Reactive oxygen species mediated apoptotic death of colon cancer cells: therapeutic potential of plant derived alkaloids.

Colorectal cancer (CRC) is one of the most deaths causing diseases worldwide. Several risk factors including hormones like insulin and insulin like growth factors (e.g., IGF-1) have been considered responsible for growth and progression of colon cancer. Though there is a huge advancement in the available screening as well as treatment techniques for CRC. There is no significant decrease in the mortality of cancer patients. Moreover, the current treatment approaches for CRC are associated with serious challenges like drug resistance and cancer re-growth. Given the severity of the disease, there is an urgent need for novel therapeutic agents with ideal characteristics. Several pieces of evidence suggested that natural products, specifically medicinal plants, and derived phytochemicals may serve as potential sources for novel drug discovery for various diseases including cancer. On the other hand, cancer cells like colon cancer require a high basal level of reactive oxygen species (ROS) to maintain its own cellular functions. However, excess production of intracellular ROS leads to cancer cell death via disturbing cellular redox homeostasis. Therefore, medicinal plants and derived phytocompounds that can enhance the intracellular ROS and induce apoptotic cell death in cancer cells via modulating various molecular targets including IGF-1 could be potential therapeutic agents. Alkaloids form a major class of such phytoconstituents that can play a key role in cancer prevention. Moreover, several preclinical and clinical studies have also evidenced that these compounds show potent anti-colon cancer effects and exhibit negligible toxicity towards the normal cells. Hence, the present evidence-based study aimed to provide an update on various alkaloids that have been reported to induce ROS-mediated apoptosis in colon cancer cells via targeting various cellular components including hormones and growth factors, which play a role in metastasis, angiogenesis, proliferation, and invasion. This study also provides an individual account on each such alkaloid that underwent clinical trials either alone or in combination with other clinical drugs. In addition, various classes of phytochemicals that induce ROS-mediated cell death in different kinds of cancers including colon cancer are discussed.

The Incidence and Severity of COVID-19 Infection Post Vaccination in Saudi Arabia.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). Presently, there is ongoing continuous research for more therapeutic options with a wide variety of vaccine availability. However, many people have worried about the vaccine's side effects. Hence, the current study was conducted to determine the prevalence of vaccinated individuals, side effects, and the rate of infectivity post vaccination including the three doses of vaccinations. Methods A cross-sectional questionnaire-based survey was conducted using Google Forms (Google, Inc., Mountain View, CA). Five hundred forty-three individuals participated and reported their status of COVID-19 infection, vaccination, and side effects. All the participants from Saudi Arabia received all the vaccine shots including the booster dose. Results Most of the Saudi nationals were fully vaccinated, and most received Pfizer vaccines for their first and second shots. Pain at the injection site was reported as the most common adverse effect followed by fever, headache, fatigue, and joint pain. Conclusion From the findings, it is concluded that most of the population of Saudi Arabia was vaccinated effectively. Pain at the injection site is identified as the primary adverse effect of vaccination. Most of the population is vaccinated with the Pfizer vaccine. Long-term side effect monitoring is recommended with large population studies to confirm the status of vaccines and adverse effects.

PRDM16, LRP1 and TRPM8 genetic polymorphisms are risk factor for Pakistani migraine patients.

