The diabetic brain and cognition.

The prevalence of both Alzheimer's disease (AD) and vascular dementia (VaD) is increasing with the aging of the population. Studies from the last several years have shown that people with diabetes have an increased risk for dementia and cognitive impairment. Therefore, the authors of this consensus review tried to elaborate on the role of diabetes, especially diabetes type 2 (T2DM) in both AD and VaD. Based on the clinical and experimental work of scientists from 18 countries participating in the International Congress on Vascular Disorders and on literature search using PUBMED, it can be concluded that T2DM is a risk factor for both, AD and VaD, based on a pathology of glucose utilization. This pathology is the consequence of a disturbance of insulin-related mechanisms leading to brain insulin resistance. Although the underlying pathological mechanisms for AD and VaD are different in many aspects, the contribution of T2DM and insulin resistant brain state (IRBS) to cerebrovascular disturbances in both disorders cannot be neglected. Therefore, early diagnosis of metabolic parameters including those relevant for T2DM is required. Moreover, it is possible that therapeutic options utilized today for diabetes treatment may also have an effect on the risk for dementia. T2DM/IRBS contribute to pathological processes in AD and VaD.

Observations on the expression of human papillomavirus major capsid protein in HeLa cells.

BACKGROUND: The goal of this study was to identify the nature of the inclusion bodies that have been found in HeLa cells (cervical cancer immortal cell line) by electron microscope and to determine whether the major capsid protein (L1) of human papillomavirus (HPV) can be expressed in HPV-positive uterine cervix cancer cells. METHODS: HPV L1 protein expression in HeLa cells was detected with anti-HPV L1 multivalent mice monoclonal antibody and rabbit polyclonal anti-HPV L1 antibody by ELISA, light microscope immunohistochemistry, electron microscope immunocytochemistry and Western blotting assays. Reverse transcriptional PCR (RT-PCR) was performed to detect the transcription of L1 mRNA in HeLa cells. The immortalized human keratinocyte HeCat was used as the negative control. RESULTS: HPV L1 proteins reacted positively in the lysate of HeLa cells by ELISA assays. HRP labeled light microscope immunohistochemistry assay showed that there was a strong HPV L1 positive reaction in HeLa cells. Under the electron microscope, irregular shaped inclusion bodies, assembled by many small and uniform granules, had been observed in the cytoplasm of some HeLa cells. These granules could be labeled by the colloidal gold carried by HPV L1 antibody. The Western blotting assay showed that there was a L1 reaction strap at 80-85 kDa in the HeLa cell lysates, hence demonstrating the existence of HPV18 L1 in HeLa cells. RT-PCR assay showed that the L1 mRNA was transcribed in HeLa cells. CONCLUSIONS: The inclusion bodies found in the cytoplasm of HeLa cells are composed of HPV18 L1 protein. Since HeLa cell line is a type of cervical cancer cells, this implies that HeLa cells have the ability to express HPV L1 proteins.

Combination of selenium-enriched green tea polysaccharides and Huo-ji polysaccharides synergistically enhances antioxidant and immune activity in mice.

BACKGROUND: The aim of this study was to investigate the influence of a combination of selenium-enriched green tea polysaccharides (Se-GTP) and Huo-ji polysaccharides (HJP) on the immune function and antioxidant activity in mice. RESULTS: The results showed that the indices of spleen and thymus were markedly increased, and the activity of natural killer (NK) cell was promoted in mice treated with the combination of Se-GTP and HJP. The combined treatment of Se-GTP and HJP also reduced the content of tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in splenocytes. In addition, the activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD) were remarkably enhanced, and malondialdehyde (MDA) levels were significantly reduced in mice treated with combination of Se-GTP and HJP. Furthermore, the combined treatment of Se-GTP and HJP increased nuclear factor erythroid 2-related factor (Nrf2) expression at mRNA and protein levels in splenocytes. The effects of the combination treatment of Se-GTP and HJP in mice were stronger than with Se-GTP or HJP treatment alone. CONCLUSION: Our study suggests that the combined administration of Se-GTP and HJP can synergistically improve immune function and decrease the oxidative stress by enhancing the mechanisms involved in the clearance of free radicals.

