Browsing by Author "Ashraf, Ghulam Md"

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Cholinesterase Inhibitors for Alzheimer's Disease
(Current Pharmaceutical Design, 2019) Kabir, Md Tanvir; Uddin, Md Sahab; Begum, Mst Marium; Thangapandiyan, Shanmugam; Rahman, Md Sohanur; Aleya, Lotfi; Mathew, Bijo; Ahmed, Muniruddin; Barreto, George E; Ashraf, Ghulam Md
In the brain, acetylcholine (ACh) is regarded as one of the major neurotransmitters. During the advancement of Alzheimer's disease (AD) cholinergic deficits occur and this can lead to extensive cognitive dysfunction and decline. Acetylcholinesterase (AChE) remains a highly feasible target for the symptomatic improvement of AD. Acetylcholinesterase (AChE) remains a highly viable target for the symptomatic improvement in AD because cholinergic deficit is a consistent and early finding in AD. The treatment approach of inhibiting peripheral AChE for myasthenia gravis had effectively proven that AChE inhibition was a reachable therapeutic target. Subsequently tacrine, donepezil, rivastigmine, and galantamine were developed and approved for the symptomatic treatment of AD. Since then, multiple cholinesterase inhibitors (ChEIs) have been continued to be developed. These include newer ChEIs, naturally derived ChEIs, hybrids, and synthetic analogues. In this paper, we summarize the different types of ChEIs which are under development and their respective mechanisms of actions.
CNS Depressant Activities of Averrhoa carambola Leaves Extract in Thiopental-Sodium Model of Swiss Albino Mice
(Daffodil International University, 2022-02-22) Akter, Aklima; Islam, Fahadul; Bepary, Sristy; . Al‑Amin, Md.; Begh, Md. Zamshed Alam; Islam, Md. Al Fahad Ul; Ashraf, Ghulam Md; Baeesa, Saleh Salem; Ullah, Mohammad Fahad
Psychological stress and anxiety have been linked to significant impairments of neurobiological functions. There is a wide range of conditions including neurological disorders such as Alzheimer’s disease and use of certain substances or medications that induce stress and anxiety in humans. Confused state of mind, anxiety and psychological stress have been associated with varying degree of disabilities and poor quality of life in humans. Anxiolytic medications are important modulators of CNS that reduce the anxiety and the related psychological effects in patients. Natural product derived drugs such as galantamine have been shown to possess promising neuro-modulatory properties in neurological disorders. Averrhoa carambola is traditionally used for anti-oxidative, anti-inflammatory, anti-microbial, and anti-ulcerative properties. In this study, we have examined the CNS depressant activity of A. carambola leaves extracts. The neuro-modulatory properties were assessed with the standard protocols that are used to identify such CNS depressant activity and included thiopental sodium-induced sleeping time test, hole cross test, hole board test, and open field test. The extract was found to decrease the motor activity and exploratory behaviour of mice in hole cross, hole board and open field tests. The extract also significantly maximized the duration of sleeping time when administered with thiopental sodium, which also demonstrated the CNS depressant activity. The findings of our study suggest that A. carambola extracts have active CNS depressant and hypnotic properties. However, further studies are warranted for isolation of bioactive constituents and understanding the molecular mechanism and modes of action for such pharmacological effects.
Current Trends of Computational Tools in Geriatric Medicine and Frailty Management
(Daffodil International University, 2022-07-19) Louka, Anna Maria; Tsagkaris, Christos; Christoforou, Panagiotis; Khan, Andleeb; Alexiou, Filia; Simou, Panagiota; Haranas, Loannis; Gkigkitzis, Loannis; Zouganelis, Georgios; Jha, Niraj Kumar; Uddin, Md Sahab; Shen, Bairong; Kamal, Mohammad A.; Ashraf, Ghulam Md; Alexiou, Athanasios
While frailty corresponds to a multisystem failure, geriatric assessment can recognize multiple pathophysiological lesions and age changes. Up to now, a few frailty indexes have been introduced, presenting definitions of psychological problems, dysregulations in nutritional intake, behavioral abnormalities, and daily functions, genetic, environmental, and cardiovascular comorbidities. The geriatric evaluation includes a vast range of health professionals; therefore, we describe a broad range of applications and frailty scales-biomarkers to investigate and formulate the relationship between frailty lesions, diagnosis, monitoring, and treatment. Additionally, artificial intelligence applications and computational tools are presented, targeting a more efficacy individualized geriatric management of healthy aging.