BACKGROUND: Migraine is a chronic neurovascular condition characterized by recurring attacks of pulsating headaches. Genome-wide association studies (GWAS) identified many potential loci associated with migraine. To check the association of polymorphisms of PRDM16 (rs2651899), LRP1 (rs11172113), and TRPM8 (rs10166942) with migraine, the first time a case-control study was conducted in understudied Pakistani population. METHODS: The study included 127 migraine patients (21 in migraine with aura and 106 with migraine without aura group) and 120 healthy control subjects from different areas of Punjab, Pakistan. Blood samples were collected from all the participants, and DNA was isolated from the lymphocytes by the modified organic method. Sanger's sequencing was done for PRDM16 (rs2651899), LRP1 (rs11172113), and TRPM8 (rs10166942) in all the samples to check the genotype. Logistic regression analysis was done using SPSS 20.0 to check the association of these SNPs with migraine susceptibility. RESULTS: We found statistically significant differences between case and control group for PRDM16 (rs2651899) at genotypic level (p < 0.001), allelic level (p < 0.001; OR 3.088; 95% CI 2.082-4.579) and for dominant model (p < 0.001; OR 5.437; 95% CI 3.112-9.498). The major findings of this study suggested that PRDM16 rs2651899 is strongly associated with migraine in overall and subgroup analysis of genotypes. LRP1 (rs11172113) showed significant association with migraine except in subgroup comparison. A similar trend of association was found for TRPM8 (rs10166942) however, significant association was found only at the allelic level but no significant difference was seen at the genotypic level between case and control. One novel mutation c.67 + 4436_67 + 4438delA was also identified in the current study near LRP1 (rs11172113) polymorphic site. CONCLUSION: In this first-ever replication report from Pakistan, PRDM16 (rs2651899) was found as a potential genetic marker in migraine susceptibility while LRP1 (rs11172113) and TRPM8 (rs10166942) showed partial association in subgroup analysis.

Catalytic Transfer Hydrogenolysis of Glycerol over Heterogeneous Catalysts: A Short Review on Mechanistic Studies.

Catalytic transfer hydrogenolysis, using liquid H-donors in the absence of pressurized H2 under mild temperatures, is regarded as the most important technology to substitute traditional hydrogenation processes in industry. Despite decade development with several breakthroughs in catalyst design, the reaction mechanism involved in H2 generation and subsequent hydrogenolysis reactions is still under debate. In this review, transfer hydrogenolysis of glycerol, as a representative example, on metallic catalysts is revised critically with respect to surface reaction mechanism and catalyst design. The detailed reaction pathways for propanol, methanol, formic acid and ethanol for H2 generation have been discussed systematically. In particular, reaction mechanism for catalytic C-H cleavage, H spillover/transfer and C-O cleavage reaction steps will be critically revised with experimental and theoretical results in literature. Insights into reaction pathways, mechanism and H2 transfer efficiency and structure-performance relation for Pd, Cu and Ni catalysts will be provided for future development of catalyst manufacture and process development. The outcome of this work is useful for successful implementation of bio-refinery.

Sulforaphane Attenuates Isoproterenol-Induced Myocardial Injury in Mice.

The development of isoproterenol- (ISO-) induced oxidative stress in the myocardium results in myocardial necrosis. Sulforaphane (SFN-0.4% of sulforaphane from standardized broccoli sprout extract) possesses chemoprotective, antidiabetic, and antibacterial activities and is also active against cardiovascular-related problems due to its antioxidant properties. This study was designed to investigate the cardioprotective effect of SFN against isoproterenol-induced myocardial injury in mice. Healthy male Swiss albino mice weighing 20-30 g were used in this study. These mice were randomly divided into five groups (n = 6). All the mice in the experimental groups received isoproterenol (5 mg/kg bw, via i.p.) consecutively for 2 days. The mice were treated with SFN (4 mg/kg bw) and α-tocopherol (TCF) (10 mg/kg bw) by oral gavage for 1-7 days as pre- and posttreatment for the prophylactic and treatment groups, respectively. On day 10, the following parameters were studied: heart weight to body weight ratio, antioxidant parameters, and cardiac markers; and mitochondrial enzymes were estimated for cardioprotection. Administration of isoproterenol in mice showed an increased level of serum cardiac markers and heart mitochondrial ATPase enzymes. An increased level of myocardial thiobarbituric acid-reactive substance and decreased levels of endogenous antioxidant enzymes indicated that oxidative stress is induced by isoproterenol in the myocardium. The administration of SFN in mice restored the levels of all biochemical parameters to near-normal levels. Histopathological studies further confirmed the protective effect of sulforaphane. This study concluded that treatment with SFN boosts the endogenous antioxidant activity and prevents isoproterenol-induced myocardial injury.

Marital Problems among Partners of Patients with Bipolar Affective Disorder.