The Role of Non-coding RNAs in Alzheimer's Disease: Pathogenesis, Novel Biomarkers, and Potential Therapeutic Targets

OBJECTIVE: Long non-coding RNAs (IncRNAs) are regulatory RNA transcripts that have recently been associated with the onset of many neurodegenerative illnesses, including Alzheimer's disease (AD). Several IncRNAs have been found to be associated with AD pathophysiology, each with a distinct mechanism. In this review, we focused on the role of IncRNAs in the pathogenesis of AD and their potential as novel biomarkers and therapeutic targets. METHODS: Searching for relevant articles was done using the PubMed and Cochrane library databases. Studies had to be published in full text in English in order to be considered. RESULTS: Some IncRNAs were found to be upregulated, while others were downregulated. Dysregulation of IncRNAs expression may contribute to AD pathogenesis. Their effects manifest as the synthesis of beta-amyloid (Aß) plaques increases, thereby altering neuronal plasticity, inducing inflammation, and promoting apoptosis. CONCLUSION: Despite the need for more investigations, IncRNAs could potentially increase the sensitivity of early detection of AD. Until now, there has been no effective treatment for AD. Hence, InRNAs are promising molecules and may serve as potential therapeutic targets. Although several dysregulated AD-associated lncRNAs have been discovered, the functional characterization of most lncRNAs is still lacking.

Reviewing methods of deep learning for diagnosing COVID-19, its variants and synergistic medicine combinations.

The COVID-19 pandemic has necessitated the development of reliable diagnostic methods for accurately detecting the novel coronavirus and its variants. Deep learning (DL) techniques have shown promising potential as screening tools for COVID-19 detection. In this study, we explore the realistic development of DL-driven COVID-19 detection methods and focus on the fully automatic framework using available resources, which can effectively investigate various coronavirus variants through modalities. We conducted an exploration and comparison of several diagnostic techniques that are widely used and globally validated for the detection of COVID-19. Furthermore, we explore review-based studies that provide detailed information on synergistic medicine combinations for the treatment of COVID-19. We recommend DL methods that effectively reduce time, cost, and complexity, providing valuable guidance for utilizing available synergistic combinations in clinical and research settings. This study also highlights the implication of innovative diagnostic technical and instrumental strategies, exploring public datasets, and investigating synergistic medicines using optimised DL rules. By summarizing these findings, we aim to assist future researchers in their endeavours by providing a comprehensive overview of the implication of DL techniques in COVID-19 detection and treatment. Integrating DL methods with various diagnostic approaches holds great promise in improving the accuracy and efficiency of COVID-19 diagnostics, thus contributing to effective control and management of the ongoing pandemic.

A Review of the Rational and Current Evidence on Colchicine for COVID-19.

The current coronavirus disease (COVID-19) pandemic has affected millions of individuals worldwide. Despite extensive research efforts, few therapeutic options currently offer direct clinical benefits for COVID-19 patients. Despite the advances in our understanding of COVID-19, the mortality rates remain significantly high owing to the high viral transmission rates in several countries and the rise of various mutations in the SARS-CoV-2. One currently available and widely used drug that combines both anti-inflammatory and immunomodulatory actions is colchicine, which has been proposed as a possible treatment option for COVID-19. Colchicine still did not get much attention from the medical and scientific communities despite its antiinflammatory and immunomodulatory mechanisms of action and positive preliminary data from early trials. This literature review article provides the scientific rationale for repurposing colchicine as a potential therapy for COVID-19. Further, we summarize colchicine's mechanisms of action and possible roles in COVID-19 patients. Finally, we supplement this review with a summary of the doses, side effects, and early efficacy data from clinical trials to date. Despite the promising early findings from multiple observational and clinical trials about the potential of colchicine in COVID-19, the data from the RECOVERY trial, the largest COVID-19 randomized controlled trial (RCT) in the world, showed no evidence of clinical benefits in mortality, hospital stays, or disease progression (n = 11340 patients). However, multiple other smaller clinical trials showed significant clinical benefits. We conclude that while current evidence does not support the use of colchicine for treating COVID-19, the present body of evidence is heterogeneous and inconclusive. The drug cannot be used in clinical practice or abandoned from clinical research without additional large RCTs providing more robust evidence. At present, the drug should not be used except for investigational purposes.

