A random forest model for predicting exosomal proteins using evolutionary information and motifs.

Non-invasive diagnostics and therapies are crucial to prevent patients from undergoing painful procedures. Exosomal proteins can serve as important biomarkers for such advancements. In this study, we attempted to build a model to predict exosomal proteins. All models are trained, tested, and evaluated on a non-redundant dataset comprising 2831 exosomal and 2831 non-exosomal proteins, where no two proteins have more than 40% similarity. Initially, the standard similarity-based method Basic Local Alignment Search Tool (BLAST) was used to predict exosomal proteins, which failed due to low-level similarity in the dataset. To overcome this challenge, machine learning (ML) based models were developed using compositional and evolutionary features of proteins achieving an area under the receiver operating characteristics (AUROC) of 0.73. Our analysis also indicated that exosomal proteins have a variety of sequence-based motifs which can be used to predict exosomal proteins. Hence, we developed a hybrid method combining motif-based and ML-based approaches for predicting exosomal proteins, achieving a maximum AUROC of 0.85 and MCC of 0.56 on an independent dataset. This hybrid model performs better than presently available methods when assessed on an independent dataset. A web server and a standalone software ExoProPred (https://webs.iiitd.edu.in/raghava/exopropred/) have been created to help scientists predict and discover exosomal proteins and find functional motifs present in them.

ToxinPred2: an improved method for predicting toxicity of proteins.

Proteins/peptides have shown to be promising therapeutic agents for a variety of diseases. However, toxicity is one of the obstacles in protein/peptide-based therapy. The current study describes a web-based tool, ToxinPred2, developed for predicting the toxicity of proteins. This is an update of ToxinPred developed mainly for predicting toxicity of peptides and small proteins. The method has been trained, tested and evaluated on three datasets curated from the recent release of the SwissProt. To provide unbiased evaluation, we performed internal validation on 80% of the data and external validation on the remaining 20% of data. We have implemented the following techniques for predicting protein toxicity; (i) Basic Local Alignment Search Tool-based similarity, (ii) Motif-EmeRging and with Classes-Identification-based motif search and (iii) Prediction models. Similarity and motif-based techniques achieved a high probability of correct prediction with poor sensitivity/coverage, whereas models based on machine-learning techniques achieved balance sensitivity and specificity with reasonably high accuracy. Finally, we developed a hybrid method that combined all three approaches and achieved a maximum area under receiver operating characteristic curve around 0.99 with Matthews correlation coefficient 0.91 on the validation dataset. In addition, we developed models on alternate and realistic datasets. The best machine learning models have been implemented in the web server named 'ToxinPred2', which is available at https://webs.iiitd.edu.in/raghava/toxinpred2/ and a standalone version at https://github.com/raghavagps/toxinpred2. This is a general method developed for predicting the toxicity of proteins regardless of their source of origin.

AntiCP 2.0: an updated model for predicting anticancer peptides.

Increasing use of therapeutic peptides for treating cancer has received considerable attention of the scientific community in the recent years. The present study describes the in silico model developed for predicting and designing anticancer peptides (ACPs). ACPs residue composition analysis show the preference of A, F, K, L and W. Positional preference analysis revealed that residues A, F and K are favored at N-terminus and residues L and K are preferred at C-terminus. Motif analysis revealed the presence of motifs like LAKLA, AKLAK, FAKL and LAKL in ACPs. Machine learning models were developed using various input features and implementing different machine learning classifiers on two datasets main and alternate dataset. In the case of main dataset, dipeptide composition based ETree classifier model achieved maximum Matthews correlation coefficient (MCC) of 0.51 and 0.83 area under receiver operating characteristics (AUROC) on the training dataset. In the case of alternate dataset, amino acid composition based ETree classifier performed best and achieved the highest MCC of 0.80 and AUROC of 0.97 on the training dataset. Five-fold cross-validation technique was implemented for model training and testing, and their performance was also evaluated on the validation dataset. Best models were implemented in the webserver AntiCP 2.0, which is freely available at https://webs.iiitd.edu.in/raghava/anticp2/. The webserver is compatible with multiple screens such as iPhone, iPad, laptop and android phones. The standalone version of the software is available at GitHub; docker-based container also developed.

