Volume 30, Issue 1

Ulcerative colitis (UC) is an idiopathic relapsing inflammatory disease. Although the etiology of UC remains unclear, it could be characterized by inflammation of the intestinal mucosa, starting from the rectum and potentially involving the entire colon. The immune response and inflammatory pathway of UC have shown that tissue damage is driven by dynamic and complexes of cells and cytokines. Various types of cells, including antigen-presenting cells (dendritic cells and macrophages), T helper cells, regulatory T cells, and natural killer T cells, play a crucial role in UC pathogenesis by regulation, suppression, and maintenance of inflammation. Moreover, cytokine networks become an important part due to their signaling function, which is indispensable for cell communication. Pro-inflammatory cytokines [tumor necrosis factor-α, interleukin (IL)-1, IL-6, IL-9, IL-13, and IL-33] play significant roles in upregulation, while anti-inflammatory cytokines (transforming growth factor-β, IL-10, and IL-37) play significant roles in downregulation of disease progression. The pathogenesis of UC consists of immuno-inflammatory pathways related to the multiple components of the intestine, including the epithelial barrier, commensal microflora, antigen recognition, dysregulation of immunological responses, leukocyte recruitment, and genetic factors. The understanding of immuno-inflammatory pathways of UC might lead to the development of a specific therapy and/or a novel treatment that could be more efficient.

Hypoxia-inducible factors (HIFs) are transcription factors that are expressed in the hypoxic tumor microenvironment. They are involved in the cellular adaptations by improving the metabolism of glucose and enhance the expression of vascular endothelial growth factor, platelet-derived growth factor and angiopoietin, thereby they play a pivotal role in the angiogenesis. Hypoxia can increase the expression of nuclear factor-kappa B which promotes the pro-inflammatory status. Abnormally high angiogenesis, inflammation, antiapoptosis and anaerobic glycolysis can augment the progression and metastasis of tumor. Hence, HIFs remain one of the promising antiangiogenic agents as well as a direct target for interfering with the energetic of cancer cells in order to regulate the tumor growth. Previous studies found agents like topotecan, acriflavine and benzophenone-1B etc. to block the HIF-α mediated angiogenesis. The effect is mediated through interfering any one of the processes in the activation of HIF such as nuclear translocation of HIF-1α; dimerization of HIF-1α with β in the nucleus; HIF-1α/HIF-2α mediated induction of VEGF or translation of HIF-1α mRNA. Despite the experimental studies on the inhibitory molecules of HIFs, none of them are available for the clinical use. This review article discusses the recent update on the HIF-targeted therapy in cancer.

Background The aim of the study was to determine the effect of caffeine on alcohol consumption with or without deprivation and alcohol-induced conditioned place preference. Methods In the present study, we examined the effects of caffeine (2.5, 5 and 10 mg/kg) on alcohol consumption in Wistar rats with or without periods of deprivation in an unlimited-access, two-bottle, free choice drinking procedure after a stable baseline alcohol consumption was established. Conditioned place preference (CPP) was established by intraperitoneal injections of alcohol (2 g/kg) in a 12-day conditioning schedule in mice. The effect of caffeine (3 mg/kg) on CPP expression was determined by a final post-conditioning test following 12 conditioning sessions with alcohol. The effect of caffeine (3 mg/kg) on the reinstatement of alcohol-induced CPP was determined in a final post-conditioning test following 12 conditioning sessions with alcohol and the extinction of alcohol-induced CPP. Results Alcohol deprivation for 3 days did not result in alcohol deprivation effect (ADE). While caffeine (10 mg/kg) caused a significant (p<0.05) reduction in alcohol consumption compared with the baseline following a period of alcohol deprivation, it did not cause a change in alcohol consumption compared with the baseline in the study without alcohol deprivation phase. Caffeine significantly (p<0.05) reduced the expression of alcohol-induced CPP compared to saline and blocked the reinstatement of alcohol-induced CPP following the injection of a priming dose (0.4 g/kg) of alcohol. Conclusions Given that caffeine is an adenosine receptor antagonist, our findings suggest a role for adenosine receptors in the alcohol reward and alcohol-seeking behaviour.

