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Protective Effect of Natural Products against Huntington's Disease: An Overview of Scientific Evidence and Understanding Their Mechanism of Action

Lum PT, Sekar M, Gan SH, Bonam SR, Shaikh MF

ACS Chem Neurosci, 2021 Feb 03;12(3):391-418.
PMID: 33475334 DOI: 10.1021/acschemneuro.0c00824

Huntington's disease (HD), a neurodegenerative disease, normally starts in the prime of adult life, followed by a gradual occurrence of characteristic psychiatric disturbances and cognitive and motor dysfunction. To the best of our knowledge, there is no treatment available to completely mitigate the progression of HD. Among various therapeutic approaches, exhaustive literature reports have confirmed the medicinal benefits of natural products in HD experimental models. Building on this information, this review presents a brief overview of the neuroprotective mechanism(s) of natural products against in vitro/in vivo models of HD. Relevant studies were identified from several scientific databases, including PubMed, ScienceDirect, Scopus, and Google Scholar. After screening through literature from 2005 to the present, a total of 14 medicinal plant species and 30 naturally isolated compounds investigated against HD based on either in vitro or in vivo models were included in the present review. Behavioral outcomes in the HD in vivo model showed that natural compounds significantly attenuated 3-nitropropionic acid (3-NP) induced memory loss and motor incoordination. The biochemical alteration has been markedly alleviated with reduced lipid peroxidation, increased endogenous enzymatic antioxidants, reduced acetylcholinesterase activity, and increased mitochondrial energy production. Interestingly, following treatment with certain natural products, 3-NP-induced damage in the striatum was ameliorated, as seen histologically. Overall, natural products afforded varying degrees of neuroprotection in preclinical studies of HD via antioxidant and anti-inflammatory properties, preservation of mitochondrial function, inhibition of apoptosis, and induction of autophagy.
Traditional Medicinal Plants Conferring Protection Against Ovalbumin-Induced Asthma in Experimental Animals: A Review

Azman S, Sekar M, Bonam SR, Gan SH, Wahidin S, Lum PT, et al.

J Asthma Allergy, 2021;14:641-662.
PMID: 34163178 DOI: 10.2147/JAA.S296391

Asthma is a chronic inflammatory disease of the respiratory tract in which the numerous immune cells, including eosinophils, neutrophils, macrophages, T-lymphocytes, mast cells and epithelial lining play key roles. The numerous anti-asthmatic drugs are available in modern medicine to treat asthma, but they have several disadvantages, including side effects and the cost variations, which compromise treatment compliance. The literature review reveals that traditional herbal medicines have good potential as alternative treatment and management for asthma. However, communities hesitated to use the traditional herbal medicines due to lack of established mechanism of action about their anti-asthmatic potential. The present review aimed to summarise the information stated in the literature about the potential effect of traditional medicinal plants (TMPs) conferring protection against ovalbumin (OVA)-induced asthma model. The literature search was conducted in database like PubMed, Scopus, Google Scholar and ScienceDirect. After screening through the literature from 2011 to date, a total of 27 medicinal plants and two polyherbal extracts have been reported to be used as traditional herbal medicines and also utilised to be tested against OVA-induced asthma, were included. We found them to be an important alternative source of treatment for asthma, since some have comparable efficacies with drugs commonly used in the modern system against asthma. All the reported medicinal plants confirmed their traditional use against asthma or its related inflammation. The present review provides faith in traditional information and also offers new insight into the potential of natural products against asthma.
Mapping the role of pH-adjusted potassium in diabetic ketoacidosis: Hypokalemia and the patient outcomes

Usman A, Mustafa N, Iqbal SP, Hasan MZ, Shaikh MF, Dujaili JA, et al.

