Investigating awareness of artificial intelligence in healthcare among medical students and professionals in Pakistan: a cross-sectional study.

Objective: The purpose of this study is to find out the level of awareness and acceptance of artificial intelligence (AI) in Pakistan's medical community so as to comment on its future in our healthcare system. Methods: A survey consisting of 15 close-ended questions was conducted. The questions inquired about awareness about AI and discovered the opinions of healthcare professionals regarding its benefits and expected problems. The data were analyzed using SPSS version 26, and descriptive statistics for percentage and frequency were computed. χ2 test was used to analyze the subgroups (Significant p value <0.05). Results: A total of 351 participants were included in this study. General familiarity with AI was low. Only 75 (21.3%) participants answered that they had good familiarity with AI, and only 56 (16%) of them had good familiarity with the role of AI in medicine. One hundred sixty-eight (47.9%) participants disagreed that AI would out-compete the physician in the important traits of professionalism. Only 71 (20.2%) participants believed AI to be diagnostically superior to the physician. Two hundred fourteen (61.0%) were worried about completely trusting AI in its decisions, and 204(58.1%) believed that AI systems lacking human traits would not be able to mirror the doctor-patient relationship. Two hundred sixty-one (74.4%) participants believed that AI would be useful in Administrative tasks. A majority, 162 (46.2%), do not believe that AI would replace them. Finally, a huge majority of participants [225 (64.1%)] demanded the integration of AI in Pakistan's healthcare system. Conclusion: This study suggests that a majority of healthcare professionals in Pakistan do not believe that they are sufficiently aware of the role of AI in healthcare. This was corroborated by their answers to various questions regarding the capabilities of AI. This study indicates the need for a more comprehensive ascertainment of healthcare professionals' perceptions regarding the role of Artificial Intelligence in medicine and bridging the gap between doctors and technology to further promote a patient-centred approach to medicine.

Countenance and implication of Β-sitosterol, Β-amyrin and epiafzelechin in nickel exposed Rat: in-silico and in-vivo approach.

The detrimental impact of reactive oxygen species on D.N.A. repair processes is one of the contributing factors to colon cancer. The idea that oxidative stress may be a significant etiological element for carcinogenesis is currently receiving more and more support. The goal of the current study is to evaluate the anti-inflammatory and anticancer activity of three powerful phytocompounds-sitosterol, amyrin, and epiafzelechin-alone and in various therapeutic combinations against colon cancer to identify the critical mechanisms that mitigate nickel's carcinogenic effect. To evaluate the ligand-protein interaction of four selected components against Vascular endothelial growth factor (VEGF), Matrix metalloproteinase-9 (MMP9) inhibitor and Interleukin-10 (IL-10) molecular docking approach was applied using PyRx bioinformatics tool. For in vivo analysis, hundred albino rats were included, divided into ten groups, each containing ten rats of weight 160-200 g. All the groups were injected with 1 ml/kg nickel intraperitoneally per week for three months, excluding the negative control group. Three of the ten groups were treated with ß-sitosterol (100 mg/kg b wt), ß-amyrin (100 mg/kg b wt), and epiafzelechin (200 mg/kg b wt), respectively, for one month. The later four groups were fed with combinatorial treatments of the three phyto compounds for one month. The last group was administered with commercial drug Nalgin (500 mg/kg b wt). The biochemical parameters Creatinine, Protein carbonyl, 8-hydroxydeoxyguanosine (8-OHdG), VEGF, MMP-9 Inhibitor, and IL-10 were estimated using ELISA kits and Glutathione (G.S.H.), Superoxide dismutase (S.O.D.), Catalase (C.A.T.) and Nitric Oxide (NO) were analyzed manually. The correlation was analyzed through Pearson's correlation matrix. All the parameters were significantly raised in the positive control group, indicating significant inflammation. At the same time, the levels of the foresaid biomarkers were decreased in the serum in all the other groups treated with the three phytocompounds in different dose patterns. However, the best recovery was observed in the group where the three active compounds were administered concomitantly. The correlation matrix indicated a significant positive correlation of IL-10 vs VEGF (r = 0.749**, p = 0.009), MMP-9 inhibitor vs SOD (r = 0.748**, p = 0.0 21). The study concluded that the three phytocompounds ß-sitosterol, ß-amyrin, and epiafzelechin are important anticancer agents which can target the cancerous biomarkers and might be used as a better therapeutic approach against colon cancer soon.