BACKGROUND: Partners of patients with bipolar affective disorder (BPAD) have problems with their marital life. Identification of these problems is important to develop strategies to solve them for improving quality of life. AIMS: To identify marital distress and problem areas in their marital life among the partners of patients with BPAD. MATERIALS AND METHODS: A cross-sectional descriptive design was used to collect data from 125 participants, 59 males and 66 females, who were partners of patients with BPAD. The study was done in outpatient clinics of Community Mental Health Clinics of District Mental Health Program. Tools used for data collection included a semi-structured interview schedule to collect socio-personal data of partners of patients with BPAD and clinical data of the patient, Couple Satisfaction Index (CSI), and Problem Areas Questionnaire (PAQ). Purposive sampling technique was used. RESULTS: Majority of the participants (male - 55.9%, female -54.5%) expressed marital distress on CSI. Handling family finances and career/job decisions were the most problematic areas for male participants, whereas household tasks, handling finances, and career/job decisions were the most problematic areas for female participants. CONCLUSION: A significant proportion of spouses of BPAD patients have marital distress in important areas of life, with a potential for long-term consequences in their lives.

Intra-operative assessment of excised breast tumour margins using ClearEdge imaging device.

INTRODUCTION: Breast conserving surgery (BCS) aims to remove a breast cancer completely and obtain clear margins. Complete excision is essential to reduce the risk of local recurrence. The ClearEdge™ (CE) imaging device examines margins of excised breast tissue intra-operatively. The aim of this study was to investigate the potential of the device in detecting margin involvement in patients having BCS. METHODS: In Phase-1 58 patients underwent BCS and had 334 margins assessed by the device. In Phase-2 the device was used in 63 patients having BCS and 335 margins were assessed. Patients with margins considered close or involved by the CE device were re-excised. RESULTS: The margin assessment accuracies in Phase-1 and Phase-2 compared to permanent section pathology were very similar: sensitivity (84.3% and 87.3%), specificity (81.9% and 75.6%), positive predictive value (67.2% and 63.6%), and negative predictive value (92.2% and 92.4%). The false positive rate (18.1% and 24.4%) and false negative rate (15.7% and 12.7%) were low in both phases. In Phase-2 re-excision rate was 37%, but in the 54 where the CE device was used appropriately the re-excision rate was 17%. Had all surgeons interpreted all images appropriately and re-excised margins detected as abnormal by the device in Phase-2 then the re-excision rate would have been 7%. CONCLUSION: This study shows that the CE device has potential to reduce re-excision after BCS and further randomized studies of its value are warranted.

Possible Protective Effects of Quercetin and Sodium Gluconate Against Colon Cancer Induction by Dimethylhydrazine in Mice.

Micronutrients in food have been found to have chemopreventive effects, supporting the conclusions from epidemiologie studies that consumption of fresh fruits and vegetables reduces cancer risk. The present study was carried out to evaluate the role of querctin (Q) and sodium gluconate (GNA) supplementation separately or in combination in ameliorating promotion of colon tumor development by dimethyl-hydrazine (DMH) in mice. Histopathological observation of colons in mice treated with DMH showed goblet cell dysplasia with inflammatory cell infiltration. This pathological finding was associated with significant alteration in oxidative stress markers in colon tissues and carcinoembryonic antigen (CEA) levels in plasma. Mice co-treated with GNA and Q showed mild changes of absorptive and goblet cells and inflammatory cell infiltration in lamina properia, with improvement in oxidative stress markers. In conclusion, findings of the present study indicate significant roles for reactive oxygen species (ROS) in pathogenesis of DMH-induced colon toxicity and initiation of colon cancer. Also, they suggest that Q, GNA or the combination of both have a positive beneficial effect against DMH induced colonic cancer induction in mice.

Effect of whole plant of Rostellularia diffusa Willd. on experimental stress in mice.