Computer-aided prediction and design of IL-6 inducing peptides: IL-6 plays a crucial role in COVID-19.

Interleukin 6 (IL-6) is a pro-inflammatory cytokine that stimulates acute phase responses, hematopoiesis and specific immune reactions. Recently, it was found that the IL-6 plays a vital role in the progression of COVID-19, which is responsible for the high mortality rate. In order to facilitate the scientific community to fight against COVID-19, we have developed a method for predicting IL-6 inducing peptides/epitopes. The models were trained and tested on experimentally validated 365 IL-6 inducing and 2991 non-inducing peptides extracted from the immune epitope database. Initially, 9149 features of each peptide were computed using Pfeature, which were reduced to 186 features using the SVC-L1 technique. These features were ranked based on their classification ability, and the top 10 features were used for developing prediction models. A wide range of machine learning techniques has been deployed to develop models. Random Forest-based model achieves a maximum AUROC of 0.84 and 0.83 on training and independent validation dataset, respectively. We have also identified IL-6 inducing peptides in different proteins of SARS-CoV-2, using our best models to design vaccine against COVID-19. A web server named as IL-6Pred and a standalone package has been developed for predicting, designing and screening of IL-6 inducing peptides (https://webs.iiitd.edu.in/raghava/il6pred/).

AlgPred 2.0: an improved method for predicting allergenic proteins and mapping of IgE epitopes.

AlgPred 2.0 is a web server developed for predicting allergenic proteins and allergenic regions in a protein. It is an updated version of AlgPred developed in 2006. The dataset used for training, testing and validation consists of 10 075 allergens and 10 075 non-allergens. In addition, 10 451 experimentally validated immunoglobulin E (IgE) epitopes were used to identify antigenic regions in a protein. All models were trained on 80% of data called training dataset, and the performance of models was evaluated using 5-fold cross-validation technique. The performance of the final model trained on the training dataset was evaluated on 20% of data called validation dataset; no two proteins in any two sets have more than 40% similarity. First, a Basic Local Alignment Search Tool (BLAST) search has been performed against the dataset, and allergens were predicted based on the level of similarity with known allergens. Second, IgE epitopes obtained from the IEDB database were searched in the dataset to predict allergens based on their presence in a protein. Third, motif-based approaches like multiple EM for motif elicitation/motif alignment and search tool have been used to predict allergens. Fourth, allergen prediction models have been developed using a wide range of machine learning techniques. Finally, the ensemble approach has been used for predicting allergenic protein by combining prediction scores of different approaches. Our best model achieved maximum performance in terms of area under receiver operating characteristic curve 0.98 with Matthew's correlation coefficient 0.85 on the validation dataset. A web server AlgPred 2.0 has been developed that allows the prediction of allergens, mapping of IgE epitope, motif search and BLAST search (https://webs.iiitd.edu.in/raghava/algpred2/).

The Role of Mitophagy in Various Neurological Diseases as a Therapeutic Approach.

Mitochondria are critical to multiple cellular processes, from the production of adenosine triphosphate (ATP), maintenance of calcium homeostasis, synthesis of key metabolites, and production of reactive oxygen species (ROS) to maintain necrosis, apoptosis, and autophagy. Therefore, proper clearance and regulation are essential to maintain various physiological processes carried out by the cellular mechanism, including mitophagy and autophagy, by breaking down the damaged intracellular connections under the influence of various genes and proteins and protecting against various neurodegenerative diseases such as Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), and Huntington disease (HD). In this review, we will discuss the role of autophagy, selective macroautophagy, or mitophagy, and its role in neurodegenerative diseases along with normal physiology. In addition, this review will provide a better understanding of the pathways involved in neuron autophagy and mitophagy and how mutations affect these pathways in the various genes involved in neurodegenerative diseases. Various new findings indicate that the pathways that remove dysfunctional mitochondria are impaired in these diseases, leading to the deposition of damaged mitochondria. Apart from that, we have also discussed the therapeutic strategies targeting autophagy and mitophagy in neurodegenerative diseases. The mitophagy cycle results in the degradation of damaged mitochondria and the biogenesis of new healthy mitochondria, also highlighting different stages at which a particular neurodegenerative disease could occur.