Phytochemical profiling and cytotoxic potential of Arnebia nobilis root extracts against hepatocellular carcinoma using in-vitro and in-silico approaches.

Hepatocellular carcinoma is the fifth most prevalent cancer worldwide. The emergence of drug resistance and other adverse effects in available anticancer options are challenging to explore natural sources. The current study was designed to decipher the Arnebia nobilis (A. nobilis) extracts for detecting phytochemicals, in-vitro evaluation of antioxidative and cytotoxic potentials, and in-silico prediction of potent anticancer compounds. The phytochemical analysis revealed the presence of flavonoids, phenols, tannins, alkaloids, quinones, and cardiac glycosides, in the ethanol (ANE) and n-hexane (ANH) extracts of A. nobilis. ANH extract exhibited a better antioxidant potential to scavenge DPPH, nitric oxide and superoxide anion radicals than ANE extract, which showed better potential only against H2O2 radicals. In 24 h treatment, ANH extract revealed higher cytotoxicity (IC50 value: 22.77 µg/mL) than ANH extract (IC50 value: 46.74 µg/mL) on cancer (HepG2) cells without intoxicating the normal (BHK) cells using MTT assay. A better apoptotic potential was observed in ANH extract (49.10%) compared to ANE extract (41.35%) on HepG2 cells using the annexin V/PI method. GCMS analysis of ANH extract identified 35 phytocompounds, from which only 14 bioactive compounds were selected for molecular docking based on druggability criteria and toxicity filters. Among the five top scorers, deoxyshikonin exhibited the best binding affinities of - 7.2, - 9.2, - 7.2 and - 9.2 kcal/mol against TNF-α, TGF-ßR1, Bcl-2 and iNOS, respectively, followed by ethyl cholate and 2-Methyl-6-(4-methylphenyl)hept-2-en-4-one along with their desirable ADMET properties. The phytochemicals of ANH extract could be used as a promising drug candidate for liver cancer after further validations.

Cross-sectional study of mammographic breast density of Pakistani women and its association with breast cancer.

OBJECTIVE: To explore if a positive association existed between breast cancer and increased breast density. METHODS: The retrospective cross-sectional study was conducted at Shifa International Hospital, Islamabad and comprised data from July 10, 2018, to July 10, 2020, of all patients who underwent mammography for screening or diagnostic purposes. Data was collected by reviewing patients' charts, and was divided into diagnostic group A and screening group B according to mammography target. Breast Imaging Reporting and Data System category was also noted. Data was analysed using SPSS 21. RESULTS: Of the 1,035 women with mean age 46.8±2.5 years (range: 35-82 years), 928(89.7%) were in group A and 107(10.3%) were in group B Prevalent breast densities overall were category A 67(6.3%), B 349(33.7%), C 530(51.2%) and D 89(8.5%). In group A, a lump was detected in 542(58.4%) patients. Of them, 367(67.7%) lesions were malignant and 175(32.3%) were benign. Breast density and malignant tumours had significant association (p<0.05). CONCLUSIONS: Mammographic breast density wsa found to have a significant association with breast cancer.

Potential effect of luteolin, epiafzelechin, and albigenin on rats under cadmium-induced inflammatory insult: In silico and in vivo approach.