Research progress of CRISPR-based biosensors and bioassays for molecular diagnosis.

CRISPR/Cas technology originated from the immune mechanism of archaea and bacteria and was awarded the Nobel Prize in Chemistry in 2020 for its success in gene editing. Molecular diagnostics is highly valued globally for its development as a new generation of diagnostic technology. An increasing number of studies have shown that CRISPR/Cas technology can be integrated with biosensors and bioassays for molecular diagnostics. CRISPR-based detection has attracted much attention as highly specific and sensitive sensors with easily programmable and device-independent capabilities. The nucleic acid-based detection approach is one of the most sensitive and specific diagnostic methods. With further research, it holds promise for detecting other biomarkers such as small molecules and proteins. Therefore, it is worthwhile to explore the prospects of CRISPR technology in biosensing and summarize its application strategies in molecular diagnostics. This review provides a synopsis of CRISPR biosensing strategies and recent advances from nucleic acids to other non-nucleic small molecules or analytes such as proteins and presents the challenges and perspectives of CRISPR biosensors and bioassays.

Glycosides as Possible Lead Antimalarial in New Drug Discovery: Future Perspectives.

Malaria remains one of the major public health problems worldwide and it is responsible for a large number of morbidity and mortality. Especially, in the third world countries, it is still alarming. The development of drugresistant to Plasmodium falciparum strains has further degraded the overall situation. However, a limited number of effective drugs available emphasize how essential it is to establish new anti-malarial compounds. New antimalarial agents with distinctive structures and mechanism of action from the natural origin are thus immediately required to treat sensitive and drug-resistant strains of malaria. Over the years, phytopharmaceuticals have provided numerous lead compounds. Similarly, the success rate of botanicals in terms of clinical significance is also very high. Of them, glycoside is one of the most widely distributed and emerging class of plant secondary metabolites. This review provides an outlook to recently isolated glycosides from plants with marked antimalarial effects in an in-vitro and in-vivo protocols and thus ideal candidates for clinical trials to ascertain their clinical utility and or led compounds.

In silico Analysis of AMP-activated Protein Kinase and Ligand-based Virtual Screening for Identification of Novel AMPK Activators.

BACKGROUND: Adenosine-Monophosphate-Activated protein kinase (AMPK) is a conserved kinase that plays an important role in maintaining the homeostasis of cells. AMPK activation has a positive impact on treatment of diseases such as diabetes, obesity and cancer as well. This observation led to the development of AMPK activators. Certain naturally occurring compounds have also been known to activate AMPK. METHODS: In this study, we retrieved the AMPK activators that include chemical drugs, xenobiotics and natural compounds and analyzed their interactions with AMPK via docking studies. Using this ligand dataset, a pharmacophore model was generated based upon ligand-based pharmacophore modeling strategy. The generated pharmacophore model was used to screen a library of ZINC database. The new hits which share the properties of our pharmacophore model were further analyzed via docking studies. RESULTS: This study led to the identification of new chemical compounds which has the potential to activate AMPK. Even some of the screened hits showed better binding energies as compared to that of the ligand dataset used thus having the potential to activate AMPK more efficiently. The promising hits obtained after virtual screening of ZINC database were also checked against the Lipinski's rule of five. CONCLUSION: Compound 7 out of the 10 compounds showed best binding energies even more efficient than the ligand dataset itself.

In silico analysis of glycinamide ribonucleotide transformylase inhibition by PY873, PY899 and DIA.