Int J Clin Pract, 2021 Aug;75(8):e14315.
PMID: 33934480 DOI: 10.1111/ijcp.14315

BACKGROUND: Incidence of hypokalemia during the management of diabetic ketoacidosis (DKA) is high despite detailed potassium replacement guidelines in its treatment.
AIM: We aimed to find the role of pH-adjusted potassium (pHK ) in the development of hypokalemia, and their mutual impact on patient outcomes during DKA management.
METHODOLOGY: Adult DKA patient's admission data of preceding 3 years (2015-2017) were retrospectively clerked. Outcomes of interest were time to develop hypokalemia and to terminate emergency department (ED) care (hours), severity of hypokalemia and hospitalisation length (days). Linear regression was used to determine significant associations/predictors.
RESULTS: The study was concluded on 85 patients. Hypokalemia was observed in nearly 3/4th of all admissions and occurred by the time of ED care termination. Each 1 mmol/L increase in pHK significantly (a) reduced the degree of hypokalemia by 0.07 mmol/L, (b) delayed time to develop hypokalemia by 4.58 hours, (c) and reduced the ED care time by 1.28 hours. Arterial pH was the other factor significantly delaying time to develop hypokalemia (36.25 hours) and facilitating early discharge from ED (13.86 hours). Moreover, each 1 mmol/L reduction in the degree of hypokalemia increased hospitalisation length by 1.86 days. Though significant, acute kidney injury negligibly increased hospitalisation length by 0.01 days.
CONCLUSION: pH-adjusted potassium shall be used as a marker for hypokalemia and to initiate potassium replacement instead of measured serum potassium in DKA. Utilising pHK will help to avoid hypokalemia, reduce its severity and shorten ED care which will subsequently reduce hospitalisation length. We expect pHK to improve pharmacoeconomics in the future.
Relationship between Type A and B personality and debrisoquine hydroxylation capacity

Gan SH, Ismail R, Wan Adnan WA, Zulmi W, Kumaraswamy N, Larmie ET

Br J Clin Pharmacol, 2004 Jun;57(6):785-9.
PMID: 15151524

A person with Type A personality is an 'aggressor' compared with the rarely harried Type B. Although debrisoquine hydroxylase (CYP2D6) capacity has been associated with personality, no study has specifically investigated its association with personality Type A and B. Therefore the aim of this research was to study the impact of CYP2D6 on Type A and B personality.
Natural Products Combating Neurodegeneration: Parkinson's Disease

Solayman M, Islam MA, Alam F, Khalil MI, Kamal MA, Gan SH

Curr Drug Metab, 2017;18(1):50-61.
PMID: 27396919 DOI: 10.2174/1389200217666160709204826

Parkinson's disease (PD) is characterized by neurodegeneration and a progressive functional impairment of the midbrain nigral dopaminergic neurons. The cause remains unknown; however, several pathological processes and central factors, such as protein aggregation, mitochondrial dysfunction, iron accumulation, neuroinflammation and oxidative stress, have been reported. The current treatment method primarily targets symptoms by using anti-Parkinson drugs such as levodopa, carbidopa, dopamine (DA) agonists, monoamine oxidase type B inhibitors and anticholinergics to replace DA. When drug therapy is not satisfactory, surgical treatments are recommended. Unfortunately, the existing conventional strategies that target PD are associated with numerous side effects and possess an economic burden. Therefore, novel therapeutic approaches that regulate the pathways leading to neuronal death and dysfunction are necessary. For many years, nature has provided the primary resource for the discovery of potential therapeutic agents. Remarkably, many natural products from medicinal plants, fruits and vegetables have been demonstrated to be efficacious anti-Parkinson agents. These products possess neuroprotective properties as a result of not only their wellrecognized anti-oxidative and anti-inflammatory activities but also their inhibitory roles regarding iron accumulation, protein misfolding and the maintenance of proteasomal degradation, as well as mitochondrial homeostasis. The aim of this review is to report the available anti-Parkinson agents based on natural products and delineate their therapeutic actions, which act on various pathways. Overall, this review emphasizes the types of natural products that are potential future resources in the treatment of PD as novel regimens or supplementary agents.
Fulltext Familial primary antiphospholipid syndrome: A report of co-occurrence in three Malaysian family members

Islam MA, Wong KK, Sasongko TH, Gan SH, Wong JS

Eur J Rheumatol, 2016 Sep;3(3):139-141.
PMID: 27733946 DOI: 10.5152/eurjrheum.2015.0068