DeePred-BBB
(Daffodil International University, 2022-05-03) Kumar, Rajnish; Sharma, Anju; Alexiou, Athanasios; Bilgrami, Anwar L.; Kamal, Mohammad Amjad; Ashraf, Ghulam Md
The blood-brain barrier (BBB) is a selective and semipermeable boundary that maintains homeostasis inside the central nervous system (CNS). The BBB permeability of compounds is an important consideration during CNS-acting drug development and is difficult to formulate in a succinct manner. Clinical experiments are the most accurate method of measuring BBB permeability. However, they are time taking and labor-intensive. Therefore, numerous efforts have been made to predict the BBB permeability of compounds using computational methods. However, the accuracy of BBB permeability prediction models has always been an issue. To improve the accuracy of the BBB permeability prediction, we applied deep learning and machine learning algorithms to a dataset of 3,605 diverse compounds. Each compound was encoded with 1,917 features containing 1,444 physicochemical (1D and 2D) properties, 166 molecular access system fingerprints (MACCS), and 307 substructure fingerprints. The prediction performance metrics of the developed models were compared and analyzed. The prediction accuracy of the deep neural network (DNN), one-dimensional convolutional neural network, and convolutional neural network by transfer learning was found to be 98.07, 97.44, and 97.61%, respectively. The best performing DNN-based model was selected for the development of the “DeePred-BBB” model, which can predict the BBB permeability of compounds using their simplified molecular input line entry system (SMILES) notations. It could be useful in the screening of compounds based on their BBB permeability at the preliminary stages of drug development. The DeePred-BBB is made available at https://github.com/12rajnish/DeePred-BBB.
Dietary Alterations in Impaired Mitochondrial Dynamics Due to Neurodegeneration
(Daffodil International University, 2022-07-11) Ashraf, Ghulam Md; Chatzichronis, Stylianos; Alexiou, Athanasios; Firdousi, Gazala; Kamal, Mohammad Amjad; Ganash, Magdah
Alzheimer’s disease is still an incurable disease with significant social and economic impact globally. Nevertheless, newly FDA-approved drugs and non-pharmacological techniques may offer efficient disease treatments. Furthermore, it is widely accepted that early diagnosis or even prognosis of Alzheimer’s disease using advanced computational tools could offer a compelling alternative way of management. In addition, several studies have presented an insight into the role of mitochondrial dynamics in Alzheimer’s development. In combination with diverse dietary and obesity-related diseases, mitochondrial bioenergetics may be linked to neurodegeneration. Considering the probabilistic expectations of Alzheimer’s disease development or progression due to specific risk factors or biomarkers, we designed a Bayesian model to formulate the impact of diet-induced obesity with an impaired mitochondrial function and altered behavior. The applied probabilities are based on clinical trials globally and are continuously subject to updating and redefinition. The proposed multiparametric model combines various data types based on uniform probabilities. The program simulates all the variables with a uniform distribution in a sample of 1000 patients. First, the program initializes the variable age (30–95) and the four different diet types (“HFO_diet,” “Starvation,” “HL_diet,” “CR”) along with the factors that are related to prodromal or mixed AD (ATP, MFN1, MFN2, DRP1, FIS1, Diabetes, Oxidative_Stress, Hypertension, Obesity, Depression, and Physical_activity). Besides the known proteins related to mitochondrial dynamics, our model includes risk factors like Age, Hypertension, Oxidative Stress, Obesity, Depression, and Physical Activity, which are associated with Prodromal Alzheimer’s. The outcome is the disease progression probability corresponding to a random individual ID related to diet choices and mitochondrial dynamics parameters. The proposed model and the programming code are adjustable to different parameters and values. The program is coded and executed in Python and is fully and freely available for research purposes and testing the correlation between diet type and Alzheimer’s disease progression regarding various risk factors and biomarkers.
