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Cellular signaling in the hypoxic cancer microenvironment: Implications for drug resistance and therapeutic targeting.
Bakshi, HA, Mkhael, M, Faruck, HL, Khan, AU, Aljabali, AAA, Mishra, V, El-Tanani, M, Charbe, NB, Tambuwala, MM
Cellular signalling. 2024;:110911
Abstract
The rewiring of cellular metabolism is a defining characteristic of cancer, as tumor cells adapt to acquire essential nutrients from a nutrient-poor environment to sustain their viability and biomass. While hypoxia has been identified as a major factor depriving cancer cells of nutrients, recent studies have revealed that cancer cells distant from supporting blood vessels also face nutrient limitations. To overcome this challenge, hypoxic cancer cells, which heavily rely on glucose as an energy source, employ alternative pathways such as glycogen metabolism and reductive carboxylation of glutamine to meet their energy requirements for survival. Our preliminary studies, alongside others in the field, have shown that under glucose-deficient conditions, hypoxic cells can utilize mannose and maltose as alternative energy sources. This review aims to comprehensively examine the hypoxic cancer microenvironment, its association with drug resistance, and potential therapeutic strategies for targeting this unique niche. Furthermore, we will critically evaluate the current literature on hypoxic cancer microenvironments and explore state-of-the-art techniques used to analyze alternate carbohydrates, specifically mannose and maltose, in complex biological fluids. We will also propose the most effective analytical methods for quantifying mannose and maltose in such biological samples. By gaining a deeper understanding of the hypoxic cancer cell microenvironment and its role in drug resistance, novel therapeutic approaches can be developed to exploit this knowledge.
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The critical role of the phytosterols in modulating tumor microenvironment via multiple signaling: A comprehensive molecular approach.
Khan, AU, Khan, A, Shal, B, Khan, S, Khan, M, Ahmad, R, Riaz, M
Phytotherapy research : PTR. 2023;(4):1606-1623
Abstract
Cancer is the leading cause of mortality and morbidity worldwide, and its cases are rapidly increasing every year. Several factors contribute to the development of tumorigenesis. including radiation, dietary lifestyle, smoking, environmental, and genetic factors. The cell cycle is regulated by a variety of molecular signaling proteins. However, when the proteins involved in the cell cycle regulation are altered, cellular growth and proliferation are significantly affected. Natural products provide an important source of new drug development for a variety of ailments. including cancer. Phytosterols (PSs) are an important class of natural compounds reported for numerous pharmacological activities, including cancer. Various PSs, such as ergosterol, stigmasterol, sitosterol, withaferin A, etc., have been reported for their anti-cancer activities against a variety of cancer by modulating the tumor microenvironment via molecular signaling pathways discussed within the article. These signaling pathways are associated with the production of pro-inflammatory mediators, growth factors, chemokines, and pro-apoptotic and anti-apoptotic genes. These mediators and their upstream signaling are very active within the variety of tumors and by modulating these signalings, thus PS exhibits promising anti-cancer activities. However, further high-quality studies are needed to firmly establish the clinical efficacy as well the safety of the phytosterols.
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3.
It's all relative: analyzing microbiome compositions, its significance, pathogenesis and microbiota derived biofilms: Challenges and opportunities for disease intervention.
Zaidi, S, Ali, K, Khan, AU
Archives of microbiology. 2023;(7):257
Abstract
Concept of microorganisms has largely been perceived from their pathogenic view point. Nevertheless, it is being gradually revisited in terms of its significance to human health and now appears to be the most dominant force that shapes the immune system of the human body and also determines an individual's predisposition to diseases. Human inhabits bacterial diversity (which is predominant among all microbial communities in human body) occupying 0.3% of body mass, known as microbiota. On birth, a part of microbiota that child obtains is essentially a mother's legacy. So, the review was initiated with this critical topic of microbiotal inheritance. Since, each body site has distinct physiological specifications; therefore, they contain discrete microbiome composition that has been separately discussed along with dysbiosis-induced pathologies originating in different body organs. Factors affecting microbiome composition and may cause dysbiosis like antibiotics, delivery, feeding method etc. as well as the strategies that immune system adopts to prevent dysbiosis have been highlighted. We also tried to bring into attention the topic of dysbiosis induced biofilms, that enables cohort to survive stresses, evolve, disseminate and infection resurgence that is still in dormancy. Eventually, we put spotlight on microbiome significance in medical therapeutics. We didn't merely confine article to gut microbiota, that is being studied more extensively. Numerous community forms at diverse body sites are inter-related, and being exposed to awfully variable perturbations appear to be challenging to evaluate perturbation risks holistically. All aspects have been elaborately discussed to achieve a global depiction of human microbiota in order to meet urgent necessity for protocol standardisation. Demonstrates that environmental challenges (antibiotic use, alterations in diet, stress, smoking etc.) might cause dysbiosis i.e. transition of healthy microbiome composition to the one in which pathogenic microorganisms become more abundant, and eventually results in an infected state.