Background Testosterone, nandrolone, and stanozolol are among the highly consumed anabolic androgenic steroids (AASs). Although the desired effects of AAS are being achieved by the abusers, unfortunately, this leads to numerous physical and physiological side effects. The present study was designed to investigate and determine whether early pubertal exposure to AAS treatment had detrimental effects on blood testosterone and estradiol concentrations, mating behavior, and pregnancy outcome during the pubertal period in male rats. Materials Early pubertal rats (PND41) were given two doses (2.5 mg/kg and 5 mg/kg) each of testosterone, nandrolone, and stanozolol subcutaneously for 6 weeks. Upon completion, three rats with the highest weight were chosen from each group for mating with the females, in a ratio of one male to two females for 10 days. After 10 days, all male rats were sacrificed to obtain the testes for weight recording, and blood samples were collected for testosterone and estradiol quantitation. Pregnant females were housed separately until birth, and the number of offsprings produced was counted. Results The results clearly show a reduction in reproductive hormonal and behavioral parameters between testosterone and nandrolone, and testosterone and stanozolol. Stanozolol administration exhibited suppressing effects in all parameters including testicular weight deterioration, serum testosterone and estradiol reduction, low mating preferences, and declined pregnancy outcome. Conclusions AAS exposure during the onset of puberty results in reproductive detrimental effects, which are postulated to affect the pregnancy rate.

Background Genistein was reported to adversely influence fetal development although this is yet to be fully understood as a mechanism. Methods In this study, pregnant rats were divided into control (Cont.) and genistein force-fed (2-mg/kg and 4-mg/kg) groups. Each group was divided further into five subgroups: GD-0, GD-6, GD-13, GD-18, and GD-20 based on the terminal gestational day (GD). On the respective terminal GD, the rats were sacrificed and blood samples and amniotic fluid were carefully collected and separated and placenta homogenates were prepared. These samples were evaluated for oxidative stress and inflammatory reaction. The weights of embryonic implant and placenta tissue were also recorded. Heat shock protein (Hsp) (60 and 90), corticosterone, and oxidative stress biomarkers were determined in all the samples. Results Fetal and placental weights in all genistein-exposed groups were significantly decreased. A fluctuation in the level of the Hsp was recorded with a significant decrease recorded in Hsp90 level in the placenta and amniotic fluid towards GD-20 along with a concomitant increase in the corticosterone level in the amniotic fluid in all genistein groups compared to control. Maternal serum at GD-18 and GD -20 recorded a significant increase in antioxidant level (SOD, GSH, CAT) in all genistein-exposed groups. However, these antioxidants were significantly reduced in the placenta and the amniotic fluid compared to control. Conclusions Genistein enhances the placenta function in attenuating the risk of oxidative stress in the amniotic fluid and deferentially suppressed inflammatory activities in the placenta during early gestation and towards late gestation period.

Background: The purpose of this study was to measure sweat rate during exercise in the heat after directly inhibiting carbonic anhydrase (CA) in eccrine sweat glands via transdermal iontophoresis of acetazolamide. It was hypothesized that if CA was important for sweat production, local administration of acetazolamide, without the confounding systemic effects of dehydration typically associated with past studies, would have a significant effect on sweat rate during exercise. Methods: Ten healthy subjects volunteered to exercise in the heat following acetazolamide or distilled water iontophoresis on the forearm. Results: The distilled water iontophoresis site had a mean sweat rate during exercise in the heat of 0.59±0.31 μL/cm 2 /min, while the acetazolamide iontophoresis site had a mean sweat rate of 0.63±0.36 μL/cm 2 /min (p>0.05). Conclusions: The most important finding of the current study was that iontophoresis of acetazolamide did not significantly decrease sweat rate during exercise in the heat. Such results suggest that in past studies it was systemic dehydration, and not CA inhibition at the level of the sweat gland, that caused the reported decreased sweat rate.