In humans, purine de novo synthesis pathway consists of multi-functional enzymes. Nucleotide metabolism enzymes are potential drug targets for treating cancer and autoimmune diseases. Glycinamide ribonucleotide transformylase (GART) is one of the most important trifunctional enzymes involved in purine synthesis. Previous studies have demonstrated the role of folate inhibitors against tumor activity. In this present study, three components of GART enzyme were targeted as receptor dataset and in silico analysis was carried out with folate ligand dataset. To accomplish the task, Autodock 4.2 was used for determining the docking compatibilities of ligand and receptor dataset. Taken together, it has been suggested that folate ligands could be potentially used as inhibitors of GART.

Commonalities in Biological Pathways, Genetics, and Cellular Mechanism between Alzheimer Disease and Other Neurodegenerative Diseases: An In Silico-Updated Overview.

BACKGROUND: Alzheimer's disease (AD) is the most common and well-studied neurodegenerative disease (ND). Biological pathways, pathophysiology and genetics of AD show commonalities with other NDs viz. Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Prion disease and Dentatorubral-pallidoluysian atrophy (DRPLA). Many of the NDs, sharing the common features and molecular mechanisms suggest that pathology may be directly comparable and be implicated in disease prevention and development of highly effective therapies. METHOD: In this review, a brief description of pathophysiology, clinical symptoms and available treatment of various NDs have been explored with special emphasis on AD. Commonalities in these fatal NDs provide support for therapeutic advancements and enhance the understanding of disease manifestation. CONCLUSION: The studies concentrating on the commonalities in biological pathways, cellular mechanisms and genetics may provide the scope to researchers to identify few novel common target(s) for disease prevention and development of effective common drugs for multi-neurodegenerative diseases.

Pharmacophore-Based Virtual Screening for Identification of Novel Neuraminidase Inhibitors and Verification of Inhibitory Activity by Molecular Docking.

Oseltamivir and Zanamivir are two of the recently licensed neuraminidase inhibitors used for the treatment of influenza. However, alternative antiviral agents are needed due to the development of resistant mutations in Oseltamivir subtype H1N1 and H5N1 avian influenza A viruses, the latter being a highly pathogenic avian virus that can be transferred to humans upon immediate contact with H5N1 infected poultry or surface. Novel drug inhibiting group 1 neuraminidases may potentially be developed through addition of extra substituent moieties to existing inhibitor skeletons. Another approach involves virtual screening of existing inhibitor skeletons which we have reported using novel ligands of H5N1 via virtual screening approach. In this study, we have used 3D structure of avian influenza virus H5N1 neuraminidase as target against a ligand dataset of four known neuraminidase inhibitors for in silico analysis. Using the dataset of known four inhibitors, a pharmacophore model was developed using ligand-based pharmacophore modeling strategy. This pharmacophore model was then used for virtual screening of natural compounds library taken from Princeton database. New hits that shared features of our pharmacophore model and binding interactions with receptor residues have been reported in this study. As more antiviral agents are required, the reported hits in our study may play an important role as novel antiviral agents against influenza virus.

The Role of Endoproteolytic Processing in Neurodegeneration.

Endoproteolysis is a normal post-translational process in the eukaryotic cell that plays a role in protein evolution allowing protein catabolism and the generation of amino acids. Endoproteolytic cleavage regulates many crucial cellular processes including the activity of many proteins, their protein-protein interactions and the amplification of cell signals. Not surprisingly, disruption or alternation of endoproteolytic cleavage may be the root cause of many human diseases such as Alzheimer's disease, Huntington's disease and prion diseases. Most neurodegenerative diseases (ND) are caused by the build-up of misfolded proteins and the promotion of aggregation events. A common event that occurs in these ND is the alteration of endoproteolytic cleavage due to genetic mutations of the associated-proteases or target substrate. Endoproteolytic cleavage resulting in protein truncation has significant effects on the structure and function of a protein representing a common feature of ND. In this review, we will discuss the endoproteolytic cleavage events that lead to ND, namely Alzheimer's disease, Huntington's disease and prion diseases.

Alkaloids: An Emerging Antibacterial Modality Against Methicillin Resistant Staphylococcus aureus.

