Identification of h-TERT Promoter Mutations in Germline DNA from North Indian Lung Carcinoma Patients.

Lung cancer is a severe and the leading cause of cancer related deaths worldwide. The recurrent h-TERT promoter mutations have been implicated in various cancer types. Thus, the present study is extended to analyze h-TERT promoter mutations from the North Indian lung carcinoma patients. Total 20 histopathologically and clinically confirmed cases of lung cancer were enrolled in this study. The genomic DNA was extracted from venous blood and subjected to amplification using appropriate h-TERT promoter primers. Amplified PCR products were subjected for DNA Sanger sequencing for the identification of novel h-TERT mutations. Further, these identified h-TERT promoter mutations were analysed for the prediction of pathophysiological consequences using bioinformatics tools such as Tfsitescan and CIIDER. The average age of patients was 45 ± 8 years which was categorized in early onset of lung cancer with predominance of male patients by 5.6 fold. Interestingly, h-TERT promoter mutations were observed highly frequent in lung cancer. Identified mutations include c. G272A, c. T122A, c. C150A, c. 123 del C, c. C123T, c. G105A, c. 107 Ins A, c. 276 del C corresponding to -168 G>A, -18 T>A, -46 C>A, -19 del C, -19 C>T, -1 G>A, -3 Ins A, -172 del C respectively from the translation start site in the promoter of the telomerase reverse transcriptase gene which are the first time reported in germline genome from lung cancer. Strikingly, c. -18 T>A [C.T122A] was found the most prevalent variant with 75% frequency. Notwithstanding, other mutations viz c. -G168A [c. G272A] and c. -1 G>A [c. G105A] were found to be at 35% and 15% frequency respectively whilst the rest of the mutations were present at 10% and 5% frequency. Additionally, bioinformatics analysis revealed that these mutations can lead to either loss or gain of various transcription factor binding sites in the h-TERT promoter region. Henceforth, these mutations may play a pivotal role in h-TERT gene expression. Taken together, these identified novel promoter mutations may alter the epigenetics and subsequently various transcription factor binding sites which are of great functional significance. Thereby, it is plausible that these germline mutations may involve either as predisposing factor or direct participation in the pathophysiology of lung cancer through entangled molecular mechanisms.

Atypical Case of Highly Mutated h-TERT Promoter in Germline Genome from Buccal Mucosa Cancer.

Buccal mucosa cancer has an aggressive nature as it rapidly grows and penetrates with high recurrence rate. Strikingly, carcinoma of buccal mucosa is the most common cancer of oral cavity in India. Recently, telomerase and telomere biology have been implicated in the pathogenesis and progression in various cancers via regulation of telomere maintenance by telomerase expression which is controlled by telomerase reverse transcriptase (TERT) promoter. Strikingly, h-TERT promoter mutations have been incriminated in regulation of telomerase gene expression. Here, we present a 35 years old male with intense coughing, short breathlessness and fever since 15 days, was admitted to the pulmonary unit. He was a chronic smoker and gutka user. The cytopathological analysis of gastric aspirate revealed buccal mucosa carcinoma of IV stage. We identified h-TERT promoter mutations in isolated genomic DNA from whole blood using DNA sequencer. Genetic analysis disclosed that h-TERT promoter region was highly mutated in this patient. Identified mutations include C.-248 del G, C.-272 del G, C.-279 del G, C.-331 del G, C.-349 del G, C.-351 del C, C.-360 G > A, C.-362 T > A, C.-371 del T and C.-372 del T. Further, all identified mutations were subjected to predict the pathologic functional consequences using bioinformatics tools viz TFsitescan and CiiiDER which showed either loss or gain of transcription factors binding sites in h-TERT promoter. This is a unique case in which total 9 mutations were observed in h-TERT promoter in a single case. In conclusion, all together these mutations in h-TERT promoter may alter the epigenetics and subsequently the tenacity of binding transcription factors which are of functional significance.

A critical evaluation of risk to reward ratio of quercetin supplementation for COVID-19 and associated comorbid conditions.

