Allosteric inhibition of dengue virus RNA-dependent RNA polymerase by Litsea cubeba phytochemicals: a computational study.

RNA-dependent RNA polymerase (RdRp) is considered a potential drug target for dengue virus (DENV) inhibition and has attracted attention in antiviral drug discovery. Here, we screened 121 natural compounds from Litsea cubeba against DENV RdRp using various approaches of computer-based drug discovery. Notably, we identified four potential compounds (Ushinsunine, Cassameridine, (+)-Epiexcelsin, (-)-Phanostenine) with good binding scores and allosteric interactions with the target protein. Moreover, molecular dynamics simulation studies were done to check the conformational stability of the complexes under given conditions. Additionally, we performed post-simulation analysis to find the stability of potential drugs in the target protein. The findings suggest Litsea cubeba-derived phytomolecules as a therapeutic solution to control DENV infection.Communicated by Ramaswamy H. Sarma.

Investigating the Potential Therapeutic Mechanisms of Puerarin in Neurological Diseases.

Plants and their derived phytochemicals have a long history of treating a wide range of illnesses for several decades. They are believed to be the origin of a diverse array of medicinal compounds. One of the compounds found in kudzu root is puerarin, a isoflavone glycoside commonly used as an alternative medicine to treat various diseases. From a biological perspective, puerarin can be described as a white needle crystal with the chemical name of 7-hydroxy-3-(4-hydroxyphenyl)-1-benzopyran-4-one-8-D-glucopyranoside. Besides, puerarin is sparingly soluble in water and produces no color or light yellow solution. Multiple experimental and clinical studies have confirmed the significant therapeutic effects of puerarin. These effects span a wide range of pharmacological effects, including neuroprotection, hepatoprotection, cardioprotection, immunomodulation, anticancer properties, anti-diabetic properties, anti-osteoporosis properties, and more. Puerarin achieves these effects by interacting with various cellular and molecular pathways, such as MAPK, AMPK, NF-κB, mTOR, ß-catenin, and PKB/Akt, as well as different receptors, enzymes, and growth factors. The current review highlights the molecular mechanism of puerarin as a neuroprotective agent in the treatment of various neurodegenerative and neurological diseases. Extensive cellular, animal, and clinical research has provided valuable insights into its effectiveness in conditions such as Alzheimer's disease, Parkinson's disease, epilepsy, cerebral stroke, depression, and more.

Recent Advances in Drug Delivery Systems Targeting Insulin Signalling for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the accumulation of neurofibrillary tangles and amyloid-ß plaques. Recent research has unveiled the pivotal role of insulin signaling dysfunction in the pathogenesis of AD. Insulin, once thought to be unrelated to brain function, has emerged as a crucial factor in neuronal survival, synaptic plasticity, and cognitive processes. Insulin and the downstream insulin signaling molecules are found mainly in the hippocampus and cortex. Some molecules responsible for dysfunction in insulin signaling are GSK-3ß, Akt, PI3K, and IRS. Irregularities in insulin signaling or insulin resistance may arise from changes in the phosphorylation levels of key molecules, which can be influenced by both stimulation and inactivity. This, in turn, is believed to be a crucial factor contributing to the development of AD, which is characterized by oxidative stress, neuroinflammation, and other pathological hallmarks. Furthermore, this route is known to be indirectly influenced by Nrf2, NF-κB, and the caspases. This mini-review delves into the intricate relationship between insulin signaling and AD, exploring how disruptions in this pathway contribute to disease progression. Moreover, we examine recent advances in drug delivery systems designed to target insulin signaling for AD treatment. From oral insulin delivery to innovative nanoparticle approaches and intranasal administration, these strategies hold promise in mitigating the impact of insulin resistance on AD. This review consolidates current knowledge to shed light on the potential of these interventions as targeted therapeutic options for AD.

Mechanistic insights into the potential role of dietary polyphenols and their nanoformulation in the management of Alzheimer's disease.