Methicillin-Resistant Staphylococcus aureus (MRSA) is a Gram-positive bacterium which causes community and hospital-acquired infections. Synthetic drug/antibiotic treatment for MRSA-related infections is becoming less effective and natural products may be an emerging new alternative for future antibacterial drug development. Alkaloids are a class of natural compounds which are known for their phytochemistry and pharmacology. This review focuses on 32 alkaloids isolated from various plants that showed marked antibacterial activity against MRSA by acting through different mechanisms such as inhibition of pyruvate kinase, Quorum quenching effect, alteration in efflux pump in MRSA and intercalating of bacterial DNA, to name just a few. In addition, the use of recent plant alkaloids against clinical isolates of MRSA has also been discussed.

Psychopharmacology of Attention-Deficit Hyperactivity Disorder: Effects and Side Effects.

Attention-deficit hyperactivity disorder (ADHD) is a common psychiatric disorder in children which manifests with hyperactivity, impulsivity, and/or inattention. Several drugs are used in treatment of ADHD. Stimulants, atomoxetine, anti-depressants, and bupropion are common medications used in the treatment of ADHD. Stimulants are widely used as the first line treatment in children with ADHD. Their mechanism of action is the release of dopamine and norepinephrine in central nervous system. Methylphenidate is the most common stimulant used for the treatment of ADHD. Methylphenidate significantly reduces ADHD symptoms in children both at home and school and improves their social skills. Methylphenidate is safe in healthy children and has shown to have no cardiac side effects in these patients. Other medications include: Atomoxetine, Amphetamines, Clonidine, Melatonin, and anti-depressants. Effects, side effects, and mechanism of action these drugs have been discussed in this paper.

Inflammatory Process in Alzheimer's and Parkinson's Diseases: Central Role of Cytokines.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most widespread neurological disorders (NDs) characterized by degeneration of cognitive and motor functions due to malfunction and loss of neurons in the central nervous system (CNS). Numerous evidences have established the role of neuroinflammation in the AD and PD pathology. The inflammatory components such as microglia, astrocytes, complement system and cytokines are linked to neuroinflammation in the CNS. More specifically, cytokines have been found to play a central role in the neuroinflammation of AD and PD. A number of studies have demonstrated abnormally elevated levels of inflammatory cytokines such as interleukin-1ß (IL-1ß) and tumor necrosis factor (TNF) in AD and PD patients. Activated microglial cells have been shown to be involved in the secretion of pro-inflammatory cytokines such as IL-1, IL-6, TNF-α and transforming growth factor-ß, thereby contributing towards the progress of NDs. In addition, studies on AD pathogenesis have demonstrated that microglia produce beta-amyloid protein (Aß), which by itself is pro-inflammatory and causes activation of several inflammatory components. Similarly, chronic inflammation caused by microglial cells is the fundamental process involved in the destruction of neurons associated with dopamine (DA)-production in the brain of PD patients. Hence, there is a need to explore the key inflammatory components in AD and PD pathogenesis in order to fully understand the root cause and establish a substantial link between these two disorders. Such knowledge will help in better management and treatment of AD and PD.

Current Understanding of HSP90 as a Novel Therapeutic Target: An Emerging Approach for the Treatment of Cancer.

Heat Shock Protein 90 (HSP90) is a ubiquitous molecular chaperone that is considered to be the most abundantly expressed protein in various human cancers such as breast, lung, colon, prostate, leukemia and skin. The master regulator, HSP90 plays a pivotal role in the conformational stabilization, maturation and activity of its various labile oncogenic client proteins such as p53, ErbB2, Bcr-Abl, Akt, Her-2, Cdk4, Cdk6, Raf-1 and v-Src in altered cells. Hence, making a guaranteed attempt to inhibit such a master regulator for cancer therapy appears to be a potential approach for combinatorial inhibition of numerous oncogenic signaling pathways simultaneously. Considerable efforts are being under way to develop novel molecular targets and its inhibitors that may block key signaling pathways involved in the process of tumorigenesis and metastasis. In this regards, HSP90 has acquired immense interest as a potent anticancer drug-target due to its key functional link with multiple signaling pathways involved in the process of cell proliferation and cell survival. Notably, geldanamycin and its derivatives (17-AAG, 17-DMAG) have shown quite encouraging results in inhibiting HSP90 function in several cancers and currently almost 17 drug candidates known to be target HSP90 are being under clinical trials either as single agents or combinatorial therapy. Hence, this review is an attempt to get new insight into novel drug target therapy by focusing on recent advances made in understanding HSP90 chaperone structure-function relationships, identification of new HSP90 client proteins and, more importantly, on the advancements of HSP90 targeted therapy based on various existing and emerging classical inhibitors.