The interim results of the large, multinational trials on coronavirus disease 2019 (COVID-19) using a combination of antiviral drugs appear to have little to no effect on the 28-day mortality or the in-hospital course. Therefore, there is a still vivid interest in finding alternate re-purposed drugs and nutrition supplements, which can halt or slow the disease severity. We review here the multiple preclinical studies, partially supported by clinical evidence showing the quercetin's possible therapeutic/prophylaxis efficacy against severe acute respiratory syndrome coronavirus (SARS-CoV) as well as comorbidities like chronic obstructive pulmonary disease (COPD), diabetes mellitus, obesity, coagulopathy, and hypertension. Currently, 14 interventional clinical trials are underway assessing the efficacy of quercetin along with other antiviral drugs/nutritional supplements as prophylaxis/treatment option against COVID-19. The present review is tempting to suggest that, based on circumstantial scientific evidence and preliminary clinical data, the flavonoid quercetin can ameliorate COVID-19 infection and symptoms acting in concert on two parallel and independent paths: inhibiting key factors responsible for SARS-CoV-2 infections and mitigating the clinical manifestations of the disease in patients with comorbid conditions. Despite the broad therapeutic properties of quercetin, further high power randomized clinical trials are needed to firmly establish its clinical efficacy against COVID-19.

Computational Bioprospecting Guggulsterone against ADP Ribose Phosphatase of SARS-CoV-2.

Coronavirus Disease-2019 (COVID-19) is a highly contagious disease caused by Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2). The World Health Organization (WHO) classified the disease a as global public health hazard on 11 March 2020. Currently, there are no adequate measures to combat viral infections, including COVID-19, and the medication guidelines for the management of COVID-19 are dependent on previous findings from SARS-CoV and MERS-CoV research. Natural products have achieved widespread acceptance around the world as a means of enhancing healthcare and disease prevention. Plants are a potential source of antiviral factors such as flavonoids, phenolic acids, terpenoids, and others. Some of these agents exhibit a broad spectrum of antiviral activity. This study aimed to screen herbal leads for possible inhibitors of the SARS-CoV-2 ADP Ribose Phosphatase enzyme (ARP). Guggulsterone was found to be highly stabilized within the active site of the viral ARP enzyme by molecular dynamic simulation with very little fluctuation throughout the simulation timeframe of 100 ns. Thus, guggulsterone can be further used to develop a safe and competent medication for evolving therapy against SARS-CoV-2 in post-preclinical and clinical trials.

Elucidation of underlying molecular mechanism of 5-Fluorouracil chemoresistance and its restoration using fish oil in experimental colon carcinoma.

Latest strategies for cancer treatment primarily focus on the use of chemosensitizers to enhance therapeutic outcome. N-3 PUFAs have emerged as the strongest candidate for the prevention of colorectal cancer (CRC). Our previous studies have demonstrated that fish oil (FO) rich in n-3 PUFAs not only increased therapeutic potential of 5-Fluorouracil(5-FU) in colon cancer but also ameliorated its toxicity. Henceforth, the present study is designed to elucidate mechanistic insights of FO as a chemosensitizer to circumvent drug resistance in experimental colon carcinoma. The colon cancer was induced by 1,2-dimethylhydrazine(DMH)/dextran sulfate sodium(DSS) in male Balb/c mice and these animals were treated with 5-FU(12.5 mg/kg b.w.), FO(0.2 ml), or 5-FU + FO(12.5 mg/kg b.w + 0.2 ml) orally for 14 days. The molecular mechanism of overcoming 5-FU resistance using FO in colon cancer was delineated by estimating expression of cancer stem cell markers using flowcytometric method and drug transporters by immunohistochemistry and immunoblotting. Additionally, distribution profile of 5-FU and its cytotoxic metabolite, 5-FdUMP at target(colon), and non-target sites (serum, kidney, liver, spleen) was assessed using high-performance liquid chromatography(HPLC) method. The observations revealed that expression of CSCs markers was remarkably reduced after using fish oil along with 5-FU in carcinogen-treated animals. Interestingly, the use of FO alongwith 5-FU also significantly declined the expression of drug transporters (ABCB1,ABCC5) and consequently resulted in an increased cellular uptake of 5-FU and its metabolite, 5-FdUMP at target site (colon). It could be possibly associated with change in permeability of cell membrane owing to the alteration in membrane fluidity. The present study revealed the mechanistic insights of FO as a MDR revertant which successfully restored 5-FU-mediated chemoresistance in experimental colon carcinoma.