Biochemical and in silico molecular study of caffeic acid-O-methyltransferase enzyme associated with lignin deposition in tall fescue.

Caffeic acid-O-methyltransferase (COMT), an important enzyme governing the process of lignification in plants, functions at the level of caffeic acid methylation along with 3-O-methylation of monolignol precursors. The present investigation was carried out to decipher the role of COMT in tall fescue lignification and to clone and characterize the COMT gene. The study on COMT activity variation at different growth stages of tall fescue exhibited a significant increase in activity over all the growth stages of tall fescue. A significant relative increase of 47.8% was observed from the first vegetative to reproductive stage. COMT activity exhibited a strong positive correlation with lignin content suggesting it to be an important enzyme of tall fescue lignification. Amplification and sequencing of tall fescue COMT gene resulted in an amplicon of size 1662 (Accession No.-MW442832) and an ORF of 346 amino acids. The deduced protein was hydrophobic, thermally stable and acidic with molecular formula C1679H2623N445O482S20, molecular mass 37.4 kDa and theoretical pI of 6.12. The protein possesses a conserved dimerization domain with a highly conserved SAM binding site. The COMT protein was found to be a homo-dimer with 1 catalytic SAH/SAM ligand per monomer interacting with 14 amino acid residues within 4 Å region.

Cellular Responses to Widespread DNA Replication Stress.

Replicative DNA polymerases are blocked by nearly all types of DNA damage. The resulting DNA replication stress threatens genome stability. DNA replication stress is also caused by depletion of nucleotide pools, DNA polymerase inhibitors, and DNA sequences or structures that are difficult to replicate. Replication stress triggers complex cellular responses that include cell cycle arrest, replication fork collapse to one-ended DNA double-strand breaks, induction of DNA repair, and programmed cell death after excessive damage. Replication stress caused by specific structures (e.g., G-rich sequences that form G-quadruplexes) is localized but occurs during the S phase of every cell division. This review focuses on cellular responses to widespread stress such as that caused by random DNA damage, DNA polymerase inhibition/nucleotide pool depletion, and R-loops. Another form of global replication stress is seen in cancer cells and is termed oncogenic stress, reflecting dysregulated replication origin firing and/or replication fork progression. Replication stress responses are often dysregulated in cancer cells, and this too contributes to ongoing genome instability that can drive cancer progression. Nucleases play critical roles in replication stress responses, including MUS81, EEPD1, Metnase, CtIP, MRE11, EXO1, DNA2-BLM, SLX1-SLX4, XPF-ERCC1-SLX4, Artemis, XPG, FEN1, and TATDN2. Several of these nucleases cleave branched DNA structures at stressed replication forks to promote repair and restart of these forks. We recently defined roles for EEPD1 in restarting stressed replication forks after oxidative DNA damage, and for TATDN2 in mitigating replication stress caused by R-loop accumulation in BRCA1-defective cells. We also discuss how insights into biological responses to genome-wide replication stress can inform novel cancer treatment strategies that exploit synthetic lethal relationships among replication stress response factors.

Exploring the role of exosomes in rheumatoid arthritis.

In prosperous countries, autoimmune illnesses affect minimum 7% of the community. Rheumatoid Arthritis (RA) as an autoimmune illness is thought to be induced through a variety of genomic, physiological, and biological factors. Many experts in the field of nanomedicine have looked to stem cells as a viable strategy to repair human tissue; however, exosomes have demonstrated greater potential in recent years. Exosomes, produced from stem cells in particular, have exhibited a high propensity to give therapeutic effects. To resist local cellular stress, they are secreted in a paracrine manner from cells. As a result, exosomes produced from stem cells can provide enormous health uses. If treatment is not given, autoantibodies produce synovial inflammation and arthritis, which can lead to chronic inflammation, and impairment. Exosomes could be administered for the treatment of RA, by acting as therapeutic vectors. Exosomes are murine extracellular vesicles that influence biological mechanisms and signal transduction by transporting genetic and protein components. Diseases like RA and bone fractures could be treated using cell-free therapeutic strategies if exosomes could be isolated from stem cells efficiently and packaged with specific restorative substances. To get to this position, many breakthroughs must be achieved, and the following review summarises the most recent developments in stem cell-derived exosomes, with a focus on the important literature on exosome dynamics in RA.

