Identification of critical genes associated with lead exposure based on in silico analysis.

High blood levels of lead have been shown to relate to its toxicity, and its early detection in occupational workers is important to take necessary measures. The genes associated with lead toxicity were identified by in silico analysis of expression profile (GEO-GSE37567) based on lead exposure of peripheral blood mononuclear cells maintained in culture. The GEO2R tool was used to identify differentially expressed genes (DEGs) among three groups: control versus day-1 treatment, control versus day-2 treatment, and control versus day-1 treatment versus day-2 treatment, and their enrichment analysis was performed to categorize them for molecular function, biological process, cellular component, and KEGG pathways. The protein-protein interaction (PPI) network of DEGs was constructed using a STRING tool and hub genes were identified by using the CytoHubba plugin of Cytoscape. Top 250 DEGs were screened in the first and second groups and 211 DEGs were in the third group. Fifteen critical genes viz. MT1G, ASPH, MT1F, TMEM158, CDK5RAP2, BRCA2, MT1E, EDNRB, MT1H, KITLG, MT1X, MT2A, ARRDC4, MT1M, and MT1HL1 were selected for functional enrichment and pathway analysis. The DEGs were primarily enriched in metal ion binding, metal absorption, and cellular response to metal ions. The significantly enriched KEGG pathways included mineral absorption, melanogenesis, and cancer signaling pathways. PPI network analysis revealed that seven genes of the MT family exhibited good connectedness and served as a marker of lead induced toxicity. Our study suggests that MT1E, MT1H, MT1G, MT1X, MT1F, MT1M, and MT2A of the metallothioneins gene family may act as potential biomarkers to monitor lead exposure.

Hand sanitizer-related calls at the National Poisons Information Centre, India during the lockdown period of the Covid-19 pandemic.

Background Hand sanitizer (HS) has been increasingly used during the Covid-19 pandemic. We compared the telephonic calls received by the National Poisons Information Centre (NPIC), New Delhi, India, related to its unsafe exposure and inappropriate use during the lockdown and prelockdown periods. Methods We analysed and compared telephonic call records of 3 months of pre-lockdown and 3 months of the lockdown and HS-related calls in different age groups and zones during these periods. Results The centre received 4000 calls; of these 1583 (40%) were related to household products of which only 63 (4%) were related to HS. There was an 8-fold increase in the number of calls received at the NPIC during the lockdown compared to the pre-lockdown period seeking medical attention following unsafe exposure or inappropriate use of HS. More calls were received from the south and north zones and, in the majority of these cases, HS was ingested accidentally. In some cases, HS was ingested intentionally for suicide during the lockdown. Conclusions Our study shows that unsafe exposure of HS is common under conditions of stress as seen during the lockdown period of the Covid-19 pandemic. It should be kept out of reach of small children. Further, providing psychological help and counselling to older age groups under conditions of stress are important issues of concern.

Metformin and silymarin afford protection in cyclosporine A induced hepatorenal toxicity in rat by modulating redox status and inflammation.

The use of cyclosporine A (CsA) as an immunosuppressive agent is often limited owing to its hepatotoxic and nephrotoxic properties. The present study was designed to evaluate the protective effect of metformin and silymarin in a rat model of CsA induced hepatorenal toxicity. The study included seven groups of Wistar albino rats (n = 6 per group): normal control, experimental control (CsA alone, 25 mg/kg), CsA + metformin (50 and 500 mg/kg), CsA + silymarin (50 and 200 mg/kg) and CsA + vitamin E (100 mg/kg). All the drugs were given daily for a period of 21 days by oral gavage and their effect was evaluated on serum levels of organ function markers (serum glutamate pyruvate transaminase, serum glutamate oxaloacetate transaminase, bilirubin, urea/blood urea nitrogen, creatinine), markers of oxidative stress (thiobarbituric acid reactive substances, glutathione, superoxide dismutase), inflammation (nitrite, myeloperoxidase, tumour necrosis factor-alpha, prostaglandin E2 ), apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labelling positivity) in addition to tissue histology, cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) immunoreactivity. Administration of metformin and silymarin along with CsA ameliorated functional damage to liver and kidneys in a dose-dependent manner. Significant and comparable improvement in the tissue levels of oxidative stress, inflammation, apoptotic markers was also observed following treatment with both the test drugs. Normalization of histology scores, as well as COX-2 and iNOS immunoreactivity scores, further strengthened these findings. The hepatoprotective and nephroprotective effects of metformin and silymarin were comparable and matched with that of reference drug, vitamin E. The findings of the present study suggest that both metformin and silymarin have a potential for clinical use in patients receiving long-term CsA treatment to maintain their liver and kidney functions.