BACKGROUND: Rostellularia diffusa is an unexplored medicinal plant used as brain tonic in traditional medicine system. OBJECTIVE: This study was designed to investigate the antioxidant and anti-stress potential of R. diffusa by experimental animal models. MATERIALS AND METHODS: The extracts of R. diffusa were subjected to preliminary phytochemical screening and high performance thin layer chromatography (HPTLC) finger printing analysis. The antioxidant potential of the extracts was found by different in vitro models. The anti-stress activity was investigated by using acetic acid induced writhing test, swimming endurance test, and restraint stress in experimental mice. Serum parameters such as glucose, triglyceride and cholesterol, oxidative stress parameter thiobarbituric acid reactive substance, antioxidant parameters such as reduced glutathione, superoxide dismutase and catalase and organ weights were evaluated after restraint stress in mice. Diazepam was used as reference standard to compare the anti-stress activity of plant extract. RESULTS: High performance thin layer chromatography finger printing analysis revealed the presence of flavone compounds in both extracts. The extracts also showed good antioxidant property in different in vitro antioxidant models. Administration of extracts of R. diffusa decreased the number of wriths and immobility time when compared with control group in acetic acid-induced writhing test and swimming endurance test respectively in experimental mice. They also suppressed the restraint stress-induced alterations in serum parameters, oxidative stress, and antioxidant parameters in brain and also restored the organ weights in normal level. CONCLUSION: From these results, it has been concluded that the potential anti-stress activity of R. diffusa is through its adaptogenic and antioxidant properties.

Aqueous extract of Saussurea lappa root ameliorate oxidative myocardial injury induced by isoproterenol in rats.

Saussurea lappa Clarke (Compositae), is commonly known as Kushta. In Ayurvedha, it is mentioned that the aqueous extract of the root S. lappa was used for treatment of angina pectoris. The present study was designed to investigate the cardioprotective effect of aqueous extract of root of S. lappa against isoproterenol induced myocardial injury. Myocardial injury in rat was induced by the administration of isoproterenol at a dose of 85 mg/kg, i.p., The rats were pretreated with the aqueous extract of S. lappa (AESL) in three different doses (100, 200 and 300 mg/kg, p.o.) through the oral route. Isoproterenol alone-treated rats showed increased serum concentration of lactate dehydrogenase (LDH), creatinine kinase (CK), and aspartate transaminase (AST), increased myocardial thiobarbituric acid reactive substances (TBARS) level, and decreased myocardial glutathione (GSH) level due to myocardial damage produced by isoproterenol. This is further conformed by histopathological changes. Chronic oral administration of AESL in three different doses significantly restored the level of myocardial LDH, CK, AST, TBARS, and GSH. The extract effect was compared with the reference standard α-tocopherol which also offered similar protection in biochemical and histopathological changes. The overall beneficial effect which was observed with the dose of 200 mg/kg indicated that AESL produced significant dose-dependent activity against isoproterenol induced myocardial injury.

Protective role of Ficus benghalensis against isoniazid-rifampicin induced oxidative liver injury in rat

The present study was made to investigate the protective effect of methanolic extract of Ficus benghalensis L., Moraceae, on isoniazid-rifampicin-induced hepatotoxicity in rats. Rats were divided into six different groups; group 1 served as a control, group 2 received isoniazid and rifampicin (100 mg/kg, i.p.), in sterile water, groups 3, 4 and 5 received 100, 200 & 300 mg/kg bw, p.o. methanolic extract of F. benghalensis and group 6 received Liv 52. All the treatment protocols followed 21 days and after rats were sacrificed blood and liver were used for biochemical and histological studies, respectively. Administration of isoniazid and rifampicin caused a significant elevation in the levels of liver marker enzymes (p<0.05 and p<0.01) and thiobarbituric acid reactive substances (p<0.001) in experimental rats. Administration of methanolic extracts of F. benghalensis significantly prevented isoniazid-rifampicin-induced elevation in the levels of serum diagnostic liver marker enzymes and TBARS level in experimental groups of rats. Morever, total protein and reduced glutathione levels were significantly (p<0.001) increased in treatment group. The effect of extract was compared with a standard drug, Liv 52. The changes in biochemical parameters were supported by histological profile. It is to be concluded that the methanolic extract of F. benghalensis protects against isoniazid and rifampicin-induced oxidative liver injury in rats.