Introduction: Cadmium(Cd) an industrial poison present abundantly in the environment, causes human toxicity by an inflammatory process. Chronic exposure of cadmium can cause a number of molecular lesions that could be relevant to oncogenesis, through indirect or epigenetic mechanisms, potentially including abnormal activation of oncogenes and suppression of apoptosis by depletion of antioxidants. As induction of cyclooxygenase (COX)-2 is linked to inflammatory processes, use of luteolin, epiafzelechin, and albigenin alone or in different combinations may be used as anti-inflammatory therapeutic agents. Methods: We, herein, performed in silico experiments to check the binding affinity of phytochemicals and their therapeutic effect against COX-2 in cadmium administered rats. Wistar albino rats were given phytochemicals in different combinations to check their anti-inflammatory activities against cadmium intoxication. The level of alanine aminotransferases (ALT), 4-hydroxynonenal (4HNE), 8-hydroxy-2-deoxyguanosine (8-OHdG), tumor necrosis factor-alpha (TNF-α), isoprostanes (IsoP-2α), COX-2, and malondialdehyde (MDA) were estimated with their respective ELISA and spectrophotometric methods. Results: The generated results show that phytocompounds possessed good binding energy potential against COX-2, and common interactive behavior was observed in all docking studies. Moreover, the level of ALT, 4HNE, 8-OHdG, TNF-α, IsoP-2α, malondialdehyde, and COX-2 were significantly increased in rats with induced toxicity compared to the control group, whereas in combinational therapy of phytocompounds, the levels were significantly decreased in the group. Discussion: Taken together, luteolin, epiafzelechin, and albigenin can be used as anti-inflammatory therapeutic agents for future novel drug design, and thus it may have therapeutic importance against cadmium toxicity.

Mechanistic insight of DACH1 receptor in the development of carcinoma insurgence through MD simulation studies.

Proteins are key player in the prognosis and therapeutics of carcinomas through the interactions of downstream signalling cascades. Current work insight the structural and mutational analysis of DACH1 in association with carcinogenesis. The homology modelling was employed to predict mutant and wild protein models and their reliability and accuracy was verified through multiple online approaches. Furthermore, MD simulation technique was employed to check the mutation effects on the stability of DACH1 through root mean square deviation and fluctuation graphs. Our results proposed that DACH1 mutation (C188Y) may cause lethal effects and can disturb the DACH1 structure. The observed mutational results showed that C188Y may cause some lethal effect in human body. Based on aforementioned computational assessments, it has concluded that DACH1 could be used as good therapeutic target in the prognosis and therapeutic of carcinoma insurgence.Communicated by Ramaswamy H. Sarma.

New challenges in the use of nanomedicine in cancer therapy.

Nanomedicines are applied as alternative treatments for anticancer agents. For the treatment of cancer, due to the small size in nanometers (nm), specific site targeting can be achieved with the use of nanomedicines, increasing their bioavailability and conferring fewer toxic side effects. Additionally, the use of minute amounts of drugs can lead to cost savings. In addition, nanotechnology is effectively applied in the preparation of such drugs as they are in nm sizes, considered one of the earliest cutoff values for the production of products utilized in nanotechnology. Early concepts described gold nanoshells as one of the successful therapies for cancer and associated diseases where the benefits of nanomedicine include effective active or passive targeting. Common medicines are degraded at a higher rate, whereas the degradation of macromolecules is time-consuming. All of the discussed properties are responsible for executing the physiological behaviors occurring at the following scale, depending on the geometry. Finally, large nanomaterials based on organic, lipid, inorganic, protein, and synthetic polymers have also been utilized to develop novel cancer cures.

Phytochemical analysis and protective effects of Vaccinium macrocarpon (cranberry) in rats (Rattus norvegicus) following ethylene oxide-induced oxidative insult.

The Vaccinium genus comprises more than 126 genera of perennial flowering plants that are commonly adapted to poor and acidic soils or epiphytic environments. Their molecular and genomic characterization is a result of the recent advent in next-generation sequencing technology. In the current research, extracts were prepared in different media, such as petroleum ether, methanol and ethanol. An extract of Vaccinium macrocarpon (cranberry) was used at a dose of 200-400 mg/kg by weight (B.wt). Levels of oxidative stress markers, i.e., superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), advanced oxidation protein products (AOPPs) and malondialdehyde (MDA), were measured. A histopathological study of six vital organs in rats was also conducted. The results indicated that the antioxidant levels were lower in the group given only ethylene oxide (EtO) but higher in the groups receiving cranberry extract as a treatment. Major improvements were also observed in stress markers such as advanced oxidation protein products (AOPPs) and MDA following cranberry treatment. Histopathological changes induced by EtO were observed in the heart, kidney, liver, lung, stomach and testis and were reversed following cranberry treatment. The major toxic effects of EtO were oxidative stress and organ degeneration, as observed from various stress markers and histopathological changes. Our study showed that this extract contains strong antioxidant properties, which may contribute to the amelioration of the observed toxic effects.