Artesunate suppresses inflammation and oxidative stress in a rat model of colorectal cancer.

Anti-inflammatory drugs are well known to reduce the risk of colon cancer and prophylactic use of such agents is gaining acceptance as a cancer prevention therapy. As artesunate, an antimalarial drug, has been shown to exhibit chemopreventive properties, the present study was carried out to evaluate its inhibitory effect on oxidative stress and inflammation in a rat model of colon carcinogenesis. A chemical carcinogen, 1,2-dimethylhydrazine was injected twice at an interval of 1 week to induce preneoplastic lesions in the colon and the parameters indicating oxidative stress and inflammation were evaluated after 8 weeks. Artesunate (50 and 150 mg/kg) and aspirin (60 mg/kg) were administered orally throughout the study. Analysis of colon tissue revealed that both the drugs preserved histoarchitecture, inhibited cellular influx, decreased the levels of oxidative stress and inflammatory markers, downregulated cyclooxygenase-2, inducible nitric oxide synthase, nuclear factor κB, and interleukin 1ß in comparison to the experimental control. Suppression of oxidative stress and pro-inflammatory signaling by both the drugs were found to contribute to inhibition of colon carcinogenesis. The protection afforded by these drugs was found to be comparable. Our study shows that like aspirin, use of artesunate could also reduce the risk of colon cancer and it has a potential for further evaluation for the treatment purpose.

Effect of roxithromycin on mucosal damage, oxidative stress and pro-inflammatory markers in experimental model of colitis.

OBJECTIVE AND DESIGN: Roxithromycin, a macrolide antibiotic, exhibits anti-inflammatory property. The present study was designed to evaluate its protective effect in a rat model of colitis. METHODS: The anti-inflammatory property of roxithromycin was first validated in rat paw edema model at 5 and 20 mg/kg doses where it produced 19 and 51% inhibition of paw swelling induced by carrageenan. The efficacy of roxithromycin was evaluated at these doses in a rat model where colitis was induced by intra-colonic instillation of acetic acid. Rats were divided into six groups viz. normal control, experimental control and drug-treated groups: roxithromycin 5 and 20 mg/kg, diclofenac 10 mg/kg and mesalazine 300 mg/kg. All drugs were given orally 1 h before induction of colitis. The macro and microscopic changes, mean ulcer score, mucus content and markers of oxidative stress and inflammation were evaluated in all the groups after 24 h. RESULTS: Pretreatment with roxithromycin markedly decreased hyperemia, ulceration, edema and restored histological architecture. The protection afforded by roxithromycin was substantiated by dose-dependent increase in mucus content, normalization of markers of oxidative stress (GSH and TBARS) and levels of TNF-α, PGE2 and nitrite along with marked decrease in expression of NFκB (p65), IL-1ß and COX-2. The protective effect of roxithromycin was found to be comparable to mesalazine while diclofenac was found ineffective. CONCLUSION: Our study demonstrates that roxithromycin ameliorates experimental colitis by maintaining redox homeostasis, preserving mucosal integrity and downregulating NFκB-mediated pro-inflammatory signaling and suggests that it has a therapeutic potential in inflammatory conditions of the colon.