Understanding the Potential Role of Nanotechnology in Liver Fibrosis: A Paradigm in Therapeutics.

The liver is a vital organ that plays a crucial role in the physiological operation of the human body. The liver controls the body's detoxification processes as well as the storage and breakdown of red blood cells, plasma protein and hormone production, and red blood cell destruction; therefore, it is vulnerable to their harmful effects, making it more prone to illness. The most frequent complications of chronic liver conditions include cirrhosis, fatty liver, liver fibrosis, hepatitis, and illnesses brought on by alcohol and drugs. Hepatic fibrosis involves the activation of hepatic stellate cells to cause persistent liver damage through the accumulation of cytosolic matrix proteins. The purpose of this review is to educate a concise discussion of the epidemiology of chronic liver disease, the pathogenesis and pathophysiology of liver fibrosis, the symptoms of liver fibrosis progression and regression, the clinical evaluation of liver fibrosis and the research into nanotechnology-based synthetic and herbal treatments for the liver fibrosis is summarized in this article. The herbal remedies summarized in this review article include epigallocathechin-3-gallate, silymarin, oxymatrine, curcumin, tetrandrine, glycyrrhetinic acid, salvianolic acid, plumbagin, Scutellaria baicalnsis Georgi, astragalosides, hawthorn extract, and andrographolides.

Current trends in epigenetic, cellular and molecular pathways in management of rheumatoid arthritis.

Rheumatoid arthritis is a systemic chronic polyarticular autoimmune disorder of joints and joint membrane mainly affecting feet and hands. The pathological manifestation of the disease includes infiltration of immune cells, hyperplasia of the lining of synovium, formation of pannus and bone and cartilage destruction. If left untreated, the appearance of small focal necrosis, adhesion of granulation, and formation of fibrous tissue on the surface of articular cartilage is noted. The disease primarily affects nearly 1% of the population globally, women being more affected than men with a ratio 2:1 and can initiate regardless of any age. The synovial fibroblast in rheumatoid arthritis individuals exhibits an aggressive phenotype which upregulates the manifestation of protooncogenes, adhesive compounds, inflammatory cytokines and matrix-deteriorating enzymes. Apart from the inflammatory effects of cytokines, chemokines are also noted to induce swelling and pain in arthritic individuals by residing in synovial membrane and forming pannus. The current treatment of rheumatoid arthritis includes treatment with non-steroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, treatment with biologics such as inhibitors of TNF-α, interleukins, platelet activating factor, etc. which provides significant relief from symptoms and aids in management of the disease. The current review highlights the pathogenesis involved in the onset of rheumatoid arthritis and also covers epigenetic, cellular and molecular parameters associated with it to aid better and advanced therapeutic approaches for management of the debilitating disease.

Unveiling the Pharmacological and Nanotechnological Facets of Daidzein: Present State-of-the-Art and Future Perspectives.

Herbal drugs have been attracting much scientific interest in the last few decades and nowadays, phytoconstituents-based research is in progress to disclose their unidentified medicinal potential. Daidzein (DAI) is the natural phytoestrogen isoflavone derived primarily from leguminous plants, such as the soybean and mung bean, and its IUPAC name is 4',7-dihydroxyisoflavone. This compound has received great attention as a fascinating pharmacophore with remarkable potential for the therapeutic management of several diseases. Certain pharmacokinetic properties of DAI such as less aqueous solubility, low permeability, and poor bioavailability are major obstacles restricting the therapeutic applications. In this review, distinctive physicochemical characteristics and pharmacokinetics of DAI has been elucidated. The pharmacological applications in treatment of several disorders like oxidative stress, cancer, obesity, cardiovascular, neuroprotective, diabetes, ovariectomy, anxiety, and inflammation with their mechanism of action are explained. Furthermore, this review article comprehensively focuses to provide up-to-date information about nanotechnology-based formulations which have been investigated for DAI in preceding years which includes polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carrier, polymer-lipid nanoparticles, nanocomplexes, polymeric micelles, nanoemulsion, nanosuspension, liposomes, and self-microemulsifying drug delivery systems.

