Protective effect of hesperidin against N,N'-dimethylhydrazine induced oxidative stress, inflammation, and apoptotic response in the colon of Wistar rats.

Hesperidin (HD), a citrus bioflavonoid possesses a variety of biological activities including antioxidant, anti-inflammatory, anti-apoptotic and anti-carcinogenic properties. In the present study, we investigated the effect of HD treatment on N,N'-dimethylhydrazine (DMH) induced oxidative stress, inflammation, apoptosis and goblet cell disintegration in the colon of Wistar rats. Administration of HD was done at two doses (100 and 200 mg/kg body weight) orally to rats daily for 14 days followed by a single subcutaneous injection of DMH (40 mg/kg body weight) on the 14th day and next day animals were sacrificed. The protective potential of HD against colon toxicity was measured through membrane oxidation, antioxidant status, inflammatory and apoptotic markers expression, and histological changes. Results demonstrated that HD inhibited DMH mediated oxidative damage by diminishing the level of peroxidation of lipids and increasing the activity of superoxide dismutase, catalase, reduced glutathione, glutathione peroxidase, glutathione-s-transferase, and glutathione reductase. Moreover, HD attenuated inflammatory (NF-кB, IL-6, and COX-2) and apoptotic (p38-MAPK, p53, and caspase-3) markers expression. HD also attenuated the DMH induced goblet cell disintegration and restored histoarchitecture of the colon. The results of the present study demonstrate that HD efficiently protects against DMH induced colon toxicity by modulating oxidative stress, inflammation, and apoptosis.

Colono-protective Potentiality of Methanolic Bark Extract of Acacia catechu: A Medicinal Plant against 1,2-Dimethylhydrazine-Induced Toxicity in Wistar Rats.

The protective efficacy of methanolic bark extract of Acacia catechu Willd. (MEBA) against 1,2-dimethylhydrazine (DMH)-induced colon toxicity was investigated. Acacia catechu is considered one of the most potent medicines for various diseases in Ayurveda, a traditional system of Indian medicine. It is a widely used herb that contains a variety of bioactive components such as phenolic acids, alkaloids, and flavonoids among others. In the present study, MEBA was used as a pretreatment orally at two doses (250 and 500 mg/kg body weight [b.w.] once daily for 7 days), and DMH was administered (at a dose of 40 mg/kg b.w.) subcutaneously on day 7 in Wistar rats. The protective potential of MEBA was assessed in terms of the activity of antioxidant enzymes, lipid peroxidation, and expression of inflammatory markers (iNOS, COX-2, NF-κB, IL-6). Pretreatment with MEBA significantly abrogated oxidative damage by diminishing tissue lipid peroxidation, increasing enzymatic activities of various antioxidant enzymes (catalase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, reduced glutathione), and diminishing the induced expression of inflammatory markers in the colon tissue of Wistar rats. Furthermore, histopathological findings revealed that pretreatment with (MEBA) reduced intense filtration of inflammatory cells and significantly restored the architecture of colonic tissue. The results of this study indicate that MEBA significantly suppresses DMH-induced toxicity by ameliorating oxidative stress and inflammation and by restoring the architecture of colon tissue.

The need to train uncertified rural practitioners in India.

Uncertified rural practitioners (URPs) without formal medical qualification occupy an indispensable yet dangerous position in the rural health care system in India. The low cost, close proximity, and higher health hazards in rural areas along with the inability of established health-care setups to fulfill existing demands have favored the flourishing trade of URPs. Irrational and dangerous drug prescriptions, unauthorized interventions, improper waste disposal, and several cases of malpractice by URPs are serious threats to the exposed population. However, because of the practical compulsion and real-world necessity of their existence, URPs should be scientifically trained and sensitized to regulate, qualify, and integrate them as a part of the existing health care system in India.

Evaluation of the Protective Role of Glycine max Seed Extract (Soybean Oil) in Drug-Induced Nephrotoxicity in Experimental Rats.

This study was conducted to evaluate the nephroprotective effect of Glycine max seed extract (soybean oil) against gentamicin- and rifampicin-induced nephrotoxicity in Sprague-Dawley rats and to compare its effects with those of vitamin E, which has well-established antioxidant and nephroprotective effects. Sixty male Sprague-Dawley rats (body weight 150-210 g) were divided into 10 groups. The first five groups were treated for 14 consecutive days with normal saline (5 ml/kg, by mouth [p.o.]); gentamicin (80 mg/kg intraperitoneally [i.p.]); gentamicin (80 mg/kg, i.p.) + vitamin E (250 mg/kg p.o.); gentamicin (80 mg/kg i.p.) + soybean oil (2.5 ml/kg p.o.); and gentamicin (80 mg/kg, i.p.) + soybean oil (5 ml/kg p.o.), respectively. For the next five groups, the same group allocation was done, but gentamicin was replaced with rifampicin (1 g/kg i.p.). Various biomarkers for nephrotoxicity in serum and urine were evaluated along with histopathological examination of kidneys. Analysis of variance (ANOVA) was done following Tukey's multiple comparison test; p < .05 was considered significant. Soybean oil in both doses significantly (p < .005) decreased serum blood urea nitrogen, creatinine, urea, uric acid and urine volume, kidney weight, urinary sodium, urinary potassium, and total protein and significantly (p < .005) increased serum total protein and urine creatinine in gentamicin- and rifampicin-treated animals, exhibiting nephroprotective effects. Soybean oil also showed strong antioxidant effects, causing significant (p < .005) increase in kidney homogenate catalases, glutathione peroxidase, and superoxide dismutase and significant (p < .005) decrease in lipid peroxidase in gentamicin- and rifampicin-treated animals. Soybean oil demonstrated good nephroprotective activity due to antioxidant effects.