Protective Effect of Metformin against Acute Inflammation and Oxidative Stress in Rat.

Preclinical Research The antidiabetic drug, metformin, can inhibit the release of inflammatory mediators in several disease conditions. The present study was carried out to evaluate the efficacy of metformin in ameliorating edema formation, oxidative stress, mediator release and vascular changes associated with acute inflammation in the rat carrageenan model. Metformin dose-dependently inhibited paw swelling induced by carrageenan and normalized the tissue levels of the inflammatory markers myeloperoxidase and nitrite. It also maintained oxidative homeostasis as indicated by near normal levels of the oxidative stress markers glutathione, thiobarbituric acid reactive substances, catalase and superoxide dismutase. The histopathology of the paw tissue in metformin-treated animals was similar to that in normal paw and had similar effects to diclofenac. In a rat peritonitis model, metformin reduced vascular permeability and cellular infiltration. In conclusion, this study shows that metformin has a potential for use in treating various inflammatory conditions.

Anti-inflammatory and antioxidant effect of methanol extract of latex of Calotropis procera in rat model of colorectal cancer.

ETHNOPHARMACOLOGICAL RELEVANCE: Preparations derived from the plant Calotropis procera, have been used for medicinal purpose though the plant is known for its toxic effects. The aerial parts of the plant contain latex in plenty and have been found effective in treating disorders of gastrointestinal system and cancer. AIM OF THE STUDY: This study evaluated the efficacy of C. procera dried latex extract prepared in methanol (MeDL) against inflammation and oxidative stress in experimental model of colorectal carcinoma (CRC). MATERIALS AND METHODS: Two subcutaneous injections of chemical carcinogen, 1,2-dimethylhydrazine (DMH; 150 mg/kg) were given at an interval of one week to induce CRC in rats. The MeDL (50 and 150 mg/kg) and aspirin (60 mg/kg) were given daily and their effect was evaluated on markers of oxidative stress and inflammation after completion of 8 weeks following second injection of carcinogen. A comparison was made with normal and experimental control groups. The colon tissue levels of glutathione (GSH), thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), nitrite and myeloperoxidase (MPO) were determined. Enzyme-linked immunosorbent assay was performed to determine the levels of prostaglandin E2 (PGE2) and tumor necrosis factor-alpha (TNF-α) and immunohistochemical analysis was performed for IL-1ß. RESULTS: Induction of cancerous changes in the colon resulted in altered oxidative homeostasis as evident from a reduction in GSH level and SOD activity and rise in TBARS level when compared with normal rats. Elevated levels of nitrite, MPO, TNF-α, PGE2 and immunoreactivity of IL-1ß were also observed in these rats. The levels of these markers were normalized when the rats were treated with MeDL or anti-inflammatory drug, aspirin. CONCLUSION: This study demonstrates that suppression of oxidative stress and inflammation contributes to the beneficial effect of MeDL in rat model of colon carcinogenesis.

Protective effect of methanol extract of latex of Calotropis procera in an experimental model of colorectal cancer.