Association of interleukin-18 genotypes (-607C > A) and (-137 G > C) with the hepatitis B virus disease progression to hepatocellular carcinoma.

Chronic infection with HBV has been reported to be associated with the development of HCC. The inflammation mounted by cytokine-mediated immune system plays an important role in the pathogenesis of HBV-associated HCC. IL-18 is a pro-inflammatory cytokine whose role in the development of HBV-associated chronic to malignant disease state has not been much studied. The present study was conceived to determine the role of genetic polymorphisms in IL-18, serum levels of IL-18, and expression level of its signal transducers in the HBV disease progression. A total of 403 subjects were enrolled for this study including 102 healthy subjects and 301 patients with HBV infection in different diseased categories. Polymorphism was determined using PCR-RFLP. Genotypic distributions between the groups were compared using odd's ratio and 95% CI were calculated to express the relative risk. Circulating IL-18 levels were determined by ELISA. Expression levels of pSTAT-1 and pNFƙB was determined by western blotting. In case of IL-18(- 607C > A), the heterozygous genotype (CA) was found to be a protective factor while in case of IL-18(- 137G > C) the heterozygous genotype (GC) acted as a risk factor for disease progression from HBV to HCC. Moreover, serum IL-18 levels were significantly increased during HBV disease progression to HCC as compared to controls. Also the levels of activated signal transducers (pSTAT-1 and pNF-κB) of IL-18 in stimulated PBMCs were significantly increased during HBV to HCC disease progression. These findings suggest that IL-18 has the potential to act as a biomarker of HBV-related disease progression to HCC.

An Integrated Approach of the Potential Underlying Molecular Mechanistic Paradigms of SARS-CoV-2-Mediated Coagulopathy.

Coronavirus disease 2019 (Covid-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pandemic disease which has affected more than 6.2 million people globally, with numbers mounting considerably daily. However, till date, no specific treatment modalities are available for Covid-19 and also not much information is known about this disease. Recent studies have revealed that SARS-CoV-2 infection is associated with the generation of thrombosis and coagulopathy. Fundamentally, it has been believed that a diverse array of signalling pathways might be responsible for the activation of coagulation cascade during SARS-CoV-2 infection. Henceforth, a detailed understanding of these probable underlying molecular mechanistic pathways causing thrombosis in Covid-19 disease deserves an urgent exploration. Therefore, in this review, the hypothetical crosstalk between distinct signalling pathways including apoptosis, inflammation, hypoxia and angiogenesis attributable for the commencement of thrombotic events during SARS-CoV-2 infection has been addressed which might further unravel promising therapeutic targets in Covid-19 disease.

Apoptosis mediated chemosensitization of tumor cells to 5-fluorouracil on supplementation of fish oil in experimental colon carcinoma.

5-Fluorouracil has been considered as a cornerstone therapy for colorectal cancer; however, it suffers from low therapeutic response rate and severe side effects. Therefore, there is an urgent need to increase the clinical efficacy of 5-fluorouracil. Recently, fish oil rich in n-3 polyunsaturated fatty acids has been reported to chemosensitize tumor cells to anti-cancer drugs. This study is designed to understand the underlying mechanisms of synergistic effect of fish oil and 5-fluorouracil by evaluation of tumor cell-associated markers such as apoptosis and DNA damage. The colon cancer was developed by administration of N,N-dimethylhydrazine dihydrochloride and dextran sulfate sodium salt. Further these animals were treated with 5-fluorouracil, fish oil, or a combination of both. In carcinogen-treated animals, a decrease in DNA damage and apoptotic index was observed. There was also a decrease in the expression of Fas, FasL, caspase 8, and Bax, and an increase in Bcl-2. In contrast, administration of 5-fluorouracil and fish oil as an adjuvant increased both DNA damage and apoptotic index by activation of both extrinsic and intrinsic apoptotic pathways as compared to the other groups. The increased pro-apoptotic effect by synergism of 5-fluorouracil and fish oil may be attributed to the incorporation of n-3 polyunsaturated fatty acids in membrane, which alters membrane fluidity in cancer cells. In conclusion, this study highlights that the induction of apoptotic pathway by fish oil may increase the susceptibility of tumors to chemotherapeutic regimens.