Inhibitory Potential of Phytochemicals on Interleukin-6-Mediated T-Cell Reduction in COVID-19 Patients: A Computational Approach.

BACKGROUND: A recent COVID-19 pandemic has resulted in a large death toll rate globally and even no cure or vaccine has been successfully employed to combat this disease. Patients have been reported with multi-organ dysfunction along with acute respiratory distress syndrome which implies a critical situation for patients and made them difficult to breathe and survive. Moreover, pathology of COVID-19 is also related to cytokine storm which indicates the elevated levels of interleukin (IL)-1, IL-6, IL-12, and IL-18 along with tumor necrosis factor (TNF)-α. Among them, the proinflammatory cytokine IL-6 has been reported to be induced via binding of severe acute respiratory syndrome coronavirus 2 (SARS)-CoV-2 to the host receptors. METHODOLOGY: Interleukin-6 blockade has been proposed to constitute novel therapeutics against COVID-19. Thus, in this study, 15 phytocompounds with known antiviral activity have been subjected to test for their inhibitory effect on IL-6. Based on the affinity prediction, top 3 compounds (isoorientin, lupeol, and andrographolide) with best scores were selected for 50 ns molecular dynamics simulation and MMGB/PBSA binding free energy analysis. RESULTS: Three phytocompounds including isoorientin, lupeol, and andrographolide have shown strong interactions with the targeted protein IL-6 with least binding energies (-7.1 to -7.7 kcal/mol). Drug-likeness and ADMET profiles of prioritized phytocompounds are also very prominsing and can be further tested to be potential IL-6 blockers and thus benficial for COVID-19 treatment. The moelcular dynamics simulation couple with MMGB/PBSA binding free energy estimation validated conformational stability of the ligands and stronger intermolecular binding. The mean RMSD of the complexes is as: IL6-isoorientin complex (3.97 Å ± 0.77), IL6-lupeol (3.97 Å ± 0.76), and IL6-andrographolide complex (3.96 Å ± 0.77). In addition, the stability observation was affirmed by compounds mean RMSD: isoorientin (0.72 Å ± 0.32), lupeol (mean 0.38 Å ± 0.08), and andrographolide (1.09 Å ± 0.49). A similar strong agreement on systems stability was unraveled by MMGB/PBSA that found net binding net ~ -20 kcal/mol for the complexes dominated by van der Waal interaction energy. CONCLUSION: It has been predicted that proposing potential IL-6 inhibitors with less side effects can help critical COVID-19 patients because it may control the cytokine storm, a major responsible factor of its pathogenesis. In this study, 3 potential phytocompounds have been proposed to have inhibitory effect on IL-6 that can be tested as potential therapeutic options against SARS-CoV-2.

Assessment of clinical variables as predictive markers in the development and progression of colorectal cancer.

Colorectal cancer (CRC) is graded as one of the most common cancer. It accounts for the second leading cause of cancer deaths worldwide. The present study intends to investigate the role and importance of different biochemical variables in the development of colorectal cancer.In this cross-sectional study we recruited ninety-one patients diagnosed with colorectal cancer and fifty-three age-sex matched controls from June 2017 to June 2018. Different variables i.e. SOD, GSH, CAT, MDA, TGF, VEGF, TNF, ILs, MMPs, etc., were estimated with the help of their respective methods. Our findings suggest a significant increase in the levels of different inflammatory and stress-related markers. The NFκB, TGF-ß, VEGFß, 8OHdG, IsoP-2α were significantly found to be increased in patients with colon cancer (0.945 ± 0.067 µg/ml, 18.59 ± 1.53 pg/ml, 99.35 ± 4.29 pg/ml, 21.26 ± 1.29 pg/ml, 102.25 ± 4.25 pg/ml) as compared to controls (0.124 ± 0.024 µg/ml, 8.26 ± 0.88 pg/ml, 49.58 ± 2.62 pg/ml, 0.93 ± 0.29 pg/ml, 19.65 ± 3.19 pg/ml). Notably, the levels of different antioxidants were shown to be significantly lower in patients of colon cancer. The present study concluded that excessive oxidative stress and lipid peroxidation result in a decrease in the antioxidative capacity of cells which may influence diverse signaling cascades including NF-KB, which results in DNA modification and gene transcription that ultimately involved in the progression of colon cancer.