Background This study investigated the effect of hydroalcoholic extract of Nigella sativa ( N. sativa ) and its active component, thymoquinone (TQ) on hypertension induced by angiotensin II (AngII), the main product of renin–angiotensin system (RAS). Methods Seven animal groups (n=7 for each group) were used as follows: (1) control, (2) AngII (300 ng/kg), (3) AngII+losartan (Los; 10 mg/kg), (4) TQ (40 mg/kg)+AngII, and (5–7) three doses of N. sativa (200, 400, and 600 mg/kg)+AngII. Los and AngII were injected intravenously; TQ and extracts were injected intraperitoneally. In TQ and N. sativa -treated groups, 30 min after injection of the extract and TQ, AngII was injected. Cardiovascular parameters were recorded by power lab system after cannulation of femoral artery. The maximum changes (∆) of systolic blood pressure (SBP), mean arterial pressure (MAP), and heart rate (HR) were calculated and used for statistical analysis. Results AngII significantly increased maximal ∆SBP, ∆MAP, and ∆HR compared with the control (p<0.001), and these effects significantly were blunted by Los. TQ and two higher doses (400 and 600 mg/kg) of N. sativa significantly could antagonize effect of AngII on ∆SBP, ∆MAP (p<0.05 to p<0.001). AngII-induced changes of HR are also significantly decreased by TQ and dose 600 mg/kg of extract (p<0.01 and p<0.05, respectively). Conclusions The N. sativa and its component TQ have the beneficial effect on hypertension probably due to attenuation cardiovascular effects of AngII.

Background Acute myocardial infarction is a major cause of death all over the world. Irisin is a novel myokine released after exercise. This work aimed to study the correlation between the serum irisin level and the severity of the acute myocardial infarction in the exercise-trained rats. Methods Forty-eight male rats were classified into four groups (12 for each): group I, control sedentary (C); group II, exercise-trained (EX) (swimming for 8 weeks); group III, isoprenaline-induced infarct (MI); and group IV, exercise-trained infarct (EX-MI) (swimming for 8 weeks followed by isoprenaline-induced infarction). ECG was recorded at start and end of the study, before and after induction of infarction. The serum level of irisin, lipid peroxidation [malondialdehyde (MDA)], total antioxidant status (TAS), creatine phosphokinase-MB (CK-MB), and troponin I was determined. The hearts were excised for histopathology and immunohistochemistry for caspase-3. Results The infarct rats showed significant prolongation in QTc interval and elevation in the ST segment as well as significant elevation of serum CK-MB, troponin I, and MDA, whereas TAS and serum irisin level were significantly decreased. With exercise, we observed a high positive correlation between the serum irisin and QRS duration (+0.643), amplitude (+0.860), and TAS (+0.887). In addition, there was a high negative correlation between the serum irisin and ST elevation (−0.865), QTc (−0.886), CK-MB (−0.891), troponin (−0.882), and MDA (−0.868). This was confirmed by the negative correlation between serum irisin and both collagen deposition and caspase-3 expression (–0.823 and –0.822, respectively). Conclusions We recommend regular exercise or taking recombinant irisin as a supplement to protect at-risk individuals against acute myocardial infarction.

Background Because of the antioxidant effects of Zataria multiflora (ZM) and carvacrol (CAR) and also the role of oxidative stress in the induction of cardiotoxicity induced by Adriamycin (ADR), the aim of this study was to investigate the improvement effects of ZM extract and CAR on cardiotoxicity induced by ADR in rats. Methods Twenty-eight male rats were randomly assigned to four groups including (1) the control group; (2) the ADR group, which received ADR intravenously at the beginning of the study and the (3) ZM+ADR and (4) CAR+ADR groups, which received ZM and CAR by gavage for 28 consecutive days and ADR as single dose. Blood samples were collected on days 0 and 28 to determine serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT) and lactate dehydrogenase (LDH). Also, cardiac tissue was removed for redox marker evaluation. Results In the ADR group, malondialdehyde (MDA) significantly increased and superoxide dismutase (SOD) activity and total thiol contents significantly reduced, as compared with the control group, while CAR administration significantly improved this condition. Treatment with ZM significantly increased the SOD activity and total thiol content, as compared with the ADR group. The level of LDH significantly increased on day 28 in the ADR group compared to the control group, and administration of ZM and CAR significantly decreased it. The SGPT and SGOT levels in the ADR group significantly increased, and CAR administration significantly reduced them. Conclusion The results indicate that the administration of ZM hydroalcoholic extracts and its active ingredient, CAR, could reduce the oxidative stress damage through promotion of the cardiac and systemic antioxidant system. Also, CAR administration demonstrated better improvement in cardiotoxicity with ADR in rats.