Dissipation of tembotrione in maize and its effect on biochemical attributes of maize under mid-hill sub-humid zone.

The present study was undertaken to investigate the dissipation behavior of tembotrione in soil and its effect on the biochemical constituents of maize leaves and grain. The average recovery of tembotrione from soil, maize grain, and stover was in the range of 84.0 to 86.0%, 79.3 to 83.0%, and 81.0 to 84.4%, respectively, with RSD less than 10%. Half-life (DT50) of tembotrione ranged from 9 to 14 days at an application rate of 60 to 240 g ha-1. Terminal residues in soil, maize grain, and stover were below detectable levels (≤ 0.025 µg g-1) at studied application rates. The chemical attributes, i.e., total chlorophyll, total carotenoids, and carbohydrate content, of rice leaves were observed at monthly intervals (zero (2 h), 30, 60 days after the herbicide application) and at harvest for biochemical analysis and grain samples at maturity of the crop for carbohydrate content. The results revealed that total chlorophyll, total carotenoids, and carbohydrate content in maize leaves increased significantly with applied tembotrione treatments, and the maximum increase was noticed in treatment 120 g ha-1. A significant increase in total carbohydrate content in maize grain over the control was noticed in all the herbicide-applied treatments. It can be inferred that the application of tembotrione is safe in the production of food with better quality and food safety.

RAD51AP1 mediates RAD51 activity through nucleosome interaction.

RAD51-associated protein 1 (RAD51AP1) is a key protein in the homologous recombination (HR) DNA repair pathway. Loss of RAD51AP1 leads to defective HR, genome instability, and telomere erosion. RAD51AP1 physically interacts with the RAD51 recombinase and promotes RAD51-mediated capture of donor DNA, synaptic complex assembly, and displacement-loop formation when tested with nucleosome-free DNA substrates. In cells, however, DNA is packaged into chromatin, posing an additional barrier to the complexities of the HR reaction. In this study, we show that RAD51AP1 binds to nucleosome core particles (NCPs), the minimum basic unit of chromatin in which approximately two superhelical turns of 147 bp double-stranded DNA are wrapped around one histone octamer with no free DNA ends remaining. We identified a C-terminal region in RAD51AP1, including its previously mapped DNA-binding domain, as critical for mediating the association between RAD51AP1 and both the NCP and the histone octamer. Using in vitro surrogate assays of HR activity, we show that RAD51AP1 is capable of promoting duplex DNA capture and initiating joint-molecule formation with the NCP and chromatinized template DNA, respectively. Together, our results suggest that RAD51AP1 directly assists in the RAD51-mediated search for donor DNA in chromatin. We present a model, in which RAD51AP1 anchors the DNA template through affinity for its nucleosomes to the RAD51-ssDNA nucleoprotein filament.

Effects of nitric oxide modulators and antioxidants on endocrine and cellular markers of acute stress in rats.

The effects of nitric oxide modulators (NO-modulators) and antioxidants on acute (RSx1) restraint stress induced endocrine, cellular and oxidative/nitrosative stress markers was studied in Wistar rats. The results of our study revealed that exposure to RS(x1) enhanced malondialdehyde (MDA), heat shock protein (HSP-70), corticosterone, nuclear factor kappa B (NF-κB) levels and suppressed glutathione (GSH), superoxide dismutase (SOD) and total nitrites and nitrates (NOx) levels. NO precursor and NO synthase inhibitors were found to differentially modulate stress mechanisms, by altering NF-κB, HSP-70 and corticosterone levels. l-Ascorbic acid significantly suppressed acute stress induced elevation of NF-κB and HSP-70 levels depicting protective effects, as also evidenced by reversal of elevated plasma corticosterone levels. Therefore, modulation of oxidative and nitrosative pathways, offers an approach in modulating stress induced changes associated with various disorders.