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4.
Evaluation of COVID-19 Disease Awareness and Its Relation to Mental Health, Dietary Habits, and Physical Activity: A Cross-Sectional Study from Pakistan.
Ali, A, Sohaib, M, Iqbal, S, Hayat, K, Khan, AU, Rasool, MF
The American journal of tropical medicine and hygiene. 2021;104(5):1687-1693
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Plain language summary
Dietary factors and healthy eating habits play a crucial role in human health management. The global pandemic of COVID-19 has significantly changed the dietary patterns and eating habits of the people worldwide, particularly in the area affected by this pandemic. The aim of this study was to assess the knowledge of COVID-19 disease and its association with anxiety, depression, dietary habits, and physical activity during the COVID-19 lockdown. This study was a descriptive cross-sectional survey conducted in the Punjab Province of Pakistan. A total of 1956 participants took part in the study. Results indicate that: - only 7.4% of participants had good knowledge about COVID-19. - the physical activity of the participants was affected as 66.9% of the participants had a decrease in physical activity and around 40% of the participants also gained weight. - around 70% of the participants were suffering from anxiety, and 52% were depressed. Authors conclude that their findings can help formulate concrete policy-making for the Pakistani population in terms of public health prospects. Furthermore, mass-level educational programmes should be launched via print and electronic media to enhance public awareness about COVID-19 and to improve dietary behaviour of people.
Abstract
Coronavirus infection (COVID-19) has significantly increased the mortality and morbidity rates worldwide. The present study was conducted to assess the general public's awareness of COVID-19 and its association with mental health, dietary habits, and physical activity. A web-based survey was conducted to gather information about demographics, knowledge about COVID-19, dietary habits, mental health, and anthropometry among the general public of Pakistan. Descriptive statistics, chi-square test, and multiple logistic regression were used for data analysis. The majority of the participants were suffering from anxiety (71.0%) and depression (52.0%) during the COVID-19 pandemic; 32.4% of participants had poor COVID-19-related knowledge. COVID-19 lockdown reduced the physical activity of 66.9% of participants and increased weight of 38.8% of the survey participants. Demographic variables, including age, gender, ethnicity, education, employment, family type, and geographical location, were significantly associated with knowledge about COVID-19 (P < 0.05). Depression was inversely associated with COVID-19 knowledge (P < 0.05). Healthy changes in dietary habits including decreased consumption of fast foods, soft and cola drinks, fruit drinks, cooked meat (outside the home), sugar, and fats, and were associated with increased knowledge of COVID-19. Vitamin C and immunity-boosting supplement consumption were significantly associated with increased knowledge regarding COVID-19 (< 0.05). Inadequate knowledge about COVID-19 and the presence of anxiety and depression were found among most of the study participants. There is a need to conduct educational seminars to limit the health consequences resulting from COVID-19 lockdown.
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Repurposing drug molecule against SARS-Cov-2 (COVID-19) through molecular docking and dynamics: a quick approach to pick FDA-approved drugs.
Farhat, N, Khan, AU
Journal of molecular modeling. 2021;(11):312
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Abstract
A novel coronavirus known as severe acute respiratory syndrome is rapidly spreading worldwide. The international health authorities are putting all their efforts on quick diagnosis and placing the patients in quarantine. Although different vaccines have come for quick use as prophylactics, drug repurposing seems to be of paramount importance because of inefficient therapeutic options and clinical trial limitations. Here, we used structure-based drug designing approach to find and check the efficacy of the possible drug that can inhibit coronavirus main protease which is involved in polypeptide processing to functional protein. We performed virtual screening, molecular docking and molecular dynamics simulations of the FDA-approved drugs against the main protease of SARS-CoV-2. Using well-defined computational methods, we identified amprenavir, cefoperazone, riboflavin, diosmin, nadide and troxerutin approved for human therapeutic uses, as COVID-19 main protease inhibitors. These drugs bind to the SARS-CoV-2 main protease conserved residues of substrate-binding pocket and formed a remarkable number of non-covalent interactions. We have found diosmin as an inhibitor which binds covalently to the COVID-19 main protease. This study provides enough evidences for therapeutic use of these drugs in controlling COVID-19 after experimental validation and clinical demonstration.
