Evaluation of antiarthritic activity of Strychnos potatorum Linn seeds in Freund's adjuvant induced arthritic rat model

<p>Abstract</p> <p>Background</p> <p><it>Strychnos potatorum </it>Linn (Loganiaceae) is a moderate sized tree found in southern and central parts of India, Sri Lanka and Burma. In traditional system of medicine, <it>Strychnos potatorum </it>Linn seeds were used for various ailments including inflammation, diabetes etc. To investigate the folkloric use of the seeds the present study was carried out on Freund's adjuvant induced arthritic rats.</p> <p>Methods</p> <p>The present study states the effect of the aqueous extract (SPE) and the whole seed powder (SPP) of <it>Strychnos potatorum </it>Linn seeds on the Freund's complete adjuvant (FCA) induced arthritic rat paw edema, body weight changes and alterations in haematological and biochemical parameters in both developing and developed phases of arthritis. Histopathology of proximal interphalangeal joints and radiology of hind legs were studied.</p> <p>Results</p> <p>In FCA induced arthritic rats, there was significant increase in rat paw volume and decrease in body weight increment, whereas SPP and SPE treated groups, showed significant reduction in paw volume and normal gain in body weight. The altered haematological parameters (Hb, RBC, WBC and ESR) and biochemical parameters (blood urea, serum creatinine, total proteins and acute phase proteins) in the arthritic rats were significantly brought back to near normal by the SPP and SPE treatment at the dose of 200 mg/kg/p.o in both developing and developed phases of arthritis. Further the histopathological and radiological studies revealed the antiarthritic activity of SPP and SPE by indicating fewer abnormalities in these groups when compared to the arthritic control group.</p> <p>Conclusion</p> <p>In conclusion, both SPP and SPE at the specified dose level of 200 mg/kg, p.o. showed reduction in rat paw edema volume and it could significantly normalize the haematological and biochemical abnormalities in adjuvant induced arthritic rats in both developing and developed phases of FCA induced arthritis. Further the histopathological and radiological studies confirmed the antiarthritic activity of SPP and SPE.</p

The liver is a common non-exocrine target in primary Sjögren's syndrome: A retrospective review

BACKGROUND: The autoimmune destruction of exocrine glands that defines primary Sjögren's syndrome (1°SS) often extends to non-exocrine organs including the liver. We aimed to determine the prevalence of liver disease in patients with 1°SS and to evaluate the association of this complication with other non-exocrine features and serologic markers of autoimmunity and systemic inflammation. METHODS: We reviewed 115 charts of patients with 1°SS and further analyzed the 73 cases that fulfilled the European Epidemiology Center Criteria, seeking evidence for clinical and subclinical liver disease. RESULTS: Liver function tests had been determined in 59 of the 73 patients. Of those, 29 patients (49.1%) had abnormal liver function tests including 20.3% with clinically overt hepatic disease. Liver disease was the most common non-exocrine feature in this cohort. Risk factors for abnormal liver function tests were distributed similarly between the patients with and without liver disease. In 60% of patients with abnormal liver function tests no explanation for this complication was found except for 1°SS. Liver involvement was significantly more common in 1°SS patients who also had evidence of lung, kidney and hematological abnormalities. Patients with abnormal liver function tests were also more likely to have an elevated sedimentation rate and a positive anti-ENA during the course of their disease. CONCLUSION: Liver involvement is a common complication in 1°SS. Its presence correlates with systemic disease. We consider that this complication should be routinely sought in patients with 1°SS, especially when a positive anti-ENA or evidence of systemic inflammation is found

Hypoxia-Inducible Factor Directs POMC Gene to Mediate Hypothalamic Glucose Sensing and Energy Balance Regulation

Hypoxia-inducible factor (HIF) is a nuclear transcription factor that responds to environmental and pathological hypoxia to induce metabolic adaptation, vascular growth, and cell survival. Here we found that HIF subunits and HIF2α in particular were normally expressed in the mediobasal hypothalamus of mice. Hypothalamic HIF was up-regulated by glucose to mediate the feeding control of hypothalamic glucose sensing. Two underlying molecular pathways were identified, including suppression of PHDs by glucose metabolites to prevent HIF2α degradation and the recruitment of AMPK and mTOR/S6K to regulate HIF2α protein synthesis. HIF activation was found to directly control the transcription of POMC gene. Genetic approach was then employed to develop conditional knockout mice with HIF inhibition in POMC neurons, revealing that HIF loss-of-function in POMC neurons impaired hypothalamic glucose sensing and caused energy imbalance to promote obesity development. The metabolic effects of HIF in hypothalamic POMC neurons were independent of leptin signaling or pituitary ACTH pathway. Hypothalamic gene delivery of HIF counteracted overeating and obesity under conditions of nutritional excess. In conclusion, HIF controls hypothalamic POMC gene to direct the central nutrient sensing in regulation of energy and body weight balance