ETHNOPHARMACOLOGICAL RELEVANCE: The plant, Calotropis procera, has been used for treating various gastrointestinal disorders and cancer. Some of these medicinal properties have been attributed to the latex produced by the plant. AIM OF THE STUDY: To evaluate the efficacy of methanol extract of air-dried latex (MeDL) of C. procera in the rat model of colorectal cancer (CRC). MATERIALS AND METHODS: CRC was induced in the rats by 1,2-dimethylhydrazine (DMH) and the effect of MeDL was evaluated at two doses (50 and 150 mg/kg). MeDL and reference drug aspirin (60 mg/kg) were administered orally starting from 1 h before injecting DMH till 8 weeks after the second dose of DMH. The study also included experimental and normal control groups. Microscopic analysis was carried out to determine the count for aberrant crypt foci (ACF) and histology score whereas enzyme-linked immunosorbent assay and immunohistochemical analyses were performed for markers of carcinogenesis and angiogenesis. Other parameters that were evaluated include deoxyribonucleic acid (DNA) fragmentation, laddering, Bcl2 and Bax immunoreactivity, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positivity. RESULTS: Subcutaneous injection of DMH induced pre-neoplastic changes in the colon of rats with the appearance of ACF with multiple crypts (1-3, 4-6 or >6). In the experimental control group, total ACF count was 3.49 ± 0.23/cm of the colon length and the median histology score was 2.0 for architectural abnormalities, 2.0 for dilatation of crypts and 1.5 for hyperplasia/dysplasia against 1.0 for all the characteristics in normal rats. Oral administration of MeDL similar to aspirin, led to a reduction in ACF count and histology score of CRC concomitant with a decrease in the levels of markers of carcinogenesis - ß-catenin and proliferating cell nuclear antigen (PCNA); markers of angiogenesis - matrix metallopeptidase-9 (MMP-9) and vascular endothelial growth factor (VEGF), and an increase in apoptotic DNA fragmentation. CONCLUSION: MeDL confers protection in the rat model of CRC and the study suggests its therapeutic potential in this condition.

Effect of ascorbic acid supplementation on pulmonary functions in healthy adults: a randomized controlled pilot study.

OBJECTIVES: The fact that oxidative stress plays an important role in the pathogenesis of various pulmonary diseases is supported by the beneficial effect of antioxidants. It is also well known that an altered oxidant-antioxidant balance after the age of 35 years increases the susceptibility to develop obstructive lung diseases later in life. Given this, the present study was designed to evaluate the effect of antioxidant supplementation on lung functions in healthy adults after the age of 35 years. METHODS: Persons of age ≥35 years (n=45) were randomized into three arms (each comprising 15 participants) to receive either no intervention (NI arm), ascorbic acid 250 mg daily (AA250 arm), or ascorbic acid 500 mg daily (AA500 arm) for 6 weeks. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), FEV1/FVC, and peak expiratory flow (PEF) were measured at baseline and 6 weeks. Persons of age group (20-30 years) were also enrolled in the study to compare their lung functions and cardiovascular parameters at baseline with those ≥35 years of age. All the adverse events experienced by participants were recorded. RESULTS: Baseline pulmonary functions were found to be comparable among the three study arms and compared to ≥35 years age group, these parameters were found to be better in the younger age group (20-30 years). Most of the pulmonary functions were comparable among the three study arms at 6 weeks. A significant improvement in PEF and % predicted PEF was noted in AA250 arm when compared to baseline values (p=0.049 and 0.026, respectively) and in participants with normal pulmonary functions when compared to those with reduced functions at baseline (p=0.059 and p=0.037). CONCLUSIONS: Although ascorbic acid did not affect most of the pulmonary functions in healthy adults, it improved PEF and % predicted PEF at a daily dose of 250 mg. In this regard, it was found effective in individuals with normal pulmonary indices at baseline.

Protective effect of proteins derived from the latex of Calotropis procera against inflammatory hyperalgesia in monoarthritic rats.

Calotropis procera (family: Apocynaceae) is a plant growing in the wild and has been used in the traditional medicinal system for the treatment of various diseases. The plant produces milky latex that possesses potent antiinflammatory and analgesic properties. In present study the non-dialysable protein fraction isolated from the latex (LP) of this plant was evaluated for its efficacy against inflammation in rats where paw edema was induced by sub-plantar injection of carrageenin or monoarthritis was induced by intra-articular injection of Freund's complete adjuvant (FCA). The effect of LP was evaluated on edema volume in the paw model and on joint diameter, stair climbing ability, motility, dorsal flexion pain, levels of oxidative stress markers and joint histology in arthritis model. The protection afforded by LP was compared with that of standard antiinflammatory drug, diclofenac (5 mg/kg). LP exhibited a dose-dependent antiinflammatory effect and produced 32% and 60% inhibition of paw edema at 10 and 25 mg/kg doses and 12% and 36% inhibition of joint inflammation at 50 and 150 mg/kg doses. The protective effect of LP was associated with normalization of joint functions, histology and levels of oxidative stress markers in joint tissue. The findings of this study suggest that the protein fraction of latex of Calotropis procera has the potential to relieve inflammation and pain associated with various arthritic conditions.