Apoptosis-Mediated Chemoprevention by Different Ratios of Fish Oil in Experimental Colon Carcinogenesis.

Apoptosis plays an important role in prevention of colon cancer. In the present study, different ratios of fish oil and corn oil increased Fas expression in both phases and a decrease in FasL expression only in post initiation phase. Treatment with fish oil activated the intrinsic apoptotic pathway by increasing Bax expression and Cyt c release and decreasing Bcl-2 levels in both phases. This suggests that intrinsic pathway is upregulated by fish oil; however, Fas-FasL activity may be involved in inhibition of reversal of immune surveillance in tumor cells.

Documentation of Ultrastructural Changes in Nucleus and Microvilli by Fish Oil in Experimental Colon Carcinogenesis.

Fish oil (FO) exerts a chemopreventive effect by regulating apoptosis in colon carcinogenesis. The present study reports the ultrastructural changes in various organelles on supplementation of FO in experimental colon carcinogenesis. The carcinogen treatment led to abnormal nuclear shape and alteration in microvilli number indicating cancer establishment. On the other hand, different ratios of FO and corn oil increased chromatin condensation along with an extensive loss of microvilli in a dose- and time-dependent manner which depicts an increase in apoptosis. The associated ultrastuctural alterations support the facilitation of apoptosis by FO as a mechanism for its beneficial effect in colon carcinogenesis.

Examining the Pre- and Post-percutaneous Coronary Intervention Blood Pressure Variability Using Ambulatory Blood Pressure Monitoring in Patients With Stable and Unstable Coronary Artery Disease.

Introduction The World Health Organization has drawn attention to the fact that coronary artery disease (CAD) is our modern "epidemic." Nowadays, sudden death during sleep has become prevalent due to a lack of oxygen supply to the heart. CAD causes more deaths and disabilities and incurs greater economic costs than any other illness in the developed world. The prevalence of cardiovascular disorders and heart disease is on the rise in India. Hypertension is one of the leading risk factors for all cardiovascular diseases. This study aims to compare blood pressure variability before and after percutaneous coronary intervention (PCI), using ambulatory blood pressure monitoring (ABPM) in patients with stable and unstable CAD. Materials and methods This prospective observational study was conducted among 52 patients with stable and unstable CAD, admitted to the medicine department, who required PCI at a tertiary care hospital. Before and after PCI, the same antihypertensive drugs were orally administered. ABPM was performed before PCI and one day after PCI. ABPM was conducted every 30 minutes during the day and every 60 minutes during the night over a 24-hour period using a mobil-o-graph (IEM, Germany). The results of the observed parameters were analyzed using the HMS Client-Server 4.0 system (Informer Technologies, Inc., Los Angeles, USA). The collected data were analyzed using SPSS Statistics version 21.0 software (IBM Corp. Released 2012. IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp.). Results Out of 52 patients, 28 (53.8%) had stable CAD and 24 (46.2%) had unstable CAD. The mean age of patients with stable and unstable CAD was 56.64±9.44 and 57.04±12.36 years, respectively. The majority of patients with stable (67.9%) and unstable CAD (62.5%) were males. Various other variables were considered, such as lipid profile, blood sugar, cardiac troponin-I, and medical history, including hypertension and type 2 diabetes mellitus. Among stable CAD patients, a comparison between pre- and post-PCI systolic blood pressure (SBP) did not show a significant difference in all SBP measurements (p>0.05). However, the mean diurnal index was significantly lower following PCI compared to before PCI (p=0.019). Among unstable CAD patients, a comparison between pre- and post-PCI SBP showed a significant change in peak daytime, average daytime, and diurnal index (p<0.05). For all other SBP measurements, the difference between pre- and post-PCI measurements was not statistically significant (p>0.05). In patients with stable CAD, a statistically significant change in diastolic blood pressure (DBP) following PCI was observed for peak daytime, peak nighttime, and average nighttime values. In contrast, for patients with unstable CAD, a statistically significant change in DBP following PCI was observed for peak daytime, peak nighttime, and minimum daytime values (p<0.05). Statistically, post-PCI, there was no significant difference between the two groups for SBP and DBP measurements (p>0.05). Additionally, there was no significant difference between the two groups pre- and post-PCI in the pattern of dipping. Conclusion A comparison of the ABPM before and after PCI showed that, within 48 hours post-PCI, the ambulatory blood pressure indicators did not differ statistically from those before PCI.