Here we present a case report of three familial primary antiphospholipid syndrome (PAPS) patients from Malaysia. The three familial patients comprised two females and one male with a mean age of 26.3 years. The first diagnosis was made between 2005 and 2009, and all patients demonstrated deep vein thrombosis, high levels of IgM and IgG anticardiolipin antibodies, and received warfarin treatment international normalized ratio (INR) 2.0-3.0. The patients ceased to show clinical symptoms after treatment. Recently (August 2014), we investigated whether the levels of antiphospholipid antibodies remained elevated, and we found that seronegativity occurred in the patients. We suspect that prolonged anticoagulant treatment might be one of the causes of reduced levels of antiphospholipid antibodies in these familial PAPS patients.
In silico analysis of nonsynonymous single nucleotide polymorphisms of the human adiponectin receptor 2 (ADIPOR2) gene

Solayman M, Saleh MA, Paul S, Khalil MI, Gan SH

Comput Biol Chem, 2017 Jun;68:175-185.
PMID: 28359874 DOI: 10.1016/j.compbiolchem.2017.03.005

Polymorphisms of the ADIPOR2 gene are frequently linked to a higher risk of developing diseases including obesity, type 2 diabetes and cardiovascular diseases. Though mutations of the ADIPOR2 gene are detrimental, there is a lack of comprehensive in silico analyses of the functional and structural impacts at the protein level. Considering the involvement of ADIPOR2 in glucose uptake and fatty acid oxidation, an in silico functional analysis was conducted to explore the possible association between genetic mutations and phenotypic variations. A genomic analysis of 82 nonsynonymous SNPs in ADIPOR2 was initiated using SIFT followed by the SNAP2, nsSNPAnalyzer, PolyPhen-2, SNPs&GO, FATHMM and PROVEAN servers. A total of 10 mutations (R126W, L160Q, L195P, F201S, L235R, L235P, L256R, Y328H, E334K and Q349H) were predicted to have deleterious effects on the ADIPOR2 protein and were therefore selected for further analysis. Theoretical models of the variants were generated by comparative modeling via MODELLER 9.16. A protein structural analysis of these amino acid variants was performed using SNPeffect, I-Mutant, ConSurf, Swiss-PDB Viewer and NetSurfP to explore their solvent accessibility, molecular dynamics and energy minimization calculations. In addition, FTSite was used to predict the ligand binding sites, while NetGlycate, NetPhos2.0, UbPerd and SUMOplot were used to predict post-translational modification sites. All of the variants showed increased free energy, though F201S exhibited the highest energy increase. The root mean square deviation values of the modeled mutants strongly indicated likely pathogenicity. Remarkably, three binding sites were detected on ADIPOR2, and two mutations at positions 328 and 201 were found in the first and second binding pockets, respectively. Interestingly, no mutations were found at the post-translational modification sites. These genetic variants can provide a better understanding of the wide range of disease susceptibility associated with ADIPOR2 and aid the development of new molecular diagnostic markers for these diseases. The findings may also facilitate the development of novel therapeutic elements for associated diseases.
Evaluation of factors affecting time to achieve dry weight among hemodialysis patients using bioimpedance spectroscopy

Khan A, Khan AH, Adnan AS, Sulaiman SAS, Ahmad N, Gan SH

Ir J Med Sci, 2019 Feb;188(1):311-319.
PMID: 29680929 DOI: 10.1007/s11845-018-1813-2

BACKGROUND: Achieving and maintaining dry weight appears to be an effective strategy for controlling and maintaining normotension among hypertensive patients on hemodialysis (HD).
OBJECTIVE: The present study aimed to determine the time at which the majority of patients achieve postdialysis dry weight using bioimpedance spectroscopy (BIS).
METHODS: A total of 220 HD patients were prospectively assessed for fluid overload using the Fresenius body composition monitor (BCM). BCM readings were taken at 30 and 45 min postdialysis.
RESULTS: Among the 220 patients included in this study, 120 (54.5%) achieved a euvolemic state at 30 min, and 25 (11.4%) achieved it at 45 min according to the BCM. In the multivariate analysis, vascular access other than arteriovenous fistula (AVF) (OR = 0.286, p value = 0.049) and cardiovascular disease (OR = 0.384, p value = 0.026) had a statistically significant negative association and receiving HD at Hospital Universiti Sains Malaysia (HUSM) (OR = 2.705, p value = 0.008) had a statistically significant positive association with achieving a euvolemic state at 30 min.
CONCLUSION: This suggests that assessing the hydration status at 45 min postdialysis in all patients or in those with identified risk factors for not achieving a euvolemic state at 30 min will provide a relatively accurate assessment for most patients.
Antiphospholipid antibodies in epilepsy: A systematic review and meta-analysis

Islam MA, Alam F, Cavestro C, Calcii C, Sasongko TH, Levy RA, et al.