Role of Oxidative Stress and the Identification of Biomarkers Associated With Thyroid Dysfunction in Schizophrenics.

Background: Schizophrenia is associated with a deficiency of dietary antioxidants like vitamin B6, B9, and B12 resulting in defective methylation leading to hyperhomocysteinemia. Hyperhomocysteinemia causes mitochondrial DNA damage, oxidative stress, vascular damage, and lipid peroxidation. Oxidative stress and increase in reactive oxygen species result in 8-oxodG production which induces apoptosis of both astrocytes and thyrocytes thus predisposing them to thyroid dysfunction and neurodegeneration. Furthermore, the presence of excessive free radicals increases thyroid thermogenesis causing hyperthyroidism or its excess may cause hypothyroidism by inhibiting iodide uptake. In the present study, we evaluated the various biomarkers associated with thyroid dysfunction in schizophrenics. Materials and Methods: 288 patients suffering from schizophrenia and 100 control subjects were screened for liver function tests (LFTs) such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TB). Also, the stress markers, namely malondialdehyde (MDA), homocysteine, cysteine, methionine, the thyroid profile including triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH), thyroxine peroxide antibody (TPO-Ab); TSH receptor-Ab (TSHr-Ab), dietary antioxidants, lipids, cytokines, aminoacids and hormones, vitamins and trace elements, and other biochemical parameters. Results: The LFTs showed elevated levels of ALT (45.57 ± 4.87 Vs. 26.41 ± 3.76 U/L), AST (40.55 ± 1.34 Vs. 21.92 ± 3.65 U/L), ALP (121.54 ± 4.87 Vs. 83.76 ± 5.87 U/L), and total bilirubin (2.63 ± 0.987 Vs. 1.10 ± 0.056 mg/dl), in schizophrenics than controls. Increased levels of MDA (3.71 ± 0.967 Vs. 1.68 ± 0.099) and homocysteine (17.56 ± 2.612 Vs. 6.96 ± 1.987 µmol/L were observed in schizophrenics compared to the controls, indicating increased stress. Levels of cysteine and methionine were decreased in schizophrenics than the controls (1.08 ± 0.089 Vs. 4.87 ± .924 µmol/L and 17.87 ± 1.23 Vs. 99.20 ± 5.36 µmol/L). The levels of TPO-Ab (IU/ml), Tg-Ab (pmol/L), and TSHr-Ab (IU/L) were observed to be higher in the patients' group as compared to control subjects (9.84 ± 2.56 Vs. 5.81 ± 1.98, 55.50 ± 2.98 Vs. 32.95 ± 2.87 and 2.95 ± 0.0045 Vs. 1.44 ± 0.0023 respectively). Levels of Vitamin B6, B9, and B12 were also significantly decreased in the patients compared to the healthy controls. Conclusion: The schizophrenics, demonstrated altered liver function, increased stress markers, and decreased dietary antioxidants. Reduced primary and secondary antioxidant levels, may result in hyperhomocysteinemia and cause further DNA and mitochondrial damage. Therefore, homocysteine and/or prolactin levels may serve as candidate prognostic markers for schizophrenia. Also, both neurological symptoms and the susceptibility to thyroid disorders may be prevented in the initial stages of this debilitating disorder by appropriate dietary supplementation of antioxidants which can rectify a reduction in primary and secondary antioxidants, and disturbed prolactin-serotonin-dopamine interactions in schizophrenics.

Influence of foliar glutathione and putrescine on metabolism and mineral status of genetically diverse rapeseed cultivars under hexavalent chromium stress.