Background The negative impact of diabetes on the liver is well documented. The white butterfly ( Clerodendrum volubile ) leaf has been used in traditional practices for the treatment of various diseases, such as hypertension, diabetes, and rheumatism, but without scientific validation. This work was designed to evaluate the hepatoprotective properties of Clerodendrum volubile leaves on oxidative stress in streptozotocin (STZ)-induced diabetes in rats. Methods The rats were divided into ten groups of five rats each. Diabetes was induced by a single injection of STZ (65 mg/kg body weight; i.p), while the C. volubile extract (at the respective doses of 50, 100 and 200 mg/kg body weight) was given to diabetic and non-diabetic rats orally for 14 days. Metformin (100 mg/kg body weight) served as the positive control. Biochemical assays were conducted on the plasma for hematological parameters, along with hepatic marker damages and antioxidant enzyme determination in vivo to assess hepatic injury. Results The diabetic control rats showed significant increase (p<0.05) in marker enzymes: aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and malondiadehyde with reduction in reduced glutathione, glutathione peroxidase, superoxide dismutase, catalase activities and plasma total protein content. Likewise, there were alterations in hematological indices in the diabetic control rats when compared with the normal control. However, treatment with C. volubile caused a reversal of the above parameters towards normal levels, thereby suggesting the modulating effect of the extract on oxidative stress, which may be a result of the high polyphenolic content and antioxidant capacity. Conclusions The protection of the liver tissues and the modulation of oxidative stress in STZ diabetic rats compare favorably to metformin, a standard antidiabetic drug.

Background Proline is a proteinogenic amino acid with multiple biological functions. Several investigations have been supposed that cellular proline accumulation is a stress response mechanism. This amino acid acts as an osmoregulator, scavenges free radical species, boosts cellular antioxidant defense mechanisms, protects mitochondria, and promotes energy production. The current study was designed to investigate the effect of proline treatment on the liver in bile duct ligated (BDL) rats as an animal model of cholestasis/cirrhosis. Methods BDL rats were supplemented with proline-containing drinking water (0.25% and 0.5% w:v), and samples were collected at scheduled time intervals (3, 7, 14, 28, and 42 days after BDL surgery). Results Drastic elevation in the serum level of liver injury biomarkers and significant tissue histopathological changes were evident in BDL rats. Markers of oxidative stress were also higher in the liver of BDL animals. It was found that proline supplementation attenuated BDL-induced alteration in serum biomarkers of liver injury, mitigated liver histopathological changes, and alleviated markers of oxidative stress at the early stage of BDL operation (3, 7, and 14 days after BDL surgery). Conclusions The hepatoprotection provided by proline in BDL animals might be associated with its ability to attenuate oxidative stress and its consequences.

Background The aim of this study is to investigate the effects of pravastatin (PS) against doxorubicin (DOX)-induced testicular toxicity. Methods A total of 24 healthy male Sprague-Dawley rats were equally divided into four groups. Group I received normal saline, Group II received PS (20 mg/kg b.w.) by gavage, Group III was treated with DOX alone (15 mg/kg b.w., i.p.) and Group IV received the combination of DOX and PS. Results After 8 weeks, the results displayed that DOX caused a decrease in testicular volume and index, epididymal sperm count, seminiferous tubule diameter and germinal epithelium. DOX also reduced the number of spermatogonia, spermatoctyes and Sertoli cells as well as increased the lumen diameter of seminiferous tubules (p<0.05) and the incidence of histopathological changes of the testis. Moreover, elevated malondialdehyde (MDA) levels and declined glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities were observed (p<0.05). On the contrary, PS treatment significantly ameliorated nearly all of these abnormalities (p<0.05). Conclusions PS protects against DOX-induced testicular toxicity in rats, which is likely via the inhibition of oxidative stress and the increase of antioxidant enzyme activity.