Protective effect of aqueous suspension of dried latex of Calotropis procera against oxidative stress and renal damage in diabetic rats.

Calotropis species have been used in the traditional medicinal system for the treatment of diseases of the liver and abdomen. In view of the antioxidant and anti-hyperglycemic properties of an aqueous suspension obtained from the dried latex of Calotropis procera, the present study was carried out to evaluate its efficacy in affording protection against alloxan induced changes in rat kidney. A single intraperitoneal injection of alloxan (150 mg/kg) in rats produced hyperglycemia within 3 days and altered kidney functions over a period of 90 days. Daily oral administration of the aqueous suspension (100 and 400 mg/kg) in diabetic rats produced anti-hyperglycemic effect that was comparable to that of glibenclamide (10 mg/kg). Unlike glibenclamide, the aqueous suspension did not increase the serum insulin levels in diabetic rats. However, it produced a marked reduction in the levels of urinary glucose and protein and normalized the renal tissue levels of thiobarbituric acid-reactive substances (TBARS) and glutathione (GSH) in diabetic rats and the effect was comparable to that of glibenclamide. The protection afforded by the aqueous suspension was also evident from the histological analysis of the renal tissue. Our study shows that by exhibiting antioxidant and anti-hyperglycemic property the aqueous suspension of dried latex of C. procera affords protection against the complications associated with diabetes.

Effect of roxithromycin on contractile activity of gastrointestinal smooth muscles in colitic rats.

OBJECTIVES: Roxithromycin, a macrolide antibiotic, has been shown to ameliorate acetic acid induced colitis in rats by suppressing inflammation and oxidative stress. The aim of this study was to evaluate the effect of roxithromycin on small intestinal transit and cholinergic responsiveness of the colonic smooth muscles of colitic rats. METHODS: Colitis was induced in rats by acetic acid and the small intestinal transit was determined by measuring the distance traversed by charcoal meal from the gastro-duodenal junction in 1 h. The test drug roxithromycin, reference drug mesalazine and anti-inflammatory drug diclofenac were administered orally before inducing colitis and their effect on intestinal transit was compared with colitic control group. The effect on cholinergic responsiveness of colonic smooth muscles was evaluated in vitro by plotting a dose-response curve using different concentrations of acetylcholine. The concentration producing 50% of maximal response (EC50) was calculated for all the treatment groups. RESULTS: The small intestinal transit was enhanced in colitic rats as compared to normal rats (86.00 ± 1.36 vs. 57.00 ± 1.34 cm; p<0.001). Like mesalazine, roxithromycin normalized intestinal transit while diclofenac was ineffective. The results of in vitro experiment show that colitis increased cholinergic responsiveness of the colonic smooth muscles that was not affected by roxithromycin and mesalazine while diclofenac significantly decreased it. CONCLUSIONS: This study shows that like mesalazine, roxithromycin affords protection in colitis mainly by normalizing propulsive movement of the small intestine than by affecting cholinergic responsiveness of the colonic smooth muscles.

Effect of Helicobacter pylori-eradication therapy on hepatic steatosis in patients with non-alcoholic fatty liver disease: a randomized-controlled pilot study.