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Prediction of putative epitope-based vaccine against all corona virus strains for the Chinese population: Approach toward development of vaccine.
Batool, H, Batool, S, Mahmood, MS, Mushtaq, N, Khan, AU, Ali, M, Sahibzada, KI, Ashraf, NM
Microbiology and immunology. 2021;(4):154-160
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Currently, the whole world is facing the coronavirus disease-19 pandemic. As of now, approximately 0.15 million people around the globe are infected with the novel coronavirus. In the last decade, two strains of the coronavirus family, severe acute respiratory syndrome-related coronavirus and Middle East respiratory syndrome coronavirus, also resulted in epidemics in south Asian and the Middle Eastern countries with high mortality rate. This scenario demands the development of a putative vaccine which may provide immunity against all current and new evolving coronavirus strains. In this study, we designed an epitope-based vaccine using an immunoinformatic approach. This vaccine may protect against all coronavirus strains. The vaccine is developed by considering the geographical distribution of coronavirus strains and host genetics (Chinese population). Nine experimentally validated epitopes sequences from coronavirus strains were used to derive the variants considering the conservancy in all strains. Further, the binding affinities of all derived variants were checked with most abundant human leukocyte antigen alleles in the Chinese population. Three major histocompatibility complex (MHC) Class I epitopes from spike glycoprotein and nucleoprotein showed sufficient binding while one MHC Class II epitope from spike glycoprotein was found to be an effective binder. A cocktail of these epitopes gave more than 95% population coverage in the Chinese population. Moreover, molecular dynamics simulation supported the aforementioned predictions. Further, in vivo studies are needed to confirm the immunogenic potential of these vaccines.
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Zinc oxide‑selenium heterojunction composite: Synthesis, characterization and photo-induced antibacterial activity under visible light irradiation.
Ahmad, A, Ullah, S, Ahmad, W, Yuan, Q, Taj, R, Khan, AU, Rahman, AU, Khan, UA
Journal of photochemistry and photobiology. B, Biology. 2020;:111743
Abstract
The designing of new antibacterial agents with high and long-lasting activities are urgently needed in order to cope with the fast-emerging bacterial resistance. Zinc oxide nanoparticles (ZnO) have shown a significant promise as broad-spectrum antibacterial agents, and are efficient material in compromising bacterial membrane stability that leads to an increased cell permeability to nano-products. However, further engineering is required to improve their biological activities and to minimize their toxicity to healthy cells. In an attempt to resolve this issue, two semiconductor materials, ZnO and selenium (Se), were fabricated into a unique structural composite by a newly developed facile green method, and the designed composite was applied as an antibacterial nanomedicine. The developed methodology involves the initial preparation of ZnO, followed by its fabrication with Se at different temperatures (70 °C to 95 °C). Our experimental data showed that well defined interpenetrated crystalline Se network on ZnO (ZnO-Se) can be obtained at 80 °C for 180 min. The as-prepared ZnO-Se showed promising results in inhibiting the challenged bacterial strains under light irradiation (visible light) as compared to free ZnO. The enhanced biocidal property of ZnO-Se could be ascribed to its improved light-harvesting ability for sustainable induction of reactive oxygen species (ROS) and an active contact killing mechanism. Thus, ZnO-Se composite with a novel architecture could be a promising material in the treatment of bacterial infections by a mutual antibacterial synergy from the incorporated elements. Interestingly, the ZnO-Se has the ability to scavenge the overproduction of hydroxyl radicals, thus protecting the healthy cells from oxidative damage.
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An Updated List of Neuromedicinal Plants of Pakistan, Their Uses, and Phytochemistry.