Cloning and in silico characterization of cinnamyl alcohol dehydrogenase gene involved in lignification of Tall fescue (Festuca arundinacea Schreb.).

Tall fescue, a promising temperate forage grass of Himalayan region, possesses extraordinary property of rapid growth with high biomass production, but its poor digestibility due to higher lignin content limits its utilization in livestock feeding. The lignification in Tall fescue is under the control of enzymatic cascade of different regulatory enzymes. Cinnamyl alcohol dehydrogenase (CAD) is a crucial regulatory enzyme that catalyzes the last step of monolignol biosynthesis and is a potential candidate for altering the content and types of lignin, and hence increasing the digestibility of fodder crops. Hence, the present investigation was conducted on isolation, cloning and characterization of CAD gene from Tall fescue. Isolation and amplification of CAD gene resulted in an amplicon of 1521 bp. The CAD gene sequence was submitted to NCBI database with an accession number MW442831. Translation of the CAD gene sequence exhibited an ORF of 361 amino acids. The deduced CAD protein was predicted to be hydrophobic, acidic and thermally stable with molecular formula C1712H2734N460O520S23, molecular mass of 38.82 kDa, theoretical pI of 5.60 and 3 strong transmembrane helices. The CAD protein was predicted to have a dimer forming behavior with putative NAD(P) binding site between amino acids 48 and 301, putative substrate-binding site between amino acids 48 and 301, catalytic zinc-binding site between amino acids 48 and 164 and structural zinc-binding site between amino acid residue 101 and 115. A conserved 189GLGGVG194 motif is the binding site for NADP(H). The conserved motif pattern of CAD's zinc catalytic center was found to be 69GHEVVGEV(X)EVG(X)2V83. The zinc-binding site was found to be conserved between amino acid 89 and 115 and was found to be 89G(X)2VG(X)G(X)2VGXC(X)2C(X)2C(X)5QYC115. The deciphered sequence and putative protein information might be useful in subsequent research in lignin bioengineering for enhanced digestibility, biomass conversion as well as impact of lignin on cell wall mechanics.

Exploring the role of polyphenols in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic, inflammatory and autoimmune disorder which is mainly characterized by inflammation in joints, bone erosions and cartilaginous destruction that leads to joint dysfunction, deformation, and/or permanent functional impairment. The prevalence of RA is increasing, incurring a considerable burden on healthcare systems globally. The exact etiology of RA is unknown, with various pathways implicated in its pathophysiology. Non-steroidal anti-inflammatory drugs (NSAIDs) including celecoxib, diclofenac and ibuprofen, disease-modifying anti-rheumatic drugs (DMARD) including azathioprine, methotrexate and cyclosporine, biological agents including anakinra, infliximab, and rituximab and immunosuppressants are used for symptomatic relief in patients with RA, but these medications have severe adverse effects such as gastric ulcers, hypertension, hepatotoxicity and renal abnormalities which restrict their use in the treatment of RA; new RA treatments with minimal side-effects are urgently required. There is accumulating evidence that dietary polyphenols may show therapeutic efficacy in RA through their antioxidant, anti-inflammatory, apoptotic, and immunosuppressant activities and modulation of the tumor necrosis factor-α (TNF-α), interleukin (IL)-6, mitogen-activated protein kinase (MAPK), IL-1ß, c-Jun N-terminal kinase (JNK), and nuclear factor κ light-chain-enhancer of activated B cell (NF-κB) pathways. While resveratrol, genistein, carnosol, epigallocatechin gallate, curcumin, kaempferol, and hydroxytyrosol have also been studied for the treatment of RA, the majority of data are derived from animal models. Here, we review the various pathways involved in the development of RA and the preclinical and clinical data supporting polyphenols as potential therapeutic agents in RA patients. Our review highlights that high-quality clinical studies are required to decisively establish the anti-rheumatic efficacy of polyphenolic compounds.