BACKGROUND: Helicobacter pylori infection has been associated with insulin resistance and non-alcoholic fatty liver disease (NAFLD). This study was done to evaluate the effect of H. pylori-eradication therapy (HPET) in patients with NAFLD compared to standard management therapy (SMT). METHODS: Eighty NAFLD patients with H. pylori co-infection were randomized into SMT (diet and exercise, n = 36) and HPET (SMT plus amoxicillin, clarithromycin, and pantoprazole, n = 44) groups. The controlled attenuation parameter (CAP), anthropometric parameters, liver enzymes, lipid profile, and glycemic parameters including homeostasis model assessment-insulin resistance (HOMA-IR) were measured and compared between two groups at the baseline and 24 weeks. RESULTS: Sixty-four participants (SMT group [n = 28] and HPET group [n = 36]) were included in a modified intention-to-treat analysis. Both the SMT group and the HPET group had a significant reduction in CAP scores at 24 weeks (P = 0.002 and P < 0.001, respectively), but the change between the groups was insignificant (P = 0.213). Successful eradication of H. pylori occurred in 68% of the HPET group and led to greater improvement in HOMA-IR at 24 weeks compared to SMT or non-responder patients (P = 0.007). The liver enzymes reduced significantly at 24 weeks in both groups, but the changes between the groups were similar. The lipid parameters remained unchanged within the groups and between the groups at 24 weeks. A significant increase in the levels of reduced glutathione was noted in the HPET group, but the change between the two groups was not statistically different. CONCLUSIONS: HPET was found to be comparable to SMT alone in reducing hepatic steatosis and liver enzymes at 24 weeks in NAFLD patients. However, successful eradication of H. pylori led to greater improvement in HOMA-IR (Trial registration CTRI/2017/05/008608).

Germinating seeds of the mung bean, Vigna radiata (Fabaceae), as a model for the preliminary evaluation of cytotoxic effects of drugs.

Cytotoxic properties of plant extracts and drugs being developed for cancer treatment are usually evaluated by a variety of in vivo and in vitro tests carried out in animal or plant based models. In the present study we have evaluated the possibility of using the germinating mung beans (Vigna radiata), for rapid and inexpensive screening of drugs exhibiting cytotoxic properties. Mung beans were allowed to germinate either in tap water or in different drug solutions, and parameters like percent germination, increase in radicle length, change in seedling weight and mitotic index of apical root meristems were determined at two time intervals coinciding with the time at which the radicle length in control group was 1.0 to 1.5 cm (time 0, T0) and 48 h later (T48). Methanol extract of Calotropis procera latex as well as drugs like podophyllotoxin, cyclophosphamide, cyproheptadine and aspirin produced a dose-dependent inhibitory effect on seed germination, seed weight gain, radicle growth and mitotic index in the radicle meristems. The inhibitory effect of some of the drugs tested was associated with reduction in water imbibition. Some of the drugs at higher concentrations allowed seed germination to take place but produced radicle decay and seedling weight loss. Our study shows that germinating V radiata beans could be used as a convenient model for the preliminary screening of drugs exhibiting cytotoxic properties.

Protection afforded by methanol extract of Calotropis procera latex in experimental model of colitis is mediated through inhibition of oxidative stress and pro-inflammatory signaling.

Calotropis procera, a latex producing plant is known to possess medicinal properties including its beneficial effect in gastrointestinal disorders. The anti-inflammatory effect of its latex in various experimental models is noteworthy and in light of this the present study was carried out with an objective to evaluate its efficacy in ulcerative colitis, an inflammatory condition of the colon. Colitis was induced in rats by acetic acid and the rats were divided into four groups where one group served as experimental control and the other groups were treated with two doses of methanol extract of dried latex of C. procera (MeDL; 50 and 150 mg/kg) and mesalazine (MSZ; 300 mg/kg). The study also included normal control (NC) group for comparison of various parameters related to colon like macroscopic changes, ulcer score, adherent mucus content, weight/length ratio, small intestinal transit, oxidative stress and inflammatory markers, tissue histology and immunoreactivity of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and nuclear factor kappa beta (NFκB) subunit p65. Treatment of colitic rats with MeDL produced a significant reduction in colonic mucosal damage as revealed by macroscopic and microscopic evaluation and normalization of tissue levels of oxidative stress markers and pro-inflammatory mediators. The protection afforded by MeDL was also evident from its restorative effect on tissue histology and expression of COX-2, iNOS and NFκB(p65). This study shows that by targeting oxidative stress and NFκB(p65) mediated pro-inflammatory signaling, the latex of C. procera affords protection in colitis and its effect was comparable to that of mesalazine. This study suggests that latex of C. procera could serve as a promising therapeutic option for treating inflammatory conditions of the colon.