Unlocking the Pharmacological Potential of Benzimidazole Derivatives: A Pathway to Drug Development.

Heterocyclic molecules have fascinated a massive interest in medicinal chemistry. They are heterocyclic compounds that have gained significance due to their diverse variety of pharmacological activities. Benzimidazole is a heterocyclic compound consisting of benzene and imidazole rings. The ease of synthesis and the structural versatility of benzimidazole make it a promising scaffold for drug development. Many biological actions of benzimidazole derivatives have been well documented, including antibacterial, antiviral, anticancer, anti-inflammatory, antitubercular, and anthelmintic properties. The mechanism of action of benzimidazole derivatives varies with their chemical structure and target enzyme. This review has explored numerous methods for producing benzimidazole derivatives as well as a broad range of pharmacological activities. SAR investigations are also discussed in this review as they provide crucial details regarding the essential structural qualities that benzimidazole derivatives must have in order to be biologically active, which could aid in the rational design of new drug candidates. Benzimidazole scaffold is an exclusive structure in drug design and discovery. Many new pharmaceutical drugs containing benzimidazole are anticipated to be available within the next ten years as a result of the extensive therapeutic applications of benzimidazole and its derivatives. This review inspired many researchers to develop more biologically active compounds bearing benzimidazole, expanding the scope of finding a remedy for other diseases. From this study, we concluded that 2-substituted benzimidazole was considered more extensively by researchers.

Pyrazoles as Anti-inflammatory and Analgesic Agents: In-vivo and In-silico Studies.

BACKGROUND: Pyrazole is a well-known nucleus in the pharmacy field with a wide range of other activities in addition to anti-inflammatory and analgesic, i.e., anticonvulsant, antiviral, and anticancer activities. There are well-known marketed drugs having pyrazole moiety as celecoxib, and lonazolac as COX-II inhibitors. AIMS: We aim to synthesize better anti-inflammatory than existing ones. Thiophene is also known for its analgesic and anti-inflammatory action. Thus, the fusion of both gives better anti-inflammatory agents. In the present studies, derivatives from two series of pyrazole were prepared by reacting substituted chalcone (3a-3f) derivatives prepared from 2-acetyl thiophene. They substituted aromatic aldehydes with phenyl hydrazine to form (5a-5f) and with 2, 4-dinitro phenyl hydrazine giving compounds (6a-6f) separately. METHODS: Purified and characterized pyrazoles have been analyzed for in-vivo analgesic and anti-inflammatory activities by using standard methods. Compounds 5e, 5f, and 6d were proved to be potent analgesics and series (5a-5f) was found to have anti-inflammatory action, which was further validated using docking and ADME studies. RESULTS: The ADME profile of synthesized compounds was found to be satisfactory. CONCLUSION: The synthesized compounds can serve as lead for further drug designing.

Potential use of cidofovir, brincidofovir, and tecovirimat drugs in fighting monkeypox infection: recent trends and advancements.