Khan, AW, Khan, AU, Shah, SMM, Ullah, A, Faheem, M, Saleem, M
Evidence-based complementary and alternative medicine : eCAM. 2019;:6191505
Abstract
BACKGROUND Almost every region of Pakistan is stacked with a large number of medicinal plants. Due to high cost and unavailability of allopathic medicines for the neurological diseases, especially in rural areas, traditional healers prescribe phytotherapy for various neurological diseases like epilepsy, depression, anxiety, insomnia, Alzheimer, and migraine. Such treatments are considered to be most effective by the native people. METHODS The data was collected from articles published on medicinal plants of various districts of Pakistan, using article search engines like Medline, Pubmed, Web of Science, Science Direct, and Google Scholar. Also, information regarding various neurological uses and mode of applications of medicinal plants was obtained from traditional healers, folk medicine users, and local elderly people having knowledge of medicinal plants. RESULTS A total of 54 families were found to be used in various neurological diseases, of which the highest use was of Solanaceae (22.22%), Asteraceae (12.96%), Lamiaceae, Papaveraceae, and Poaceae, 9% each, and Caprifoliaceae, Cucurbitaceae, Rhamnaceae, and Rosaceae, 5.5% each. According to districts, 15% of plants that were effective in neurological affections were found in Bahawalpur, 11% in Swat, 8% in Muzaffarabad, 7% in Malakand, and 6% in Bahawalnagar, Dir, Gilgat, and Sarghoda each, with 5% in Dera ghazi khan and Jhelum each. According to the plant's habit, out of total of 103 plants, 61.15% were found to be herbs, 22.33% trees, 11.65% shrubs, and 4.85% climbers. According to the part used of plant, whole plant, leaves, fruits, roots, seeds, and flowers were found to be used 32.03%, 24.27%, 20.38%, 16.50%, 13.59%, and 11.65%, respectively. According to disease's types, 45.63% were found to be effective in insomnia, 31.06% in epilepsy 12.62% in depression, 6.80% in anxiety, 7.77% in hysteria, and 5.88% in migraine. CONCLUSION Taking into consideration this useful knowledge on medicinal properties of the plants for curing neurologic diseases, it is believed that research in areas of ethnomedicine and ethnopharmacology can bring auspicious results that have potential of adding value to the very rich natural resources of Pakistan. This study will help all the researchers from diverse backgrounds working on plants based medicine for neurological diseases.
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Structure, Function of Serine and Metallo-β-lactamases and their Inhibitors.
Salahuddin, P, Kumar, A, Khan, AU
Current protein & peptide science. 2018;(2):130-144
Abstract
Antibiotic resistance in gram-negative bacteria has emerged as a major health threat that occurs because these bacteria actively produce β-lactamases responsible for the inactivation of β-lactam antibiotics. The first β lactamase was reported in E. coli back in 1940, before the release of the first antibiotic penicillin in clinical settings. Later on, large numbers of β-lactamases have been discovered in Gram-positive, Gram-negative bacteria as well as mycobacteria. Currently, numerous three-dimensional structures of serine and metallo-β-lactamases have been solved. The serine β-lactamases essentially consist of two structural domains (an all α and an α/β domain) and the active site is located at the groove between the two domains. The catalysis of serine β-lactamase proceeds via acylation and deacylation reactions. The three dimensional structure of metallo-β-lactamases displayed a common four layer "αβ/βα" motif, with a central "ββ"- sandwich by Zn2+ ion(s), and two α-helices are located on the either side. The active site of metallo-β-lactamases contain either 1 or 2 Zn2+ ions, which is coordinated to metal ligating amino acids and polarized water molecule(s) necessary for the hydrolysis of β-lactam antibiotics. Keeping the above views in mind, in this review we have shed light on the current knowledge of the structures and mechanisms of catalysis of serine and metallo-β-lactamases. Moreover, mutational studies on β-lactamases highlight the importance of the active site residues and residues in the vicinity to the active site pocket in the catalysis. To combat bacterial infections more effeciently novel inhibitors of β-lactamase in combination with antibiotics have been used which also form the theme of the review.
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Structural and functional insight of New Delhi Metallo β-lactamase-1 variants.
Khan, S, Ali, A, Khan, AU
Future medicinal chemistry. 2018;(2):221-229
Abstract
New Delhi Metallo β-lactamase-1 (NDM-1) is a member of the Metallo-β-lactamase family, capable of catalyzing the hydrolysis of all β-lactam antibiotics. The rapid dissemination of NDM producers, 'superbugs', has become a worldwide concern to health workers. Seventeen different variants of NDM have been reported so far, across the world. These variants varied in their sequences either by single or multiple amino acid substitutions. This review summarizes the crystal structure of NDM and provides a comparative analysis of all variants. Moreover, we have for the first time highlighted the role of α-helix, β-sheet and loop structures of NDM enzyme, having different mutations occurred in these regions. The effect of these substitutions on its structure and functional aspect has to be thoroughly understood to design effective inhibitors in future.