Autoimmun Rev, 2018 Aug;17(8):755-767.
PMID: 29885542 DOI: 10.1016/j.autrev.2018.01.025

BACKGROUND: Autoimmunity is believed to play an important causative role in the pathogenesis of epilepsy. There are evidences for the presence of autoantibodies in patients with epilepsy. To date, many studies have assessed the presence of antiphospholipid antibodies (aPLs) in epilepsy patients, though the relationship has been inconclusive.

AIMS: The aim of this systematic review and meta-analysis was to evaluate the presence of aPLs in epileptic patients as compared to healthy controls.

METHODS: Five electronic databases (PubMed, Web of Science, Embase, Scopus and Google Scholar) were searched systematically. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using random-effects model. Quality assessment was carried out by using the modified 9-star Newcastle-Ottawa Scale (NOS). L'Abbé plots were generated to visually inspect heterogeneity while publication bias was evaluated via visualization of contour- enhanced funnel plots, and Begg's and Egger's tests.

RESULTS: Based on the inclusion criteria, 14 studies were selected involving 1248 epilepsy patients and 800 healthy controls. The majority of epilepsy was categorised as generalised or partial and none had comorbidity with autoimmune diseases. Significant presence of both anticardiolipin (aCL) antibodies (OR: 5.16, 95% CI: 3.21-8.28, p 
Thrombotic management of antiphospholipid syndrome: towards novel targeted therapies

Islam MA, Alam F, Wong KK, Kamal MA, Gan SH

Curr Vasc Pharmacol, 2017;15(4):313-326.
PMID: 28056758 DOI: 10.2174/1570161115666170105120931

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombosis and/or pregnancy morbidity with persistent levels of antiphospholipid antibodies (aPLs). The development of thrombosis in APS is mediated by aPLs and contributes to the high mortality rate in APS patients. However, although APS has been reported for more than 30 years, there has been no optimal regimen for its prevention or for the management of thrombosis, mainly because the mainstay treatment strategies for managing APS are not targeted towards aPL-mediated thrombotic pathophysiology. Instead, the treatments commonly used are aimed at general thrombotic disorders. Warfarin is the most commonly used vitamin K antagonist (VKA), in addition to anti-platelet medications, such as aspirin and clopidogrel. Over the last decade, novel non-VKA oral anticoagulants, including rivaroxaban, apixaban and dabigatran, as well as immunomodulatory agents, such as rituximab, eculizumab, hydroxychloroquine, statins and sirolimus, have also been used. In this review, we discuss the current treatment strategies and future treatment outlook for thrombotic APS.
Alzheimer's Disease and Natural Products: Future Regimens Emerging from Nature

Islam MA, Khandker SS, Alam F, Khalil MI, Kamal MA, Gan SH

Curr Top Med Chem, 2017;17(12):1408-1428.
PMID: 28049401 DOI: 10.2174/1568026617666170103163054

Alzheimer's disease (AD), which largely affects the elderly, has become a global burden. Patients with AD have both short- and long-term memory impairments. The neuronal loss in AD occurs due to abnormally folded amyloid beta proteins and aggregation of hyperphosphorylated tau proteins in the brain. Eventually, amyloid plaques and neurofibrillary tangles are formed, which subsequently disintegrate the neuronal transport system. There are several factors which are involved in AD pathogenesis, including oxidative stress, inflammation and the presence of metal ions. The modern therapies utilized for AD treatment have many adverse effects, driving the quest for more safe and effective medications. Many dietary components, including different types of fruits, vegetables, spices, and marine products as well as a Mediterranean diet, are a good source of antioxidants and have anti-inflammatory properties, with many showing substantial potential against AD pathogenesis. In this review, we discuss the potential of these foods for treating AD and opportunities for developing disease-targeted drugs from active compounds extracted from natural dietary products.
Therapeutic Suppression of Nonsense Mutation: An Emerging Target in Multiple Diseases and Thrombotic Disorders