Recent years have witnessed the rise of more recent pandemic outbreaks including COVID-19 and monkeypox. A multinational monkeypox outbreak creates a complex situation that necessitates countermeasures to the existing quo. The first incidence of monkeypox was documented in the 1970s, and further outbreaks led to a public health emergency of international concern. Yet as of right now, neither vaccines nor medicines are certain to treat monkeypox. Even the inability of conducting human clinical trials has prevented thousands of patients from receiving effective disease management. The current state of the disease's understanding, the treatment options available, financial resources, and lastly international policies to control an epidemic state are the major obstacles to controlling epidemics. The current review focuses on the epidemiology of monkeypox, scientific ideas, and available treatments, including potential monkeypox therapeutic methods. As a result, a thorough understanding of monkeypox literature will facilitate in the development of new therapeutic medications for the prevention and treatment of monkeypox.

Serum copper status of patients with colorectal cancer: A systematic review and meta-analysis.

BACKGROUND: Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide and a public health problem. Several clinical studies have shown that copper (Cu) is involved in carcinogenesis, possibly via cuproptosis, a new form of programmed cell death, but the conclusions from published reports are inconsistent. This study aimed at evaluating the potential of Cu dysregulation as a CRC susceptibility factor. METHODS: In this systematic review and meta-analysis, we searched Cochrane Library, EBSCOhost, EMBASE, ProQuest, PubMed/MEDLINE, Scopus, and Web of Science for studies reporting serum Cu concentrations in CRC patients and controls from articles published till June 2023. The studies included reported measurements of serum/plasma/blood Cu levels. Meta-analyses were performed as well as study quality, heterogeneity, and small study effects were assessed. Based on a random effects model, summary standardized mean differences (SMDs) and the corresponding 95% confidence intervals (95% CIs) were applied to compare the levels of Cu between CRC patients and controls. RESULTS: 26 studies with a pooled total of9628 participants and 2578 CRC cases were included. The pooled SMD was equal to 0.85 (95% CIs -0.44; 2.14) showing that the CRC patients had higher mean Cu levels than the control subjects, but the difference was not significant (p = 0.185) and the heterogeneity was very high, I2 = 97.9% (95% CIs: 97.5-98.3%; p < 0.001). CONCLUSION: The pooled results were inconclusive, likely due to discordant results and inaccuracy in reporting data of some studies; further research is needed to establish whether Cu dysregulation might contribute to the CRC risk and whether it might reflect different CRC grades.

Advancements and recent explorations of anti-cancer activity of chrysin: from molecular targets to therapeutic perspective.

In recent times, there have been notable advancements in comprehending the potential anti-cancer effects of chrysin (CH), a naturally occurring flavonoid compound found abundantly in various plant sources like honey, propolis, and certain fruits and vegetables. This active compound has garnered significant attention due to its promising therapeutic qualities and minimal toxicity. CH's ability to combat cancer arises from its multifaceted mechanisms of action, including the initiation of apoptosis and the inhibition of proliferation, angiogenesis, metastasis, and cell cycle progression. CH also displays potent antioxidant and anti-inflammatory properties, effectively counteracting the harmful molecules that contribute to DNA damage and the development of cancer. Furthermore, CH has exhibited the potential to sensitize cancer cells to traditional chemotherapy and radiotherapy, amplifying the effectiveness of these treatments while reducing their negative impact on healthy cells. Hence, in this current review, the composition, chemistry, mechanisms of action, safety concerns of CH, along with the feasibility of its nanoformulations. To conclude, the recent investigations into CH's anti-cancer effects present a compelling glimpse into the potential of this natural compound as a complementary therapeutic element in the array of anti-cancer approaches, providing a safer and more comprehensive method of combating this devastating ailment.

Selenium levels in colorectal cancer: A systematic review and meta-analysis of serum, plasma, and colorectal specimens.