Recent updates on development of protein-tyrosine phosphatase 1B inhibitors for treatment of diabetes, obesity and related disorders.

The aim of this review was to discuss an overview of type 2 diabetes; biology of PTP1B; role of PTP1B in metabolic disorders; and recent updates in the development of PTP1B inhibitors reported in literature since 1994. In this study, extensive literature search was carried out on PTP1B inhibitors of natural as well as synthetic origin in various scientific databases and research articles related to discovery of PTP1B inhibitors were selected for this study. Protein tyrosine phosphatase 1B (PTP1B) is an important therapeutic target for several human diseases including type 2 diabetes, obesity and cancer because of its seminal part as a negative modulator in both insulin and leptin signaling pathways. A large number of molecules of broad chemical diversity were reported as potent and selective PTP1B inhibitors over other protein tyrosine phosphatases. Several of these molecules have shown their potential in the treatment of various human diseases including type 2 diabetes, obesity, inflammation and cancer in various animal models. But only a very limited number of PTP1B inhibitors (including ertiprotafib, trodusquemine and JTT-551) has entered clinical trials and are finally withdrawn owing to their unsatisfactory effectiveness and undesirable adverse effects. Consequently, it is still highly imperative and of great importance to develop potent, highly selective and safe PTP1B inhibitors.

Unravelling the potential neuroprotective facets of erythropoietin for the treatment of Alzheimer's disease.

During the last three decades, recombinant DNA technology has produced a wide range of hematopoietic and neurotrophic growth factors, including erythropoietin (EPO), which has emerged as a promising protein drug in the treatment of several diseases. Cumulative studies have recently indicated the neuroprotective role of EPO in preclinical models of acute and chronic neurodegenerative disorders, including Alzheimer's disease (AD). AD is one of the most prevalent neurodegenerative illnesses in the elderly, characterized by the accumulation of extracellular amyloid-ß (Aß) plaques and intracellular neurofibrillary tangles (NFTs), which serve as the disease's two hallmarks. Unfortunately, AD lacks a successful treatment strategy due to its multifaceted and complex pathology. Various clinical studies, both in vitro and in vivo, have been conducted to identify the various mechanisms by which erythropoietin exerts its neuroprotective effects. The results of clinical trials in patients with AD are also promising. Herein, it is summarized and reviews all such studies demonstrating erythropoietin's potential therapeutic benefits as a pleiotropic neuroprotective agent in the treatment of Alzheimer's disease.

Expatiating the Pharmacological and Nanotechnological Aspects of the Alkaloidal Drug Berberine: Current and Future Trends.

Traditionally, herbal compounds have been the focus of scientific interest for the last several centuries, and continuous research into their medicinal potential is underway. Berberine (BBR) is an isoquinoline alkaloid extracted from plants that possess a broad array of medicinal properties, including anti-diarrheal, anti-fibrotic, antidiabetic, anti-inflammatory, anti-obesity, antihyperlipidemic, antihypertensive, antiarrhythmic, antidepressant, and anxiolytic effects, and is frequently utilized as a traditional Chinese medicine. BBR promotes metabolisms of glucose and lipids by activating adenosine monophosphate-activated protein kinase, stimulating glycolysis and inhibiting functions of mitochondria; all of these ameliorate type 2 diabetes mellitus. BBR has also been shown to have benefits in congestive heart failure, hypercholesterolemia, atherosclerosis, non-alcoholic fatty liver disease, Alzheimer's disease, and polycystic ovary syndrome. BBR has been investigated as an interesting pharmacophore with the potential to contribute significantly to the research and development of novel therapeutic medicines for a variety of disorders. Despite its enormous therapeutic promise, the clinical application of this alkaloid was severely limited because of its unpleasant pharmacokinetic characteristics. Poor bioavailability, limited absorption, and poor water solubility are some of the obstacles that restricted its use. Nanotechnology has been suggested as a possible solution to these problems. The present review aims at recent updates on important therapeutic activities of BBR and different types of nanocarriers used for the delivery of BBR in different diseases.