Partial protection by 18ß Glycrrhetinic acid against Cisplatin induced oxidative intestinal damage in wistar rats: Possible role of NFkB and caspases.

BACKGROUND: Cisplatin (CP) is a potent chemotherapeutic agent commonly used for the treatment of various malignancies. It has varied undesirable effects such as nephrotoxicity, intestinal toxicity which limit its wide and extensive clinical usage. 18ß-Glycyrrhetinic acid (GA) is a pentacyclic triterpenoid derivative, obtained from the herb liquorice having pharmacological properties such as anti-inflammatory, hepatoprotective and antioxidant. The present study was designed to investigate in vivo efficacy of GA against CP induced small intestinal toxicity. METHODS: Rats were subjected to prophylactic oral treatment of GA (50 and 100mg/kg body weight) for 21days against intestinal toxicity induced by single intra peritoneal injection of CP (10mg/kg body weight) on day 18th and sacrificed on 21st day. RESULTS: The plausible mechanism of CP induced small intestinal toxicity is via deficit in anti-oxidant armory, induction of oxidative stress; TNF-α, NFkB, activation of apoptotic pathway proteins by up regulation of caspases. However prophylactic treatment of GA diminished oxidative stress markers, TNF-α, NFkB expression and enhanced anti-oxidant status, down regulated apoptosis, recovered histopatholgical alterations in small intestine. CONCLUSION: Therefore, results of the present finding provide strong evidence that GA may be a useful modulator in alleviating CP induced intestinal toxicity.

Addiction to Snake Venom.

The nature of addiction depends on various factors. The tendency to have already used several addictive substances and to seek high sensation experiences as a result of specific personality traits may lead to extreme and peculiar forms of addictions. Even belonging to specific social and cultural background may lead to such forms of addiction such as intentional snake bite and willful envenomation. In this article, we have discussed the peculiarities and practical insight of such addiction to snake venom. The possible molecular mechanism behind such venom-mediated reinforcement has also been highlighted. Finally, we have stressed upon the treatment and de-addiction measures.

Probuphine® (buprenorphine implant): a promising candidate in opioid dependence.

Opioid dependence leads to physical dependence and addiction which finally results in profound medical, psychological and social dysfunction. One of the useful medications for opioid dependence is buprenorphine, the partial opioid agonist, which is used alone or in combination with naloxone. However, buprenorphine is the victim of its own success due to its illicit use and accidental poisoning in children. Also, buprenorphine typically requires daily self-administration and its effectiveness heavily depends on patient adherence. So, poor treatment adherence results in ineffective treatment manifesting as craving and withdrawal symptoms. Short-term use of buprenorphine in opioid dependence is also often followed by relapse. Buprenorphine when used sublingually often results in inadequate or fluctuating blood concentrations and poorer treatment retention compared with methadone. All of these led to the development of Probuphine®, a polymeric matrix composed of ethylene vinyl acetate and buprenorphine in the form of implants, that are implanted subdermally in office practice and deliver the active drug over 6 months. Buprenorphine release from such implant is fairly consistent, avoiding plasma peaks and troughs, and the implant is also reported to be safe. In this review article, we have highlighted these aspects of treatment of opioid addiction, stressing on the pharmacology of buprenorphine and Probuphine®, and relevant clinical trials addressing the efficacy and safety of Probuphine®. This sustained-release implantable formulation of buprenorphine has the potential to be a suitable alternative to daily or alternate day sublingual buprenorphine which can thereby eliminate the need for daily supervision, minimizing fluctuations in plasma concentrations, and allowing these patients to reduce clinic or pharmacy visits.

Methanolic bark extract of Acacia catechu ameliorates benzo(a)pyrene induced lung toxicity by abrogation of oxidative stress, inflammation, and apoptosis in mice.

Benzo(a)pyrene [B(a)P] is a well-known carcinogen present in the environment. In this study, we evaluated the protective potential of methanolic bark extract of Acacia catechu Willd. (MEBA) against the lung toxicity induced by B(a)P in Swiss albino mice. To determine the protective efficacy of MEBA, it was orally administered to the mice at two doses (200 and 400 mg/kg body weight) once daily for 7 days. Mice were also exposed (orally) to B(a)P at a dose of 125 mg/kg body weight on 7th day. Administration of B(a)P increased the activities of toxicity markers such as LDH, LPO, and XO with a subsequent decrease in the activities of tissue anti-oxidant armory (CAT, SOD, GST, GPx, GR, QR, and GSH). It also caused activation of the apoptotic and inflammatory pathway by upregulation of TNF-α, NF-kB, COX-2, p53, bax, caspase-3, and downregulating Bcl-2. Pretreatment with MEBA at two different doses (200 and 400 mg/kg body weight) significantly ameliorates B(a)P-induced increased toxicity markers and activities of detoxifying enzymes along with the levels of glutathione content. It also significantly attenuated expression of apoptotic and inflammatory markers in the lungs. Histological results further confirmed the protective role of MEBA against B(a)P-induced lung toxicity. The results indicate that MEBA may be beneficial in ameliorating the B(a)P-induced oxidative stress, inflammation, and apoptosis in the lungs of mice. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1566-1577, 2017.

