsis.. A rat model of sepsis induced by cecal ligation and puncture (CLP) was used. Rats were randomly divided into five groups: sham, CLP, CLP + PA 1 mg/kg, CLP + PA 5 mg/kg, CLP + PA 10 mg/kg. CLP + PA groups received PA by intraperitoneal injection daily for consecutive 3 days, respectively, and the rats in sham and CLP groups were given equivalent volume of olive oil. We killed the animals 12 h after CLP and collected blood samples to determine PaO2, PaCO2, tumor necrosis factor-alpha (TNF-a), interleukin-1β (IL-1β) and IL-6. Lung samples were taken for wet/dry weight ratios and histologic assessment. Meanwhile, the levels of lung tissue myeloperoxidase (MPO), malondialdehyde (MDA) and superoxide dismutase (SOD) were determined.. The results revealed that PA treatment significantly improved the survival of septic rats and attenuated CLP-induced ALI. In PA-treated rats, the wet/dry weight ratios and the serum levels of TNF-a, IL-1β and IL-6 were down-regulated compared with the CLP group. PA also markedly decreased MDA and MPO contents and increased SOD level.. These findings indicate that PA administration ameliorates ALI in a rat model of sepsis induced by CLP.

Topics: Acute Lung Injury; Animals; Cytokines; Disease Models, Animal; Ligation; Lung; Male; Oxidative Stress; Rats; Rats, Wistar; Sepsis; Survival Rate; Triterpenes