Asiful Islam M, Alam F, Kamal MA, Gan SH, Wong KK, Sasongko TH

Curr Pharm Des, 2017;23(11):1598-1609.
PMID: 27875971 DOI: 10.2174/1381612823666161122142950

Nonsense mutations contribute to approximately 10-30% of the total human inherited diseases via disruption of protein translation. If any of the three termination codons (UGA, UAG and UAA) emerges prematurely [known as premature termination codon (PTC)] before the natural canonical stop codon, truncated nonfunctional proteins or proteins with deleterious loss or gain-of-function activities are synthesized, followed by the development of nonsense mutation-mediated diseases. In the past decade, PTC-associated diseases captured much attention in biomedical research, especially as molecular therapeutic targets via nonsense suppression (i.e. translational readthrough) regimens. In this review, we highlighted different treatment strategies of PTC targeting readthrough therapeutics including the use of aminoglycosides, ataluren (formerly known as PTC124), suppressor tRNAs, nonsense-mediated mRNA decay, pseudouridylation and CRISPR/Cas9 system to treat PTC-mediated diseases. In addition, as thrombotic disorders are a group of disease with major burdens worldwide, 19 potential genes containing a total of 705 PTCs that cause 21 thrombotic disorders have been listed based on the data reanalysis from the 'GeneCards® - Human Gene Database' and 'Human Gene Mutation Database' (HGMD®). These PTC-containing genes can be potential targets amenable for different readthrough therapeutic strategies in the future.
Fulltext Tualang Honey Protects the Rat Midbrain and Lung against Repeated Paraquat Exposure

Tang SP, Kuttulebbai Nainamohamed Salam S, Jaafar H, Gan SH, Muzaimi M, Sulaiman SA

Oxid Med Cell Longev, 2017;2017:4605782.
PMID: 28127418 DOI: 10.1155/2017/4605782

Paraquat (PQ) is a dopaminergic neurotoxin and a well-known pneumotoxicant that exerts its toxic effect via oxidative stress-mediated cellular injuries. This study investigated the protective effects of Tualang honey against PQ-induced toxicity in the midbrain and lungs of rats. The rats were orally treated with distilled water (2 mL/kg/day), Tualang honey (1.0 g/kg/day), or ubiquinol (0.2 g/kg/day) throughout the experimental period. Two weeks after the respective treatments, the rats were injected intraperitoneally with saline (1 mL/kg/week) or PQ (10 mg/kg/week) once per week for four consecutive weeks. After four weekly exposures to PQ, the glutathione peroxidase activity and the number of tyrosine-hydroxylase immunopositive neurons in the midbrain were significantly decreased in animals from group PQ (p < 0.05). The lungs of animals from group PQ showed significantly decreased activity of superoxide dismutase and glutathione-S-transferase. Treatment with Tualang honey ameliorated the toxic effects observed in the midbrain and lungs. The beneficial effects of Tualang honey were comparable to those of ubiquinol, which was used as a positive control. These findings suggest that treatment with Tualang honey may protect against PQ-induced toxicity in the rat midbrain and lung.
Dietary Phytochemicals: Natural Swords Combating Inflammation and Oxidation-Mediated Degenerative Diseases

Islam MA, Alam F, Solayman M, Khalil MI, Kamal MA, Gan SH

Oxid Med Cell Longev, 2016;2016:5137431.
PMID: 27721914

Cumulatively, degenerative disease is one of the most fatal groups of diseases, and it contributes to the mortality and poor quality of life in the world while increasing the economic burden of the sufferers. Oxidative stress and inflammation are the major pathogenic causes of degenerative diseases such as rheumatoid arthritis (RA), diabetes mellitus (DM), and cardiovascular disease (CVD). Although a number of synthetic medications are used to treat these diseases, none of the current regimens are completely safe. Phytochemicals (polyphenols, carotenoids, anthocyanins, alkaloids, glycosides, saponins, and terpenes) from natural products such as dietary fruits, vegetables, and spices are potential sources of alternative medications to attenuate the oxidative stress and inflammation associated with degenerative diseases. Based on in vitro, in vivo, and clinical trials, some of these active compounds have shown good promise for development into novel agents for treating RA, DM, and CVD by targeting oxidative stress and inflammation. In this review, phytochemicals from natural products with the potential of ameliorating degenerative disease involving the bone, metabolism, and the heart are described.
Fulltext Erratum to "Nonpharmacologic Interventions in Prevention and Treatment of Hypertension"