Background Obesity has been implicated in impaired salivary secretion. This study aimed at evaluating the influence of diet-induced obesity on salivary secretion and how re-feeding with normal diet would affect changes in salivary secretion associated with diet-induced obesity. Methods Weaning rats weighing 55–65 g were randomly divided into three groups (control, diet-induced obese, re-fed obese) of seven rats each. The diet-induced obese group was fed a high-fat diet for 15 weeks, whereas the re-fed obese group received normal diet for another 15 weeks following the 15 weeks of high-fat diet. After treatment, blood and stimulated saliva samples were collected for the analyses of total protein, electrolytes, amylase, Immunoglobulin A (IgA), leptin and ghrelin. Tissue total protein, nitric oxide level, expressions of Na + /K + -ATPase, muscarinic (M3) receptor and aquaporin 5 in the submandibular glands were determined. Data were presented as mean±SEM and compared using independent student t-test and ANOVA with Tukey’s post-hoc test. Results Results indicated increases in the levels of salivary calcium, phosphate, bicarbonate and leptin, whereas the levels of salivary amylase and ghrelin showed reduction in the obese group compared with the control. Most of these changes were reversed in the re-fed obese group. There were no significant differences in salivary lag time, flow rate, levels of tissue total protein, nitric oxide and the relative expressions of M3 receptor, Na + +/K + -ATPase and aquaporin 5 in the submandibular glands between the obese and control groups. Conclusions Diet-induced obesity lead to some changes in salivary factors which were reversed by returning to normal diet.

Background The current study evaluates the analgesic effect of different extracts of Hopea odorata leaves in mice followed by molecular docking and absorption, distribution, metabolism, excretion, and toxicity (ADME/T) analysis of isolated compounds derived from the plant with the COX-1 enzyme. Methods In the present study, the dried leaves of H. odorata were subjected to extraction using methanol, ethanol, and water. In vivo analgesic activity was evaluated by using the acetic acid-induced writhing test and formalin-induced paw licking test, and in silico molecular docking and ADME/T study were performed using Schrödinger Maestro (version 11.1) and online-based tools, respectively, on eight isolated compounds. Results The results showed that the methanolic extract of leaves has highest significant dose-dependent analgesic activity at both 200 and 400 mg/kg followed by ethanolic extract of leaves. Among all the compounds, ampelopsin showed the best docking score of −7.055, ensuring strong binding affinity between the ligand and the receptor, and ADME/T analysis using Web-based tools ensures the compound has not violated Lipinski’s rule of five indicating its safety consumption. Conclusions The result confirms the analgesic activity of H. odorata leaves in both in vivo and in silico assays. The data support ampelopsin to be a potent analgesic compound worthy of future clinical trials and its “drug-likeliness”

Background Development of drug-induced hepatic damage (DIHD) during chemotherapy is the most common reason for interruption in chemotherapy. This study evaluated the hepatoprotective activity of the ethanolic extract of Tamarindus indica stem bark (EETI) against the induced DIHD in Sprague Dawley rats. Methods The rats were divided into five groups (n=5). Group I, group III, group IV, and group V rats received 1 mL 1% carboxymethyl cellulose, EETI 100 mg/kg body weight (b.wt), EETI 200 mg/kg b.wt, and silymarin 100 mg/kg b.wt, respectively, orally once every day for 28 days. After 1 h–group II, group III, group IV, and group V rats were administered with isoniazid (INH) and rifampicin (RIF) 50 mg/kg b.wt each orally once every day for 28 days. Then, 24 h after the last dosing, blood was withdrawn from the rats and analyzed for liver specific enzymes and biochemical markers. They were examined for histopathology. Results Co-administration of INH and RIF in group II significantly increased alanine transaminase, aspartate transaminase, alkaline phosphatase, lactate dehydrogenase, serum bilirubin, and cholesterol levels while reduced the total protein and albumin levels compared to that of group I. EETI in group III and group IV rats significantly restored the liver specific enzymes and biochemical markers altered due to co-administration of INH and RIF to normal in a dose-dependent manner. EETI 200 mg/kg b.wt showed better protection to liver than EETI 100 mg/kg b.wt and was comparable to silymarin 100 mg/kg b.wt. It was well supported with histopathology of liver tissues. Conclusions EETI possesses hepatoprotective activity against DIHD in rats. It may have a substantial impact on developing clinical strategies to treat patients with hepatic damage.

We report a 26-year-old male patient diagnosed with extensively drug-resistant pulmonary tuberculosis presenting with reversible bilateral toxic optic neuropathy induced by the use of linezolid along with high-dose isoniazid. The case emphasizes the importance of recognizing toxic optic neuritis in patients on antitubercular therapy. Prompt recognition and treatment of such adverse drug reactions will reduce the associated morbidity.