Sesame oil enhances endogenous antioxidants in ischemic myocardium of rat

The present study was designed to evaluate the potency of antioxidant activity of sesame oil in-vitro model of myocardial ischemic reperfusion injury of rat. Sesame oil was administered orally to Wistar albino rats (180-200 g) in two different doses (n=6), by gastric gavage at a dose of 5 mL/kg b.w. (S1) and 10 mL/kg b.w (S2) daily for thirty days. Control and sesame oil treated rat hearts were subjected to invitro global ischemic reperfusion injury (5 min perfusion, 9 min noflow and 12 min reperfusion). A significant rise in TBARS and decrease of GSH, catalase, LDH, CK and AST occurred in the hearts subjected to in-vitro myocardial ischemic reperfusion injury indicate the myocardial damage through oxidative stress. In sesame oil treated rats there was a significant decrease in TBARS and significant increase in endogenous antioxidants and myocardial marker enzymes in all the groups. In 10 mL/kg treatment group, a significant rise in the levels of GSH, SOD and catalase were observed with marker enzymes, and it shows better recovery profile than the other groups subjected to in-vitro ischemic reperfusion injury. In histological studies, control rats which subjected to IR injury show extensive myocardial damage and all the treatment groups, shows preserved myocardium. The effect of sesame oil was compared with reference compound captopril. The present study demonstrates that the sesame oil treated by the dose 10 mL/kg augments endogenous antioxidant compounds of the rat heart and also prevents the myocardium from in-vitro model of myocardial ischemic reperfusion injury.

Large thymic carcinoma presenting with right ventricular failure: a case report.

Thymic carcinoma is an overall rare tumour with variable clinical manifestations. Right ventricular failure remains an uncommon occurrence and has not been reported in literature so far. A 40-year-old lady presented with the complaints of progressively worsening retrosternal chest pain, shortness of breath, easy fatigability and cough since 1 year. Computed tomography scan of the thorax revealed a mass measuring 12 x 10 cm in the anterior mediastinum. This mass appeared to be adherent to both lungs and pericardium and was impinging on the right atrium and right ventricle. It appeared to be infiltrating the ascending aorta, pulmonary arteries and superior vena cava. Ultrasound of the abdomen showed hepatomegaly and moderate ascites. Echocardiography showed evidence of right ventricular dysfunction as well as elevated right ventricular systolic pressures secondary to extrinsic compression. Percutaneous biopsy of the thymus was performed showing a malignant thymoma. Radical thymectomy with resection of pericardium was planned. Intra-operatively, the tumour was separated from the right and left lungs, pulmonary artery and aortic arch. Morphologically, immunochemically and clinically, the features were consistent with those seen in Masoka stage III thymic carcinoma. She also received six cycles of chemotherapy (PAC regimen) including cisplatin (50 mg/m2), doxorubicin (50 mg/m2) and cyclophosphamide (500 mg/m2). Radiation therapy in the adjuvant setting was planned but the patient was lost to follow-up after 4 months. Although right ventricular failure is a very rare presentation of thymic carcinoma, clinicians should be aware of this presentation to appreciate the complete clinical spectrum of presentation of this neoplasm.

Anti-inflammatory activity of the leaf extacts of Gendarussa vulgaris Nees.

OBJECTIVE: To evaluate the anti-inflammatory property of the leaf exacts of Gendarussa vulgaris (G. vulgaris) Nees. METHODS: G. vulgaris Nees of the family Apocynaceae is a medium sized tree grown in semishade or no shade and is common in the Ernad and Nilambur taluks of Kerala.Various parts of this plant have been used in the treatment of ulcers, sores, inflammation, dyspepsia, healing of wounds, etc. The present study aimed at the evaluation of anti-inflammatory property of the aqueous and alcoholic extracts of the leaves by both in vitro and in vivo methods. In vitro method was estimated by human red blood cell membrane stabilisation (HRBC) method and in vivo method was estimated on the carrageenan induced paw oedima. RESULTS: Both the methods showed significant anti-inflammatory property of the different extracts tested. CONCLUSIONS: The alcoholic extract at a concentration of 300 mg/mL showed potent activity on comparing with the standard drug diclofenac sodium.

In vivo evaluation of a novel albumin-binding prodrug of doxorubicin in an orthotopic mouse model of prostate cancer (LNCaP).