Erejuwa OO, Gan SH, Romani AMP, Kamal MA, Nammi S

Int J Hypertens, 2019 10 13;2019:2907675.
PMID: 31737360 DOI: 10.1155/2019/2907675

[This corrects the article DOI: 10.1155/2019/6709817.].
Implication of Physiological and Biochemical Variables of Prognostic Importance in Lead Exposed Subjects

Malik A, Ashraf MAB, Khan MW, Zahid A, Shafique H, Waquar S, et al.

Arch Environ Contam Toxicol, 2020 Apr;78(3):329-336.
PMID: 31620805 DOI: 10.1007/s00244-019-00673-2

The use of leaded gasoline adversely affects cardiovascular, nervous, and immune systems. Study projects to rule out different variables of prognostic importance in lead-exposed subjects. A total of 317 traffic wardens with 5 years of outdoor experience and Hb levels
Fulltext Efficacy and Safety of Pioglitazone Monotherapy in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomised Controlled Trials

Alam F, Islam MA, Mohamed M, Ahmad I, Kamal MA, Donnelly R, et al.

Sci Rep, 2019 03 29;9(1):5389.
PMID: 30926892 DOI: 10.1038/s41598-019-41854-2

Pioglitazone, the only thiazolidinedione drug in clinical practice is under scrutiny due to reported adverse effects, it's unique insulin sensitising action provides rationale to remain as a therapeutic option for managing type 2 diabetes mellitus (T2DM). We conducted a systematic review and meta-analysis comparing pioglitazone monotherapy with monotherapies of other oral antidiabetic drugs for assessing its efficacy and safety in T2DM patients. Mean changes in glycated haemoglobin (HbA1c), and mean changes in fasting blood sugar (FBS) level, body weight (BW) and homeostasis model assessment-insulin resistance (HOMA-IR) were primary and secondary outcomes, respectively. Safety outcomes were changes in lipid parameters, blood pressure and incidences of adverse events. Metafor package of R software and RevMan software based on random-effects model were used for analyses. We included 16 randomised controlled trials. Pioglitazone monotherapy showed equivalent efficacy as comparators in reducing HbA1c by 0.05% (95% CI: -0.21 to 0.11) and greater efficacy in reducing FBS level by 0.24 mmol/l (95% CI: -0.48 to -0.01). Pioglitazone showed similar efficacy as comparators in reducing HOMA-IR (WMD: 0.05, 95% CI: -0.49 to 0.59) and increasing high-density lipoprotein level (WMD: 0.02 mmol/l, 95% CI: -0.06 to 0.10). Improved blood pressure (WMD: -1.05 mmHg, 95% CI: -4.29 to 2.19) and triglycerides level (WMD: -0.71 mmol/l, 95% CI: -1.70 to 0.28) were also observed with pioglitazone monotherapy. There was a significant association of pioglitazone with increased BW (WMD: 2.06 kg, 95% CI: 1.11 to 3.01) and risk of oedema (RR: 2.21, 95% CI: 1.48 to 3.31), though the risk of hypoglycaemia was absolutely lower (RR: 0.51, 95% CI: 0.33 to 0.80). Meta-analysis supported pioglitazone as an effective treatment option for T2DM patients to ameliorate hyperglycaemia, adverse lipid metabolism and blood pressure. Pioglitazone is suggested to prescribe following individual patient's needs. It can be a choice of drug for insulin resistant T2DM patients having dyslipidaemia, hypertension or history of cardiovascular disease.
'Non-criteria' neurologic manifestations of antiphospholipid syndrome: a hidden kingdom to be discovered

Islam MA, Alam F, Kamal MA, Wong KK, Sasongko TH, Gan SH

CNS Neurol Disord Drug Targets, 2016;15(10):1253-1265.
PMID: 27658514 DOI: 10.2174/1871527315666160920122750