We studied the physio-biochemical involvement of exogenous signaling compounds, glutathione and putrescine (alone and in combination), on three contrasting genotypes (cvs. Shiralee, Rainbow, and Dunkled) of canola (Brassica napus L.) of plants exposed to chromium stress. Seeds were germinated in Cr-contaminated soil (0 and 50 µg/g Cr6+), and both signaling compounds were applied as a foliar spray to 20-day-old plants. Changes in root, stem, and leaf nitro-oxidative metabolism, endogenous GSH level, secondary metabolites, and mineral nutrients were investigated from 60-day-old plants. Exposure to Cr6+ increased stem GSH and NO concentrations in all cultivars. Maximum root Cr6+ bioaccumulation was recorded in cv. Rainbow and the least in cv. Shiralee. Also, Cr6+ stress decreased number and weight of seeds and pod length. Disturbances in root and shoot mineral profile were evident; however, its magnitude varied in all cultivars. The exogenous GSH improved root and shoot P, Fe, S, and Zn concentrations; however, the effect was cultivar specific. Leaf endogenous GSH was increased by exogenous GSH while NO levels remained unaffected. The GSH application also promoted shoot Cr6+ bioaccumulation while PUT application caused a recovery in seed number and seed weight. Both PUT and GSH differentially affected tissue-specific secondary metabolite profile. Overall, the exogenous GSH was much more effective in alleviating the Cr+6 toxicity in canola.

Individual Rather Than Simultaneous Priming with Glutathione and Putrescine Reduces Chromium Cr6+ Toxicity in Contrasting Canola (Brassica napus L.) Cultivars.

The chromium (Cr6+) toxicity mechanisms have not been fully revealed yet in plants mainly due to its complex electronic chemistry. Both putrescine (PUT) and glutathione (GSH) are reported to be involved in plethora of plant cellular processes. Therefore, we hypothesized that exogenous individual or co-application of PUT and GSH could alleviate the Cr6+ stress in genetically diverse canola cultivars. The seed priming with GSH (0.1 mM) alleviated inhibitory effects of Cr6+ on root growth, and thus plants raised from GSH-treated seed had higher leaf chlorophyll a contents (78, 69 and 82%, in Shiralee, Rainbow and Dunkled cultivar, respectively), carotenoids contents, stem phenolics, root GSH, leaf and root NO concentration. The foliar treatment with PUT caused 37 and 11.9% decrease in the accumulation of Cr in shoot of Shiralee and Dunkled, respectively. Overall, the results suggested that seed priming with GSH regulated leaf photosynthetic pigments to cope with Cr6+ shock at early growth stage whereas foliar treatment with PUT decreased Cr transport to the shoot, and thus increased tolerance at later growth stage irrespective of cultivars.

Synergistic Effect of Barbadensis miller and Marsdenia Condurango Extracts Induces Apoptosis Promotes Oxidative Stress by Limiting Proliferation of Cervical Cancer and Liver Cancer Cells.

BACKGROUND: Drug synergy is the combine effect of drug efficacy. Synergistic combinations of active ingredients have proven to be highly effective and more useful in therapeutics. In contrast, the individual effect of drug is usually undesirable and mostly used for selecting drug-resistant mutations. Purpose of this study was to check synergistic effects of both plants (Barbadensis miller and Marsdenia condurango) against liver and cervical cancer. METHODOLOGY: Culturing of HeLa (cervical cancer cell line) and HepG2 (liver cancer cell line) cells, IC50 evaluation, viability assays (trypan blue, crystal violet), p53 ELISA and immunocytochemistry, MUSE analysis (count and viability), antioxidants (GSH, SOD, CAT), at the end RT-PCR was performed. RESULTS: IC50 evaluation was done of each plant individually and with combination for synergistic effects, IC50 with plants combination (synergism) was applied on further viability assays (trypan blue, crystal violet, MUSE analysis via count and viability kit) p53 ELISA and immunocytochemistry for evaluation of cellular apoptosis, antioxidants assays (GSH, SOD, CAT), and RT-PCR with proliferative and apoptotic markers along with internal control. CONCLUSION: According to current study it was observed that synergistic effect of these plants has more anticancer properties with minimum effective dose. It was also observed that extracts possess the ability to induce apoptosis, restrict proliferation and enhanced oxidative stress.

In Vivo Evaluation of Inorganic Nanoparticle Complexes against CCL4 Induced Hepatotoxicity.