PSA, which is overexpressed in prostate carcinoma, represents a molecular target for selectively releasing an anticancer agent from a prodrug formulation. In this study, we report on the in vivo antitumor efficacy of an efficacious albumin-binding prodrug of doxorubicin (PSA9) that incorporates p-aminobenzyloxycarbonyl (PABC) as a self-immolative spacer in addition to the heptapeptide, Arg-Ser-Ser-Tyr-Tyr-Ser-Leu, which serves as a substrate for PSA. The prodrug is cleaved very efficiently by PSA releasing H-Ser-Leu-PABC-doxorubicin and subsequently doxorubicin in PSA-positive cell lysates and prostate tumor homogenates as the final cleavage product. PSA9 at 3 × 6 mg kg(-1) doxorubicin equivalents (intravenous) was compared with conventional doxorubicin at equitoxic doses (at 3 × 3 mg kg(-1); intravenous) in an orthotopic mouse model of prostate cancer using LNCaP lentiviral luciferase-neomycin cells transduced with luciferase. Whereas doxorubicin did not show any efficacy against the primary tumor or metastases, the prodrug reduced the primary tumor by 30-50% and circulating PSA levels, and in addition, showed a pronounced reduction in lung and bone metastases by ∼77% and ∼96%, respectively, and a positive trend regarding the activity against liver and lymph-node metastases compared with control and doxorubicin-treated animals. The incorporation of PABC as a self-immolative spacer together with a PSA substrate demonstrates superior antitumor effects over doxorubicin attributed to an efficient cleavage by PSA releasing doxorubicin as the final active agent in prostate tumor homogenates. Using this approach for developing effective prodrugs against prostate cancer, is worthy of further preclinical optimization.

Red wine: A drink to your heart.

Mortality and morbidity are still high in cardiovascular disease (CVD). Myocardial ischemia reperfusion injury leading to myocardial infarction is one of the most frequent causes of the death in humans. Atherosclerosis and generation of reactive oxygen species through oxidative stress is the major risk factor for CVD. From the literature collection, it has been identified that moderate consumption of red wine helps in preventing CVD through several mechanisms, including increasing the high-density lipoprotein cholesterol plasma levels, decreasing platelet aggregation, by antioxidant effects, and by restoration of endothelial function. The aim of this review is to discuss the accumulating evidence that suggests that red wine possesses a diverse range of biological actions and may be beneficial in the prevention of CVD.

Pre-operative lymphoscintigraphy before sentinel lymph node biopsy for breast cancer.

Pre-operative lymphoscintigram for axillary sentinel lymph node biopsy (SLNB) may not be required for successful SLNB. The 117 consecutive patients who underwent SLNB had pre-operative lymphoscintigraphy. The operating surgeon was blinded to the results of the lymphoscintigram before SLNB. After SLNB was complete, the surgeon was unblinded to the results of the lymphoscintigram; re-exploration carried out if more nodes were predicted on the lymphoscintigram. 116 patients (99%) had successful SLNB before unblinding. In 85 patients (73%), operative findings corresponded with scintigraphic findings. In 26 patients (22%), the lymphoscintigram predicted more sentinel nodes than had been found; further nodes were identified and excised in only 4 patients (3%). None were positive for cancer. SLNB was successful in 99% of cases without pre-operative lymphoscintigraphy. Only 3% of patients had further nodes identified as a result of the lymphoscintigram. Pre-operative lymphoscintigraphy does not improve the ability to perform axillary SLNB during breast cancer surgery.

ACE inhibitors - angiotensin II receptor antagonists: A useful combination therapy for ischemic heart disease.

Morbidity and mortality from cardiovascular diseases are still high, even with the use of the best available therapies. There is mounting evidence that excessive renin-angiotensin system activation triggers much of the damaging and progressive nature of cardiovascular and kidney diseases through expression of angiotensin II. Moreover, angiotensin II play a major role in the development of end organ damage through a variety of inflammatory mechanisms. Today, angiotensins-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists have clearly demonstrated their efficacy in preventing target organ damage and in reducing cardiovascular morbidity and mortality in ischemic heart disease (IHD). Moreover, the development of angiotensin II receptor antagonists has enabled a large gain in tolerability and safety. Several clinical trials have firmly established that these drugs act on the renin-angiotensin system, reducing the incidence of coronary events with monotherapy and combination therapy. In this review we summarize the role mono- and combined therapy of ACE inhibitors and angiotensin II receptor antagonists play in ischemic heart disease. In this respect the review will improve ideas for developing new formulations with combinations of these drugs in the future.