Current status of 5alpha-reductase inhibitors in the treatment of benign hyperplasia of prostate.

Benign prostatic hyperplasia (BPH) is a common problem in aging men, which is associated with lower urinary tract symptoms. This condition is dependent on the presence of androgens for its progression, and medical therapy is the first-line treatment for BPH patients with moderate-to-severe symptoms and includes the use of either alpha 1-adrenergic blockers or 5alpha-reductase inhibitors. Adrenergic blocking drugs reduce the dynamic component while the 5alpha-reductase inhibitors reduce the static component of bladder outlet obstruction in BPH. By inhibiting the generation of active form of testosterone, viz., dihydrotestosterone, the 5alpha-reductase inhibitors not only reduce the symptoms of BPH but also decrease the need for surgery and further progression of BPH. Besides, prolonged use of combination of 5alpha-reductase inhibitors and alpha 1-adrenergic blockers has been found to be more beneficial than either of the two drugs given alone. This review gives a brief account of rationale and efficacy of treatment by 5alpha-reductase inhibitors in the management of BPH.

Pharmacotherapy of ulcerative colitis - current status and emerging trends.

Ulcerative colitis (UC) is a chronic mucosal inflammation of the large intestine restricted to the rectum and colon. Its clinical course follows an intermittent pattern with episodes of relapse, followed by remission and eventually resulting in mucosal damage. Although there is no permanent cure for UC, the currently available pharmacotherapy aims to induce and maintain clinical remission, promote the healing of colonic mucosa and avert any surgical intervention. The conventional drug therapy comprising of 5-aminosalicylates, thiopurines and corticosteroids has advanced recently in terms of formulations and dosing schedule, resulting in improved efficacy, safety and compliance. Calcineurin inhibitors, such as cyclosporin and tacrolimus, have emerged as steroid sparing agents. The treatment paradigm of UC patients who are refractory to conventional drugs has changed in view of the availability of biologics. Currently, there are four biologics approved by the US FDA for the treatment of UC, namely, infliximab, adalimumab, golimumab and vedolizumab, and several others are undergoing clinical trial. In this comprehensive review, the advantages and limitations of the medical therapy of UC are elaborated with an emphasis on the pharmacokinetic and pharmacodynamic aspects of the drugs.

Artesunate affords protection against aspirin-induced gastric injury by targeting oxidative stress and proinflammatory signaling.

BACKGROUND: Prolonged use of aspirin, a commonly prescribed non steroidal anti-inflammatory drug, is well known to produce gastrointestinal toxicity which could be minimized by various anti-secretory agents. The present study was carried out to evaluate the protective effect of artesunate against aspirin induced gastric injury in rats. METHODS: Gastric injury was induced in fasted Wistar rats by oral administration of aspirin. The effect of 50 and 150mg/kg of artesunate was studied on macroscopic changes, gastric secretions, histology, oxidative stress and inflammatory markers in the stomach tissue after 5h of induction of gastric injury. Immunohistochemical analysis for the expression of IL-1ß, IL-6, NF-κB(p65) and COX-2 was also carried out. The effect of artesunate was compared with that of standard anti-ulcer drug famotidine (20mg/kg). RESULTS: Artesunate pretreatment produced a dose-dependent reduction in aspirin induced gastric injury and restored the gastric juice parameters. It normalized the tissue levels of oxidative stress markers (glutathione, malondialdehyde and superoxide dismutase activity) and mediators of inflammation (myeloperoxidase and TNF-α). The protection afforded by artesunate was evident from the histoarchitecture of stomach tissue and marked reduction in tissue expression of IL-1ß, IL-6, NF-κB(p65) and COX-2. The effect of artesunate was found to be comparable to that of standard drug famotidine. CONCLUSION: Artesunate markedly ameliorated aspirin induced gastric injury in rats by targeting oxidative stress and COX-2 dependent as well as COX-2 independent proinflammatory signaling pathways and could have a therapeutic potential in gastric ulcer disease.