Alzheimer's disease (AD) is a very common neurodegenerative disorder associated with memory loss and a progressive decline in cognitive activity. The two major pathophysiological factors responsible for AD are amyloid plaques (comprising amyloid-beta aggregates) and neurofibrillary tangles (consisting of hyperphosphorylated tau protein). Polyphenols, a class of naturally occurring compounds, are immensely beneficial for the treatment or management of various disorders and illnesses. Naturally occurring sources of polyphenols include plants and plant-based foods, such as fruits, herbs, tea, vegetables, coffee, red wine, and dark chocolate. Polyphenols have unique properties, such as being the major source of anti-oxidants and possessing anti-aging and anti-cancerous properties. Currently, dietary polyphenols have become a potential therapeutic approach for the management of AD, depending on various research findings. Dietary polyphenols can be an effective strategy to tackle multifactorial events that occur with AD. For instance, naturally occurring polyphenols have been reported to exhibit neuroprotection by modulating the Aß biogenesis pathway in AD. Many nanoformulations have been established to enhance the bioavailability of polyphenols, with nanonization being the most promising. This review comprehensively provides mechanistic insights into the neuroprotective potential of dietary polyphenols in treating AD. It also reviews the usability of dietary polyphenol as nanoformulation for AD treatment.

Psychedelics for alzheimer's disease-related dementia: Unveiling therapeutic possibilities and pathways.

Psychedelics have traditionally been used for spiritual and recreational purposes, but recent developments in psychotherapy have highlighted their potential as therapeutic agents. These compounds, which act as potent 5-hydroxytryptamine (5HT) agonists, have been recognized for their ability to enhance neural plasticity through the activation of the serotoninergic and glutamatergic systems. However, the implications of these findings for the treatment of neurodegenerative disorders, particularly dementia, have not been fully explored. In recent years, studies have revealed the modulatory and beneficial effects of psychedelics in the context of dementia, specifically Alzheimer's disease (AD)-related dementia, which lacks a definitive cure. Psychedelics such as N,N-dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), and Psilocybin have shown potential in mitigating the effects of this debilitating disease. These compounds not only target neurotransmitter imbalances but also act at the molecular level to modulate signalling pathways in AD, including the brain-derived neurotrophic factor signalling pathway and the subsequent activation of mammalian target of rapamycin and other autophagy regulators. Therefore, the controlled and dose-dependent administration of psychedelics represents a novel therapeutic intervention worth exploring and considering for the development of drugs for the treatment of AD-related dementia. In this article, we critically examined the literature that sheds light on the therapeutic possibilities and pathways of psychedelics for AD-related dementia. While this emerging field of research holds great promise, further studies are necessary to elucidate the long-term safety, efficacy, and optimal treatment protocols. Ultimately, the integration of psychedelics into the current treatment paradigm may provide a transformative approach for addressing the unmet needs of individuals living with AD-related dementia and their caregivers.

Point-of-Care Ultrasound for High-Risk Pregnancy Screening in Rural Nepal.

By training nurses and midwives on the basics of obstetric ultrasound, high-risk pregnancies in remote Nepalese villages can be identified and triaged. American radiology residents traveling to Nepal can improve their real-time, hands-on ultrasound scanning skills while learning the intricacies of practicing medicine in a low- and middle-income country. Global outreach work is increasing in popularity among US radiologists, emphasizing the importance of training radiology residents in point-of-care ultrasound.

Corrigendum: Cytokinin and abiotic stress tolerance -What has been accomplished and the way forward?

[This corrects the article DOI: 10.3389/fgene.2022.943025.].

Unveiling the impact of aging on BBB and Alzheimer's disease: Factors and therapeutic implications.

Alzheimer's disease (AD) is a highly prevalent neurodegenerative condition that has devastating effects on individuals, often resulting in dementia. AD is primarily defined by the presence of extracellular plaques containing insoluble ß-amyloid peptide (Aß) and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein (P-tau). In addition, individuals afflicted by these age-related illnesses experience a diminished state of health, which places significant financial strain on their loved ones. Several risk factors play a significant role in the development of AD. These factors include genetics, diet, smoking, certain diseases (such as cerebrovascular diseases, obesity, hypertension, and dyslipidemia), age, and alcohol consumption. Age-related factors are key contributors to the development of vascular-based neurodegenerative diseases such as AD. In general, the process of aging can lead to changes in the immune system's responses and can also initiate inflammation in the brain. The chronic inflammation and the inflammatory mediators found in the brain play a crucial role in the dysfunction of the blood-brain barrier (BBB). Furthermore, maintaining BBB integrity is of utmost importance in preventing a wide range of neurological disorders. Therefore, in this review, we discussed the role of age and its related factors in the breakdown of the blood-brain barrier and the development of AD. We also discussed the importance of different compounds, such as those with anti-aging properties, and other compounds that can help maintain the integrity of the blood-brain barrier in the prevention of AD. This review builds a strong correlation between age-related factors, degradation of the BBB, and its impact on AD.

Orchestration and theranostic applications of synthetic genome with Hachimoji bases/building blocks.