Emerging Promise of Therapeutic Approaches Targeting Mitochondria in Neurodegenerative Disorders
(Emerald Publishing Limited, 2023-04-12) Rahman, Md Mominur; Tumpa, Mst Afroza Alam; Rahaman, Md Saidur; Islam, Fahadul; Islam, Fahadul; Sutradhar, Popy Rani; Ahmed, Muniruddin; Alghamdi, Badrah S.; Hafeez, Abdul; Alexiou, Athanasios; Perveen, Asma; Ashraf, Ghulam Md
Mitochondria are critical for homeostasis and metabolism in all cellular eukaryotes. Brain mitochondria are the primary source of fuel that supports many brain functions, including intracellular energy supply, cellular calcium regulation, regulation of limited cellular oxidative capacity, and control of cell death. Much evidence suggests that mitochondria play a central role in neurodegenerative disorders (NDDs) such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Ongoing studies of NDDs have revealed that mitochondrial pathology is mainly found in inherited or irregular NDDs and is thought to be associated with the pathophysiological cycle of these disorders. Typical mitochondrial disturbances in NDDs include increased free radical production, decreased ATP synthesis, alterations in mitochondrial permeability, and mitochondrial DNA damage. The main objective of this review is to highlight the basic mitochondrial problems that occur in NDDs and discuss the use mitochondrial drugs, especially mitochondrial antioxidants, mitochondrial permeability transition blockade, and mitochondrial gene therapy, for the treatment and control of NDDs.
Estrogen Signaling in Alzheimer’s Disease
(Molecular Neurobiology, Springer, 2020-04-15) Uddin, Md. Sahab; Rahman, Md. Motiar; Jakaria, Md.; Rahman, Md. Sohanur; Hossain, Md. Sarwar; Islam, Ariful; Ahmed, Muniruddin; Mathew, Bijo; Omar, Ulfat Mohammed; Barreto, George E.; Ashraf, Ghulam Md
Estrogens play a crucial physiological function in the brain; however, debates exist concerning the role of estrogens in Alzheimer’s disease (AD). Women during pre-, peri-, or menopause periods are more susceptible for developing AD, suggesting the connection of sex factors and a decreased estrogen signaling in AD pathogenesis. Yet, the underlying mechanism of estrogen-mediated neuroprotection is unclarified and is complicated by the existence of estrogen-related factors. Consequently, a deeper analysis of estrogen receptor (ER) expression and estrogen-metabolizing enzymes could interpret the importance of estrogen in age-linked cognitive alterations. Previous studies propose that hormone replacement therapy may attenuate AD onset in postmenopausal women, demonstrating that estrogen signaling is important for the development and progression of AD. For example, ERα exerts neuroprotection against AD by maintaining intracellular signaling cascades and study reported reduced expression of ERα in hippocampal neurons of AD patients. Similarly, reduced expression of ERβ in female AD patients has been associated with abnormal function in mitochondria and improved markers of oxidative stress. In this review, we discuss the critical interaction between estrogen signaling and AD. Moreover, we highlight the potential of targeting estrogen-related signaling for therapeutic intervention in AD.
Exposure of Metal Toxicity in Alzheimer's Disease
(Daffodil International University, 2022-08-12) Islam, Fahadul; Shohag, Sheikh; Akhter, Shomaya; Islam, Md. Rezaul; Sultana, Sharifa; Mitra, Saikat; Chandran, Deepak; Khandaker, Mayeen Uddin; Ashraf, Ghulam Md; Idris, Abubakr M.; Emran, Talha Bin; Cavalu, Simona
Metals serve important roles in the human body, including the maintenance of cell structure and the regulation of gene expression, the antioxidant response, and neurotransmission. High metal uptake in the nervous system is harmful because it can cause oxidative stress, disrupt mitochondrial function, and impair the activity of various enzymes. Metal accumulation can cause lifelong deterioration, including severe neurological problems. There is a strong association between accidental metal exposure and various neurodegenerative disorders, including Alzheimer’s disease (AD), the most common form of dementia that causes degeneration in the aged. Chronic exposure to various metals is a well-known environmental risk factor that has become more widespread due to the rapid pace at which human activities are releasing large amounts of metals into the environment. Consequently, humans are exposed to both biometals and heavy metals, affecting metal homeostasis at molecular and biological levels. This review highlights how these metals affect brain physiology and immunity and their roles in creating harmful proteins such as β-amyloid and tau in AD. In addition, we address findings that confirm the disruption of immune-related pathways as a significant toxicity mechanism through which metals may contribute to AD.