Inhibition of precancerous lesions development in kidneys by chrysin via regulating hyperproliferation, inflammation and apoptosis at pre clinical stage.

Chrysin (CH) is natural, biologically active compound, belongs to flavoniod family and possesses diverse pharmacological activities as anti-inflammatory, anti-oxidant and anti-cancer. It is found in many plants, honey and propolis. In the present study, we investigated the chemopreventive efficacy of CH against N-nitrosodiethylamine (DEN) initiated and Fe-NTA induced precancerous lesions and its role in regulating oxidative injury, hyperproliferation, tumor incidences, histopathological alterations, inflammation, and apoptosis in the kidneys of Wistar rats. Renal cancer was initiated by single intraperitoneal (i.p.) injection of DEN (200 mg/kg bw) and promoted by twice weekly injection of ferric nitrilotriacetate (Fe-NTA) 9 mg Fe/kg bw for 16 weeks. CH attenuated Fe-NTA enhanced renal lipid peroxidation, serum toxicity markers and restored renal anti oxidant armory significantly. CH supplementation suppressed the development of precancerous lesions via down regulation of cell proliferation marker like PCNA; inflammatory mediators like TNF-α, IL-6, NFkB, COX-2, iNOS; tumor incidences. CH up regulated intrinsic apoptotic pathway proteins like bax, caspase-9 and caspase-3 along with down regulation of Bcl-2 triggering apoptosis. Histopathological and ultra structural alterations further confirmed biochemical and immunohistochemical results. These results provide powerful evidence for the chemopreventive efficacy of CH against chemically induced renal carcinogenesis possibly by modulation of multiple molecular pathways.

Lysergic acid diethylamide: a drug of 'use'?

Lysergic acid diethylamide (LSD), described as a classical hallucinogen, began its journey from the middle of the last century following an accidental discovery. Since then, it was used as a popular and notorious substance of abuse in various parts of the world. Its beneficial role as an adjunct to psychotherapy was much unknown, until some 'benevolent' experiments were carried out over time to explore some of its potential uses. But, many of its effects were unclear and seemed to be a psychedelic enigma. In this review article, we have described the receptor pharmacology, mechanism of action, effects and adverse effects of LSD on the normal body system. We have also highlighted its addictive potentials and the chances of developing tolerance. We have assimilated some of the interesting therapeutic uses of this drug, such as an antianxiety agent, a creativity enhancer, a suggestibility enhancer, and a performance enhancer. We have also described LSD to be successfully used in drug and alcohol dependence, and as a part of psychedelic peak therapy in terminally ill patients. The relevant chronological history and literature in the light of present knowledge and scenarios have been discussed. Based on available evidence, LSD could be tried therapeutically in certain specific conditions under controlled settings. But as we mention, due to all the safety concerns, the use of this nonaddictive 'entheogen' in actual practice warrants a lot of expertise, caution, cooperation and ethical considerations.

Brexpiprazole: so far so good.

This article describes the role of a newly approved antipsychotic agent brexpiprazole in the treatment of schizophrenia and major depressive disorder. This drug has high affinity for 5-HT1A, 5-HT2A, D2 and α1B,2C receptors. It displays partial agonism at 5-HT1A and D2 receptors and potent antagonism at 5-HT2A and α1B,2C adrenergic receptors. It also has some affinity (antagonism) for D3, 5-HT2B, 5-HT7 and α1A,1D receptors, and moderate affinity for H1 and low affinity for M1 receptors. These all lead to a favorable antipsychotic profile in terms of improvement of cognitive performance and sleep patterns, as well as effects on affective states and potential to treat core symptoms in schizophrenia and major depressive disorder, including cognitive deficits with a low risk of adverse effects (extrapyramidal symptoms, metabolic complications, weight gain, akathisia potential) that are commonly encountered with other typical and second-generation antipsychotic drugs. In our review, we have made an attempt to decipher the pharmacological profile of brexpiprazole from two major trials (VECTOR and BEACON). We have also tried to give a concise but detailed overview of brexpiprazole by head to head comparison of the pharmacological profile of brexpiprazole and its earlier congeners aripiprazole and prototype antipsychotic drug chlorpromazine by accessing individual summaries of product characteristics from the US Food and Drug Administration database, 2015. Relevant preclinical and clinical studies associated with this drug have been discussed with emphasis on efficacy and safety concerns. From the studies done so far, it can be concluded that brexpiprazole can be an effective monotherapy for schizophrenia and as an adjunct to other antidepressant medications in major depressive disorder.