BACKGROUND: Combination of different chemotherapy drugs and nanoparticles as a carrier has shown promising delivery system in cancer treatment. Doxorubicin is considered a potent anticancer drug. However, its off-target activities and possible side effects make its use limited. Recently, in the field of nanomedicine, different nanoconjugates have been developed as a unique platform for the delivery of therapeutic drugs. OBJECTIVE: The aim of the present study is to evaluate the best possible combination for efficient delivery of DOX with combination of gold, silver and zinc oxide nanoparticles to target site against carbon tetrachloride induced rat hepatotoxicity. METHODOLOGY: Effect of different conjugates administrated for 14 consecutive days was evaluated. RESULTS: In comparison to DOX, Au:DOX, ZnoO:DOX and Ag:DOX showed less sign of liver fibrosis as evaluated by serum enzymes and histopathological analysis. However, among all the conjugates, Ag: DOX conjugate showed the most significant results. The serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase values were (111.2 ± 38.21, 323.2 ± 46.88 and 303.6 ± 73.80 respectively) very close to control group (72.2 ± 19.41, 368 ± 59.78 and 259.4 ± 61.54 respectively). CONCLUSION: Our results demonstrated that Ag: DOX may exhibit hepato-protective activity against CCl4 induced liver damage.

The emerging role and significance of circular RNAs in viral infections and antiviral immune responses: possible implication as theranostic agents.

Circular RNAs (circRNAs) are ubiquitously expressed, covalently closed rings, produced by pre-mRNA splicing in a reversed order during post-transcriptional processing. Circularity endows 3'-5'-linked circRNAs with stability and resistance to exonucleolytic degradation which raises the question whether circRNAs may be relevant as potential therapeutic targets or agents. High stability in biological systems is the most remarkable property and a major criterion for why circRNAs could be exploited for a range of RNA-centred medical applications. Even though various biological roles and regulatory functions of circRNAs have been reported, their in-depth study is challenging because of their circular structure and sequence-overlap with linear mRNA counterparts. Moreover, little is known about their role in viral infections and in antiviral immune responses. We believe that an in-depth and detailed understanding of circRNA mediated viral protein regulations will increase our knowledge of the biology of these novel molecules. In this review, we aimed to provide a comprehensive basis and overview on the biogenesis, significance and regulatory roles of circRNAs in the context of antiviral immune responses and viral infections including hepatitis C virus infection, hepatitis B virus infection, hepatitis delta virus infection, influenza A virus infection, Epstein-Barr virus infection, kaposi's sarcoma herpesvirus infection, human cytomegalovirus infection, herpes simplex virus infection, human immunodeficiency virus infection, porcine epidemic diarrhoea virus infection, ORF virus infection, avian leukosis virus infection, simian vacuolating virus 40 infection, transmissible gastroenteritis coronavirus infection, and bovine viral diarrhoea virus infection. We have also discussed the critical regulatory role of circRNAs in provoking antiviral immunity, providing evidence for implications as therapeutic agents and as diagnostic markers.

Notch signalling pathway in development of cholangiocarcinoma.

Cholangiocarcinoma (CCA) comprises of extra-hepatic cholangiocarcinoma and intrahepatic cholangiocarcinoma cancers as a result of inflammation of epithelium cell lining of the bile duct. The incidence rate is increasing dramatically worldwide with highest rates in Eastern and South Asian regions. Major risk factors involve chronic damage and inflammation of bile duct epithelium from primary sclerosing cholangitis, chronic hepatitis virus infection, gallstones and liver fluke infection. Various genetic variants have also been identified and as CCA develops on the background of biliary inflammation, diverse range of molecular mechanisms are involved in its progression. Among these, the Notch signalling pathway acts as a major driver of cholangiocarcinogenesis and its components (receptors, ligands and downstream signalling molecules) represent a promising therapeutic targets. Gamma-Secretase Inhibitors have been recognized in inhibiting the Notch pathway efficiently. A comprehensive knowledge of the molecular pathways activated by the Notch signalling cascade as well as its functional crosstalk with other signalling pathways provide better approach in developing innovative therapies against CCA.

Phytochemical profiling, antioxidant and antiproliferation potential of Euphorbia milii var.: Experimental analysis and in-silico validation.