Free Radical Scavenging, Thrombolytic and Cytotoxic Effects of the Medicinal Herb, Crassocephalum Crepidioides
(Research Journal of Pharmacy and Technology, 2021) Kabir, Md. Tanvir; Samiha, Mayesha; Yasmin, Hasina; Rahman, Mohammed S.; Rahman, Md. Sohanur; Ashraf, Ghulam Md; Akter, Raushanara
Crassocephalum crepidioides belongs to the Asteraceae family and the leaves of the plant were used in the phytochemical screening. The objective of this study was phytochemical analysis of C. crepidioides in order to evaluate its antioxidant, thrombolytic and cytotoxic effects. In this study, DPPH assay and total phenolic content (TPC) were used to evaluate the antioxidant property. Brine shrimp lethality test was performed to find the cytotoxicity. The TPC of methanolic extract of C. crepidioides was 637.22 mg/gm and gallic acid was standard in this procedure. The IC50 value of the plant extract of DPPH assay was 136.016 µg/mL obtained by using ascorbic acid as reference standard. Furthermore, the obtained IC50 value of ascorbic acid was 94.12 µg/mL. In this study, lethal concentrations of vincristine sulfate and the plant extract were 3.064 µg/mL and 69.245 µg/mL respectively. Indeed, the plant exhibited significant antioxidant, cytotoxic and thrombolytic activity
Hutchinson-Gilford Progeria Syndrome
(Scopus, 2021) Rahman, Md Mominur; Ferdous, Kazi Sayma; Ahmed, Muniruddin; Islam, Mohammad Touhidul; Khan, Md Robin; Perveen, Asma; Ashraf, Ghulam Md; Uddin, Md Sahab
Lamin A/C encoded by the LMNA gene is an essential component for maintaining the nuclear structure. Mutation in the lamin A/C leads to a group of inherited disorders is known as laminopathies. In the human body, there are several mutations in the LMNA gene that have been identified. It can affect diverse organs or tissues or can be systemic, causing different diseases. In this review, we mainly focused on one of the most severe laminopathies, Hutchinson-Gilford progeria syndrome (HGPS). HGPS is an immensely uncommon, deadly, metameric ill-timed laminopathies caused by the abnormal splicing of the LMNA gene and production of an aberrant protein known as progerin. Here, we also presented the currently available data on the molecular mechanism, pathophysiology, available treatment, and future approaches to this deadly disease. Due to the production of progerin, an abnormal protein leads to an abnormality in nuclear structure, defects in DNA repair, shortening of telomere, and impairment in gene regulation which ultimately results in aging in the early stage of life. Now some treatment options are available for this disease, but a proper understanding of the molecular mechanism of this disease will help to develop a more appropriate treatment which makes it an emerging area of research.
Investigation and Drug Design for Novel Molecules From Natural Products As Inhibitors for Controlling Multiple Myeloma Disease Using In-Silico Tools
(Taylor & Francis Group, 2024-01-03) Zari, Ali; Kurdi, Lina A. F.; Jaber, Fatima A; Alghamdi, Khalid M S; Zari, Talal A; Bahieldin, Ahmed; Hakeem, Khalid Rehman; Alnahdi, Hanan S.; Edris, Sherif; Ashraf, Ghulam Md
The demand for energy across the world is constantly rising. Therefore remarkable endeavors have been dedicated to the development of high-performance energy storage devices with nanoscale design and hybrid approaches. Inorganic nanomaterials like transition metal oxide/hydroxide, metal chalcogenide, metal carbide, metal–organic framework, carbonaceous compounds, polymer-based porous materials, and their hybrid nanocomposites are being used for energy storage purposes in lithium-ion batteries, supercapacitors (SCs), etc. To produce these nanomaterials that are ideal for energy storage, it is very important to have porous structures, high surface area, high electrical conductivity, charge accommodation capacity, and tunable electronic structures. These electrodes can be synthesized via several synthetic strategies like intercalative hybridization, core–shell architecture, surface anchoring, and defect control. This book attempts to discuss the synthesis and applications of various advanced nanomaterials and their hybrid nanocomposites that are being used for designing efficient batteries and SCs-based energy storage systems. Moreover, their features, limitations, and real-time resolutions will be focused on.