Neurological manifestations or disorders associated with the central nervous system are among the most common and important clinical characteristics of antiphospholipid syndrome (APS). Although in the most recently updated (2006) APS classification criteria, the neurological manifestations encompass only transient ischemic attack and stroke, diverse 'non-criteria' neurological disorders or manifestations (i.e., headache, migraine, bipolar disorder, transverse myelitis, dementia, chorea, epileptic seizures, multiple sclerosis, psychosis, cognitive impairment, Tourette's syndrome, parkinsonism, dystonia, transient global amnesia, obsessive compulsive disorder and leukoencephalopathy) have been observed in APS patients. To date, the underlying mechanisms responsible for these abnormal neurological manifestations in APS remain unclear. In vivo experiments and human observational studies indicate the involvement of thrombotic events and/or high titers of antiphospholipid antibodies in the neuro-pathogenic cascade of APS. Although different types of neurologic manifestations in APS patients have successfully been treated with therapies involving anti-thrombotic regimens (i.e., anticoagulants and/or platelet antiaggregants), antineuralgic drugs (i.e., antidepressants, antipsychotics and antiepileptics) and immunosuppressive drugs alone or in combination, evidence-based guidelines for the management of the neurologic manifestations of APS remain unavailable. Therefore, further experimental, clinical and retrospective studies with larger patient cohorts are warranted to elucidate the pathogenic linkage between APS and the central nervous system in addition to randomized controlled trials to facilitate the discovery of appropriate medications for the 'non-criteria' neurologic manifestations of APS.
Beneficial roles of honey polyphenols against some human degenerative diseases: A review

Hossen MS, Ali MY, Jahurul MHA, Abdel-Daim MM, Gan SH, Khalil MI

Pharmacol Rep, 2017 Dec;69(6):1194-1205.
PMID: 29128800 DOI: 10.1016/j.pharep.2017.07.002

Honey contains many active constituents and antioxidants such as polyphenols. Polyphenols are phytochemicals, a generic term for the several thousand plant-based molecules with antioxidant properties. Many in vitro studies in human cell cultures as well as many animal studies confirm the protective effect of polyphenols on a number of diseases such as cardiovascular diseases (CVD), diabetes, cancer, neurodegenerative diseases, pulmonary diseases, liver diseases and so on. Nevertheless, it is challenging to identify the specific biological mechanism underlying individual polyphenols and to determine how polyphenols impact human health. To date, several studies have attempted to elucidate the molecular pathway for specific polyphenols acting against particular diseases. In this review, we report on the various polyphenols present in different types of honey according to their classification, source, and specific functions and discuss several of the honey polyphenols with the most therapeutic potential to exert an effect on the various pathologies of some major diseases including CVD, diabetes, cancer, and neurodegenerative diseases.
Computational algorithmic and molecular dynamics study of functional and structural impacts of non-synonymous single nucleotide polymorphisms in human DHFR gene

Alam MS, Saleh MA, Mozibullah M, Riham AT, Solayman M, Gan SH

Comput Biol Chem, 2021 Dec;95:107587.
PMID: 34710812 DOI: 10.1016/j.compbiolchem.2021.107587

Human dihydrofolate reductase (DHFR) is a conserved enzyme that is central to folate metabolism and is widely targeted in pathogenic diseases as well as cancers. Although studies have reported the fact that genetic mutations in DHFR leads to a rare autosomal recessive inborn error of folate metabolism and drug resistance, there is a lack of an extensive study on how the deleterious non-synonymous SNPs (nsSNPs) disrupt its phenotypic effects. In this study, we aim at discovering the structural and functional consequences of nsSNPs in DHFR by employing a combined computational approach consisting of ten recently developed in silico tools for identification of damaging nsSNPs and molecular dynamics (MD) simulation for getting deeper insights into the magnitudes of damaging effects. Our study revealed the presence of 12 most deleterious nsSNPs affecting the native phenotypic effects, with three (R71T, G118D, Y122D) identified in the co-factor and ligand binding active sites. MD simulations also suggested that these three SNPs particularly Y122D, alter the overall structural flexibility and dynamics of the native DHFR protein which can provide more understandings into the crucial roles of these mutants in influencing the loss of DHFR function.

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