Calotropis procera latex extract affords protection against inflammation and oxidative stress in Freund's complete adjuvant-induced monoarthritis in rats.

In view of the well-established anti-inflammatory properties of latex of Calotropis procera (DL), the present study was carried out to evaluate the protective effect of its methanol extract (MeDL) against inflammation and oxidative stress in monoarthritis induced by Freund's complete adjuvant (FCA) in rats. Intra-articular injection of FCA produced inflammation of the joint with a peak effect occurring on day 4 where a maximum increase in the levels of myeloperoxidase and inflammatory mediators like PGE2, TNF-alpha, and nitric oxide was observed. This was associated with oxidative stress with a marked reduction in the levels of glutathione, catalase, superoxide dismutase and glutathione peroxidase and an increase in the lipid peroxidation as indicated by the higher levels of thiobarbituric acid reactive substances (TBARSs). Subsequently on day 28 the histological analysis of the joint also revealed arthritic changes. Daily treatment of rats with MeDL (50 and 500 mg/kg) and standard anti-inflammatory drug rofecoxib (20 and 100 mg/kg), produced a significant attenuation in the inflammatory response and ameliorated the arthritic changes in the joint. The protection afforded by MeDL and rofecoxib was more pronounced than that of phenylbutazone and was associated with normalization of the levels of inflammatory mediators and biochemical parameters of oxidative stress. However, the overall protection afforded by rofecoxib was better than that of MeDL.

Calotropis procera latex-induced inflammatory hyperalgesia - effect of bradyzide and morphine.

1 The milky white latex of the plant Calotropis procera induces inflammatory response upon accidental exposure and on local administration that could be effectively ameliorated by antihistaminic and standard anti-inflammatory drugs. 2 The aim of the present study was to evaluate the anti-oedematogenic and analgesic effect of the bradykinin antagonist, bradyzide (BDZ) and the opioidergic analgesic, morphine (Mor) against inflammatory hyperalgesia induced by the dried latex (DL) of C. procera in the rat paw oedema model. 3 An aqueous solution of DL (0.1 ml of 1% solution) was injected into the sub-plantar surface of the rat paw and the paw volume was measured at different time intervals. The inhibitory effect of bradyzide and morphine on oedema formation and hyperalgesic response was compared with that of cyproheptadine (CPH), a potent inhibitor of DL-induced oedema formation. 4 The hyperalgesic response was evaluated by the dorsal flexion pain test, compression test and by observing motility, stair-climbing ability, and the grooming behaviour of the rats. 5 The effect of these drugs was also evaluated against DL-induced writhings in the mouse model. 6 Both bradyzide and morphine inhibited DL-induced oedema formation by 30-40% and CPH was more effective in this regard (81% inhibition). The antihyperalgesic effect of both the drugs was more pronounced than that of CPH. Both bradyzide and morphine markedly inhibited the grooming behaviour and the effect of morphine could be reversed by pretreatment with naloxone. 7 Thus, our study shows that DL-induced oedema formation is effectively inhibited by antihistaminic/antiserotonergic drug and associated hyperalgesia by analgesic drugs.