Natural products in the management of neurodegenerative diseases
(2024-05-16) Rajat, Goyal; Mittal, Pooja; Gautam, Rupesh K.; Kamal, Mohammad Amjad; Perveen, Asma; Garg, Vandana; Alexiou, Athanasios; Saboor, Muhammad; Haque, Shafiul; Farhana, Aisha; Papadakis, Marios; Ashraf, Ghulam Md
Neurodegenerative diseases represent one of the utmost imperative well-being health issues and apprehensions due to their escalating incidence of mortality. Natural derivatives are more efficacious in various preclinical models of neurodegenerative illnesses. These natural compounds include phytoconstituents in herbs, vegetables, fruits, nuts, and marine and freshwater flora, with remarkable efficacy in mitigating neurodegeneration and enhancing cognitive abilities in preclinical models. According to the latest research, the therapeutic activity of natural substances can be increased by adding phytoconstituents in nanocarriers such as nanoparticles, nanogels, and nanostructured lipid carriers. They can enhance the stability and specificity of the bioactive compounds to a more considerable extent. Nanotechnology can also provide targeting, enhancing their specificity to the respective site of action. In light of these findings, this article discusses the biological and therapeutic potential of natural products and their bioactive derivatives to exert neuroprotective effects and some clinical studies assessing their translational potential to treat neurodegenerative disorders.
Natural Products in the Management of Neurodegenerative Diseases
(Springer Nature, 2024-05-16) Goyal, Rajat; Mittal, Pooja; Gautam, Rupesh K.; Kamal, Mohammad Amjad; Perveen, Asma; Garg, Vandana; Alexiou, Athanasios; Saboor, Muhammad; Haque, Shafiul; Farhana, Aisha; Papadakis, Marios; Ashraf, Ghulam Md
"Neurodegenerative diseases represent one of the utmost imperative well-being health issues and apprehensions due to their escalating incidence of mortality. Natural derivatives are more efficacious in various preclinical models of neurodegenerative illnesses. These natural compounds include phytoconstituents in herbs, vegetables, fruits, nuts, and marine and freshwater flora, with remarkable efficacy in mitigating neurodegeneration and enhancing cognitive abilities in preclinical models. According to the latest research, the therapeutic activity of natural substances can be increased by adding phytoconstituents in nanocarriers such as nanoparticles, nanogels, and nanostructured lipid carriers. They can enhance the stability and specificity of the bioactive compounds to a more considerable extent. Nanotechnology can also provide targeting, enhancing their specificity to the respective site of action. In light of these findings, this article discusses the biological and therapeutic potential of natural products and their bioactive derivatives to exert neuroprotective effects and some clinical studies assessing their translational potential to treat neurodegenerative disorders. Graphical Abstract Common mechanisms, therapeutic targets, and molecular pathogenesis of neurodegeneration. It is focused on the biological and therapeutic potential of natural products and their bioactive derivatives to exert a neuroprotective effect on the pathologies of neurodegenerative diseases."