Alzheimer's Disease and Autistic Spectrum Disorder: Is there any Association?

Autism spectrum disorder (ASD) and Alzheimer's disease (AD) are neurodevelopmental and neurodegenerative disorders respectively, with devastating effects not only on the individual but also the society. Collectively, a number of factors contribute to the expression of ASD and AD. It is of utmost curiosity that these disorders express at different stages of life and there is an involvement of certain susceptible genes. This genetic basis makes the background of common associations like memory deficits, cognition changes, demyelination, oxidative stress and inflammation, an integral part of both disorders. Modern technology resulting in genetically modified crops and increase in gadgets emitting electromagnetic frequencies have resulted in enhanced risks for neurological dysfunctions and disorders like ASD and AD. Subsequent advances in the psychological, pharmacological, biochemical and nutritional aspects of the disorders have resulted in the development of newer therapeutic approaches. The common clinical features like language impairment, executive functions, and motor problems have been discussed along with the patho-physiological changes, role of DNA methylation, myelin development, and heavy metals in the expression of these disorders. Psychopharmacological and nutritional approaches towards the reduction and management of risk factors have gained attention from the researchers in recent years. Current major therapies either target the inflammatory pathways or reduce cellular oxidative stress. This contribution focuses on the commonalities of the two disorders.

Inhibition on the growth of human MDA-MB-231 breast cancer cells in vitro and tumor growth in a mouse xenograft model by Se-containing polysaccharides from Pyracantha fortuneana.

Breast cancer is the second cause of cancer-related death among Women. Current therapies for breast cancer have adverse side-effects. Selenium (Se)-containing polysaccharides have multiple health benefits to humans. Pyracantha fortuneana (P. fortuneana) contains rich Se polysaccharides. We hypothesized that Se-containing polysaccharides from P. fortuneana possess anticancer activity on breast cancer via inhibiting growth and inducing apoptosis. This study aimed to assess the anticancer effect of Se-containing polysaccharides from P. fortuneana and the underlying mechanisms. Se-containing polysaccharides were purified. Their properties and monosaccharide compositions were analyzed. Their effects on cell growth, expression of cycle proteins, apoptosis and apoptosis-related protein, and tumor growth in mouse xenograft model were examined. This extract contained 93.7% (w/w) of carbohydrate, 2.1% (w/w) of uronic acid and 3.7µg/g of Se, and was considered as Se-conjugated polysaccharides (Se-PFPs). In vitro studies showed that treatment of triple negative breast cancer (TNBC) MDA-MB-231 cells with Se-PFPs (1) inhibited cell growth dose-dependently by arresting cells at G2 phase via inhibiting CDC25C-CyclinB1/CDC2 pathway; (2) caused apoptosis associated with increased p53, Bax, Puma and Noxa, decreased Bcl2, increased Bax/Bcl2 ratio and increased activities of caspases 3/9, suggesting its effect on p53-mediated cytochrome c-caspase pathway. Treatment of nude mice bearing MDA-MB-231-derived xenograft tumors with Se-PFPs significantly reduced tumor growth without altering body weight, confirming its antitumor activity without toxic side effects. Se-PFPs enhanced doxorubicin cytotoxic effects. It is concluded that Se-containing polysaccharides from P. fortuneana potently inhibit the growth and induce apoptosis of TNBC cells and can be potential anticancer agent for TNBC.