Connective tissue activation

Four normal (NF) and 4 scleroderma skin fibro-blast (SF) strains were compared with respect to 1) basal 14 C-glucosamine and 35 SO 4 -labeled glycosaminoglycan (GAG) synthesis, 2) responsiveness to autacoid mediators, and 3) performance following maximal stimulation. Under basal conditions, SF synthesized and secreted 2–3 times more radioactive hyaluronic acid than the NF ( P < 0.001); molecular volume by gel chromatography was similar and suggested a high molecular weight product. SF were essentially as responsive to normal lymphoid and platelet factors as were NF. No consistent qualitative or quantitative differences in sulfated GAG synthesis were noted between the 2 groups of cells. Incubation of NF and SF with a false “core protein” such as p-nitrophenyl-Β-D-xyloside suggested that synthesis of the core protein was rate limiting; SF and NF were equally facile in SO 4 -GAG chain synthesis in the presence of a Β-xyloside. SF appear to retain in vitro a partially activated state for many generations, at least with respect to hyaluronic acid synthesis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/37761/1/1780261109_ftp.pd

HIF-1 and c-Src Mediate Increased Glucose Uptake Induced by Endothelin-1 and Connexin43 in Astrocytes

In previous work we showed that endothelin-1 (ET-1) increases the rate of glucose uptake in astrocytes, an important aspect of brain function since glucose taken up by astrocytes is used to supply the neurons with metabolic substrates. In the present work we sought to identify the signalling pathway responsible for this process in primary culture of rat astrocytes. Our results show that ET-1 promoted an increase in the transcription factor hypoxia-inducible factor-1α (HIF-1α) in astrocytes, as shown in other cell types. Furthermore, HIF-1α-siRNA experiments revealed that HIF-1α participates in the effects of ET-1 on glucose uptake and on the expression of GLUT-1, GLUT-3, type I and type II hexokinase. We previously reported that these effects of ET-1 are mediated by connexin43 (Cx43), the major gap junction protein in astrocytes. Indeed, our results show that silencing Cx43 increased HIF-1α and reduced the effect of ET-1 on HIF-1α, indicating that the effect of ET-1 on HIF-1α is mediated by Cx43. The activity of oncogenes such as c-Src can up-regulate HIF-1α. Since Cx43 interacts with c-Src, we investigated the participation of c-Src in this pathway. Interestingly, both the treatment with ET-1 and with Cx43-siRNA increased c-Src activity. In addition, when c-Src activity was inhibited neither ET-1 nor silencing Cx43 were able to up-regulate HIF-1α. In conclusion, our results suggest that ET-1 by down-regulating Cx43 activates c-Src, which in turn increases HIF-1α leading to the up-regulation of the machinery required to take up glucose in astrocytes. Cx43 expression can be reduced in response not only to ET-1 but also to various physiological and pathological stimuli. This study contributes to the identification of the signalling pathway evoked after Cx43 down-regulation that results in increased glucose uptake in astrocytes. Interestingly, this is the first evidence linking Cx43 to HIF-1, which is a master regulator of glucose metabolism

β-Cells with Relative Low HIMP1 Overexpression Levels in a Transgenic Mouse Line Enhance Basal Insulin Production and Hypoxia/Hypoglycemia Tolerance

Rodent pancreatic β-cells that naturally lack hypoglycemia/hypoxia inducible mitochondrial protein 1 (HIMP1) are susceptible to hypoglycemia and hypoxia influences. A linkage between the hypoglycemia/hypoxia susceptibility and the lack of HIMP1 is suggested in a recent study using transformed β-cells lines. To further illuminate this linkage, we applied mouse insulin 1 gene promoter (MIP) to control HIMP1-a isoform cDNA and have generated three lines (L1 to L3) of heterozygous HIMP1 transgenic (Tg) mice by breeding of three founders with C57BL/6J mice. In HIMP1-Tg mice/islets, we performed quantitative polymerase chain reaction (PCR), immunoblot, histology, and physiology studies to investigate HIMP1 overexpression and its link to β-cell function/survival and body glucose homeostasis. We found that the HIMP1 level increased steadily in β-cells of L1 to L3 heterozygous HIMP1-Tg mice. HIMP1 overexpression at relatively lower levels in L1 heterozygotes results in a negligible decline in blood glucose concentrations and an insignificant elevation in blood insulin levels, while HIMP1 overexpression at higher levels are toxic, causing hyperglycemia in L2/3 heterozygotes. Follow-up studies in 5–30-week-old L1 heterozygous mice/islets found that HIMP1 overexpression at relatively lower levels in β-cells has enhanced basal insulin biosynthesis, basal insulin secretion, and tolerances to low oxygen/glucose influences. The findings enforced the linkage between the hypoglycemia/hypoxia susceptibility and the lack of HIMP1 in β-cells, and show a potential value of HIMP1 overexpression at relatively lower levels in modulating β-cell function and survival