Synthetic genomics is a novel field of chemical biology where the chemically modified genetic alphabets have been considered in central dogma of life. Tweaking of chemical compositions of natural nucleotide bases could be developed as novel building blocks of DNA/RNA. The modified bases (dP, dZ, dS, and dB etc.) have been demonstrated to be adaptable for replication, transcription and follow Darwinism law of evolution. With advancement of chemical biology especially nucleotide chemistry, synthetic genetic codes have been discovered and Hachimoji nucleotides are the most important and significant one among them. These additional nucleotide bases can form orthogonal base-pairing, and also follow Darwinian evolution and other structural features. In the Hachimoji base pairing, synthetic building blocks are formed using eight modified nucleotide (DNA/RNA) letters (hence the name "Hachimoji"). Their structural conformations, like polyelectrolyte backbones and stereo-regular building blocks favor thermodynamic stability and confirm Schrodinger aperiodic crystal. From the structural genomics aspect, these synthetic bases could be incorporated into the central dogma of life. Researchers have shown Hachimoji building blocks were transcribed to its RNA counterpart as a functional fluorescent Hachimoji aptamer. Apart from several unnatural nucleotide base pairs maneuvered into its in vitro and in vivo applications, this review describes future perspective towards the development and therapeutic utilization of the genetic codes, a primary objective of synthetic and chemical biology.

Tumor-derived small extracellular vesicles in cancer invasion and metastasis: molecular mechanisms, and clinical significance.

The production and release of tumor-derived small extracellular vesicles (TDSEVs) from cancerous cells play a pivotal role in the propagation of cancer, through genetic and biological communication with healthy cells. TDSEVs are known to orchestrate the invasion-metastasis cascade via diverse pathways. Regulation of early metastasis processes, pre-metastatic niche formation, immune system regulation, angiogenesis initiation, extracellular matrix (ECM) remodeling, immune modulation, and epithelial-mesenchymal transition (EMT) are among the pathways regulated by TDSEVs. MicroRNAs (miRs) carried within TDSEVs play a pivotal role as a double-edged sword and can either promote metastasis or inhibit cancer progression. TDSEVs can serve as excellent markers for early detection of tumors, and tumor metastases. From a therapeutic point of view, the risk of cancer metastasis may be reduced by limiting the production of TDSEVs from tumor cells. On the other hand, TDSEVs represent a promising approach for in vivo delivery of therapeutic cargo to tumor cells. The present review article discusses the recent developments and the current views of TDSEVs in the field of cancer research and clinical applications.

A comprehensive update on genetic inheritance, epigenetic factors, associated pathology, and recent therapeutic intervention by gene therapy in schizophrenia.

Schizophrenia is a severe psychological disorder in which reality is interpreted abnormally by the patient. The symptoms of the disease include delusions and hallucinations, associated with extremely disordered behavior and thinking, which may affect the daily lives of the patients. Advancements in technology have led to understanding the dynamics of the disease and the identification of the underlying causes. Multiple investigations prove that it is regulated genetically, and epigenetically, and is affected by environmental factors. The molecular and neural pathways linked to the regulation of schizophrenia have been extensively studied. Over 180 Schizophrenic risk loci have now been recognized due to several genome-wide association studies (GWAS). It has been observed that multiple transcription factors (TF) binding-disrupting single nucleotide polymorphisms (SNPs) have been related to gene expression responsible for the disease in cerebral complexes. Copy number variation, SNP defects, and epigenetic changes in chromosomes may cause overexpression or underexpression of certain genes responsible for the disease. Nowadays, gene therapy is being implemented for its treatment as several of these genetic defects have been identified. Scientists are trying to use viral vectors, miRNA, siRNA, and CRISPR technology. In addition, nanotechnology is also being applied to target such genes. The primary aim of such targeting was to either delete or silence such hyperactive genes or induce certain genes that inhibit the expression of these genes. There are challenges in delivering the gene/DNA to the site of action in the brain, and scientists are working to resolve the same. The present article describes the basics regarding the disease, its causes and factors responsible, and the gene therapy solutions available to treat this disease.

Mechanisms and prospects of piezoelectric materials as smart delivery vehicles in cancer treatment.

Piezoelectric materials, capable of converting mechanical energy into electrical energy and vice versa, have emerged as promising candidates for designing intelligent drug delivery vehicles. Leveraging their inherent electrical properties, these materials respond to external stimuli, such as mechanical forces and electrical signals, to control drug release. By integrating piezoelectric materials into drug delivery systems, we can achieve exacting control over drug-release mechanisms. Piezoelectric materials hold enormous promise as smart delivery vehicles in cancer treatment, responding to mechanical and electrical cues, enabling site-specific drug release, reducing systemic toxicity and enhancing therapeutic effectiveness. Further advancements in the field are expected to lead to innovative piezoelectric-based systems that can revolutionize cancer treatment strategies, as explored in this review article.