BACKGROUND: Colorectal cancer (CRC) is a growing public health problem. Several clinical studies have shown a potentially protective effect of selenium (Se), but the reports are inconsistent. The objective of the study was to examine the evidence for relation between serum/tissue Se status and CRC. METHOD AND MATERIALS: In this Systematic Review and Meta-Analysis, we searched Cochrane Library, EBSCOhost, EMBASE, ProQuest, PubMed/MEDLINE, Scopus, and Web of Science for studies reporting serum/plasma/whole blood/tissue Se concentrations in CRC patients and controls for articles published till August 2023. Meta-analysis was performed, and study quality, heterogeneity, and small study effects were assessed. Based on a random effects model, summary mean differences in serum levels of Se between CRC patients and healthy controls, and Se levels between malignant and matched non-malignant tissue specimens were assessed. RESULTS: After initial screening, a total of 24 studies (18 serum and 6 tissue studies) with a pooled total of 2640 participants were included in the meta-analysis. CRC patients had significantly lower serum Se levels than healthy controls, being the difference between the two equal to 3.73 µg/dl (95% CI: 6.85-0.61). However, the heterogeneity was very high, I2= 99% (p < 0.01). Our meta-analysis showed higher Se levels in CRC cancerous specimens than in matched healthy colon tissue: the increase was equal to 0.07 µg/g wet tissue weight (95% CI: 0.06-0.09; p= 0.02). CONCLUSIONS: CRC patients have lower serum and higher colon cancerous tissue Se levels. Some factors, such as Se levels in different tumor grades of CRC need to be further considered for a more conclusive association between Se levels and risk of CRC.

Alterations in mitochondrial membrane in chemopreventive action of fish oil.

Mitochondria are major regulators of pathways related to tumorigenesis; therefore, mitochondrial membrane characteristics and associated cell signaling events were evaluated with different ratios of fish oil (FO) and corn oil (CO) in experimental colon carcinogenesis. Treatment with carcinogen 1,2-dimethylhydrazine (DMH) altered reactive oxygen species (ROS), Ca(2+), and membrane characteristics, which resulted in an elevation in apoptosis in initiation phase and reduction in post-initiation phase. FO+CO(2.5:1)+DMH treatment, however, altered mitochondrial membrane parameters, ROS, and Ca(2+) to increase apoptosis in both phases, whereas FO+CO(1:1)+DMH treatment enhanced apoptosis only in post-initiation phase suggesting that FO supplementation in higher ratio has better chemopreventive efficacy.

An Appraisal on Synthetic and Medicinal Aspects of Fused Pyrimidines as Anti Neoplastic Agents.

Heterocyclic compounds are recognized to possess a high grade of structural diversity and a broad spectrum of therapeutic properties. About two-thirds of the New Chemical Entities approved by the FDA against cancer entail heterocyclic rings and are the foundation stone of medicinal chemistry. Pyrimidine being a major heterocyclic compound and a crucial base component of the genetic material, has emerged as the key structural component against cancer, the deadliest disease worldwide. Though many drugs are marketed against cancer, researchers are still investigating the more promising moieties against various malignancies due to the severity of this disease. In this review, an attempt has been made to assemble the reported literature of the previous five years on various synthetic procedures and the anti-cancer potential of various classes of fused pyrimidine analogs, which would help the researchers in designing new potent derivatives. Besides this, the review intends to focus on the comprehensive discussion on biological targets, modes of action, and structure-activity relationships of each class of fused pyrimidines as potential anticancer agents.

In-Silico Design, Synthesis, and Pharmacological Evaluation of Oxadiazole-Based Selective Cyclo-oxygenase-2 Inhibitors.

A series of oxadiazole-based five-membered heterocyclic derivatives was designed and synthesized with the intent of exclusive cyclo-oxygenase-2 (COX-2) inhibition to acquire anti-inflammatory activity without the presence of gastric toxicity. Oxadiazole-based novel analogs were designed by using bioisosteric substitutions and were screened against the macromolecular target by using docking-based virtual screening to identify their potential inhibitors. These selective COX-2 inhibitors were further evaluated for their stability within the binding cavity of macromolecular complex by performing molecular dynamic simulation for 100 ns. Selected compounds were synthesized by using Naphthalene-2-yl-acetic acid as a starting material based on the fundamental structure of naphthalene. The naphthalene ring and methylene bridge of naphthalene-2-yl-acetic acid were retained in the rational molecular design by replacing the carboxyl group with biologically significant groups like 1,3,4-oxadiazoles, with the goal of obtaining a novel, superior, and relatively safe anti-inflammatory molecule with better efficacy and optimized pharmacokinetics. Anti-inflammatory as well as analgesic properties of the compounds were evaluated experimentally for their pharmacological efficiency.