This study was aimed to investigate the anticancer potential of Euphorbia milii (E. milii) using an exquisite combination of phytopharmacological and advanced computational techniques. The chloroform fraction (Em-C) of E. milii methanol extract showed the highest antioxidant activity (IC50: 6.41 ± 0.99 µg/ml) among all studied fractions. Likewise, Em-C also showed significant cytotoxicity (IC50: 11.2 ± 0.8 µg/ml) when compared with that of standard compound 5-fluorouracil (5-FU) (IC50: 4.22 ± 0.6 µg/ml) against hepatocarcinoma cell line (HepG2). However, in a human cervical cancer cell line (HeLa), Em-C demonstrated a non-significant difference in cytotoxicity (22.1 ± 0.8 µg/ml) when compared with that of 5-FU (IC50: 6.87 ± 0.5 µg/ml). Furthermore, Western blot and qRT-PCR analysis revealed that the suppression of HepG2 cells was the consequence of a tremendous decrease in CDK2 and E2F1 protein expression. The GC-MS analysis of Em-C revealed the unique presence of cyclobarbital (CBT) and benzodioxole derivative (BAN) as major constituents. Furthermore, molecular docking of compounds BAN, CBT, and MBT into the binding site of different molecular targets i.e. cyclin dependent kinase 2 (CDK2), thymidylate synthase (TS), caspase 3, BCL2 and topoisomerase II was carried out. Compounds BAN and CBT have demonstrated remarkable binding affinity towards CDK2 and thymidylate synthase, respectively. Molecular dynamic simulation studies have further confirmed the finding of docking analysis, suggesting that CDK2 and TS can act as an attractive molecular target for BAN and CBT, respectively. It can be concluded that these E. milii phytoconstituents (BAN and CBT) may likely be responsible for anti-invasive activity against HepG2 cells.

Implication of Prophetic Variables and their Impulsive Interplay in CA Prostate Patients Experiencing Osteo-Metastasis.

AIMS: To identify variables having a critical role in prostate cancer patients experiencing osteometastasis. BACKGROUND: Prostatic carcinoma is a multifactorial complex disorder that exhibits an increased propensity to develop bone metastasis. An interplay of inflammatory and bone remodeling parameters promotes the formation of pre-metastatic niches in bones of patients, which could render them more vulnerable to skeletal disabilities. OBJECTIVE: To evaluate the multi-dynamic inter-relationship of circulating variables in prostate cancer patients experiencing osteo-metastasis. MATERIALS AND METHODS: Fifty-seven (n=57) men with clinically confirmed prostate cancer, fifty-nine (n=59) with skeletal metastases, and one hundred (n=100) healthy subjects i.e., men aging from 53-84 years with no clinical evidence of prostate were recruited from the Jinnah Hospital Lahore, Pakistan. Informed consent was obtained, and a venous blood sample was drawn and stored at -70oC until assayed. Levels of variables were evaluated using appropriate methods. Levels of Matrix Metalloproteinases (MMPs), Osteopontin (OPN), TGH- ß, and sRANKL were estimated by the ELISA method. Each sample was suspended and the given protocol was employed. ELISA readings were obtained for the estimation of all variables. RESULTS: Highly significant (P˂0.05) differential expression of oxidative stress, inflammatory cytokines, and bone remodeling variables were observed in localized and osteo-metastatic CA prostate patients. A strong positive correlation was revealed among OPN, sRANKL, MMP-7, MMP-9, PSA, and TGF-ß (OPN vs. MMP-7, r=0.698* and OPN vs. MMP-9, r=0.765**, OPN vs. RANKL, =0.856*, sRANKL vs. MMP-9, r=0.825**, TGF- ß vs. RANKL, r=0.868* and PSA vs. TGF- ß, r=0.752*); lower levels of OPG were estimated in metastasized patients, showing that both osteolytic and osteoblastic phases of bone remodeling occur simultaneously. CONCLUSION: The altered oxidative and inflammatory responses endorse Matrix Metalloproteinases (MMPs) increased activity, RANKL/OPG imbalance, and enhanced bone matrix proteins turnover, which can foster the process of osteo-metastasis. The perturbed RANKL/OPG drift and enhanced PSA levels are associated with increased TGF-ß activity to aggravate Epithelial Mesenchymal transition (EM) and osteo-tropism of prostate cancer. Thus, designing novel targets of these major variables can minimize the incidence of prostate cancer patients.