Repurposing Food Molecules as a Potential BACE1 Inhibitor for Alzheimer's Disease
(Daffodil International University, 2022-08-22) Mukerjee, Nobendu; Das, Anubhab; Jawarkar, Rahul D.; Maitra, Swastika; Das, Padmashree; Castrosanto, Melvin A.; Paul, Soumyadip; Samad, Abdul; Zaki, Magdi E. A.; Al-Hussain, Sami A.; Masand, Vijay H.; Hasan, Mohammad Mehedi; Bukhari, Syed Nasir Abbas; Perveen, Asma; Alghamdi, Badrah S.; Alexiou, Athanasios; Kamal, Mohammad Amjad; Dey, Abhijit; Malik, Sumira; Bakal, Ravindra L.; Abuzenadah, Adel Mohammad; Ghosh, Arabinda; Ashraf, Ghulam Md
Alzheimer’s disease (AD) is a severe neurodegenerative disorder of the brain that manifests as dementia, disorientation, difficulty in speech, and progressive cognitive and behavioral impairment. The emerging therapeutic approach to AD management is the inhibition of β-site APP cleaving enzyme-1 (BACE1), known to be one of the two aspartyl proteases that cleave β-amyloid precursor protein (APP). Studies confirmed the association of high BACE1 activity with the proficiency in the formation of β-amyloid-containing neurotic plaques, the characteristics of AD. Only a few FDA-approved BACE1 inhibitors are available in the market, but their adverse off-target effects limit their usage. In this paper, we have used both ligand-based and target-based approaches for drug design. The QSAR study entails creating a multivariate GA-MLR (Genetic Algorithm-Multilinear Regression) model using 552 molecules with acceptable statistical performance (R2 = 0.82, Q2loo = 0.81). According to the QSAR study, the activity has a strong link with various atoms such as aromatic carbons and ring Sulfur, acceptor atoms, sp2-hybridized oxygen, etc. Following that, a database of 26,467 food compounds was primarily used for QSAR-based virtual screening accompanied by the application of the Lipinski rule of five; the elimination of duplicates, salts, and metal derivatives resulted in a truncated dataset of 8,453 molecules. The molecular descriptor was calculated and a well-validated 6-parametric version of the QSAR model was used to predict the bioactivity of the 8,453 food compounds. Following this, the food compounds whose predicted activity (pKi) was observed above 7.0 M were further docked into the BACE1 receptor which gave rise to the Identification of 4-(3,4-Dihydroxyphenyl)-2-hydroxy-1H-phenalen-1-one (PubChem I.D: 4468; Food I.D: FDB017657) as a hit molecule (Binding Affinity = −8.9 kcal/mol, pKi = 7.97 nM, Ki = 10.715 M). Furthermore, molecular dynamics simulation for 150 ns and molecular mechanics generalized born and surface area (MMGBSA) study aided in identifying structural motifs involved in interactions with the BACE1 enzyme. Molecular docking and QSAR yielded complementary and congruent results. The validated analyses can be used to improve a drug/lead candidate’s inhibitory efficacy against the BACE1. Thus, our approach is expected to widen the field of study of repurposing nutraceuticals into neuroprotective as well as anti-cancer and anti-viral therapeutic interventions.
Retinoblastoma: An Update on Genetic Origin, Classification, Conventional to Next-generation Treatment Strategies
(Elsevier, 2024-06-11) Pareek, Ashutosh; Kumar, Deepanjali; Pareek, Aaushi; Gupta, Madan Mohan; Jeandet, Philippe; Ratan, Yashumati; Jain, Vivek; Kamal, Mohammad Amjad; Saboori, Muhammad; Ashraf, Ghulam Md; Chuturgoon, Anil
The most prevalent paediatric vision-threatening medical condition, retinoblastoma (RB), has been a global concern for a long time. Several conventional therapies, such as systemic chemotherapy and focal therapy, have been used for curative purposes; however, the search for tumour eradication with the least impact on surrounding tissues is still ongoing. This review focuses on the genetic origin, classification, conventional treatment modalities, and their combination with nano-scale delivery systems for active tumour targeting. In addition, the review also delves into ongoing clinical trials and patents, as well as emerging therapies such as gene therapy and immunotherapy for the treatment of RB. Understanding the role of genetics in the development of RB has refined its treatment strategy according to the genetic type. New approaches such as nanostructured drug delivery systems, galenic preparations, nutlin-3a, histone deacetylase inhibitors, N-MYC inhibitors, pentoxifylline, immunotherapy, gene therapy, etc. discussed in this review, have the potential to circumvent the limitations of conventional therapies and improve treatment outcomes for RB. In summary, this review highlights the importance and need for novel approaches as alternative therapies that would ultimately displace the shortcomings associated with conventional therapies and reduce the enucleation rate, thereby preserving global vision in the affected paediatric population.