Computational exploration of Zika virus RNA-dependent RNA polymerase inhibitors: a promising antiviral drug discovery approach.

The emergence of the Zika virus, which belongs to the Flaviviridae family, became a significant worldwide health issue due to its link with severe neurological complications. The RNA-dependent RNA polymerase (RdRp) of the Zika virus plays a significant part in the replication of the virus and is considered a promising candidate for antiviral drug identification. In this study, we employed computer-based drug discovery approaches to identify potential natural compounds that could act as inhibitors against the RdRp protein of the Zika virus. A comprehensive virtual screening strategy was implemented using the MTiOpenScreen webserver to identify natural compounds from the NP-Lib database. Four natural compounds having the ZINC ID - ZINC000253499147, ZINC000299817665, ZINC000044404209, and ZINC000253388535 were selected based on the binding score revealed during virtual screening. Molecular docking simulations of these selected compounds and reference compounds were performed to assess the binding affinities and the molecular bonds formed during the docking. Additionally, molecular dynamics (MD) simulations, endpoint free binding energy calculation and principal component analysis (PCA) were performed to evaluate the stability and dynamics of the protein-ligand complexes. These compounds exhibited favourable binding energies and formed stable interactions within the active site of the RdRp protein. Moreover, the molecular dynamics simulations revealed the robustness of the protein-ligand complexes, suggesting the potential for sustained inhibition. These findings provide valuable insights for the design and development of novel therapeutic interventions against Zika virus infection. Further experimental validation and optimization of the identified compounds are warranted to advance their potential translation into effective antiviral drugs.Communicated by Ramaswamy H. Sarma.

Nanomedicines for the management of diabetic nephropathy: present progress and prospects.

Diabetic nephropathy (DN) is a serious microvascular consequence of diabetes mellitus (DM), posing an encumbrance to public health worldwide. Control over the onset and progress of DN depend heavily on early detection and effective treatment. DN is a major contributor to end-stage renal disease, and a complete cure is yet to be achieved with currently available options. Though some therapeutic molecules have exhibited promise in treating DN complications, their poor solubility profile, low bioavailability, poor permeation, high therapeutic dose and associated toxicity, and low patient compliance apprehend their clinical usefulness. Recent research has indicated nano-systems as potential theranostic platforms displaying futuristic promise in the diagnosis and treatment of DN. Early and accurate diagnosis, site-specific delivery and retention by virtue of ligand conjugation, and improved pharmacokinetic profile are amongst the major advantages of nano-platforms, defining their superiority. Thus, the emergence of nanoparticles has offered fresh approaches to the possible diagnostic and therapeutic strategies regarding DN. The present review corroborates an updated overview of different types of nanocarriers regarding potential approaches for the diagnosis and therapy of DN.

Algorithms at the Gate-Radiology's AI Adoption Dilemma.

In this Viewpoint a radiologist surveys the ascent of artificial intelligence (AI) in imaging and what the future likely holds for AI in this discipline.

New insights into molecular signaling pathways and current advancements in prostate cancer diagnostics & therapeutics.

Prostate adenocarcinoma accounts for more than 20% of deaths among males due to cancer. It is the fifth-leading cancer diagnosed in males across the globe. The mortality rate is quite high due to prostate cancer. Despite the fact that advancements in diagnostics and therapeutics have been made, there is a lack of effective drugs. Metabolic pathways are altered due to the triggering of androgen receptor (AR) signaling pathways, and elevated levels of dihydrotestosterone are produced due to defects in AR signaling that accelerate the growth of prostate cancer cells. Further, PI3K/AKT/mTOR pathways interact with AR signaling pathway and act as precursors to promote prostate cancer. Prostate cancer therapy has been classified into luminal A, luminal B, and basal subtypes. Therapeutic drugs inhibiting dihydrotestosterone and PI3K have shown to give promising results to combat prostate cancer. Many second-generation Androgen receptor signaling antagonists are given either as single agent or with the combination of other drugs. In order to develop a cure for metastasized prostate cancer cells, Androgen deprivation therapy (ADT) is applied by using surgical or chemical methods. In many cases, Prostatectomy or local radiotherapy are used to control metastasized prostate cancer. However, it has been observed that after 1.5 years to 2 years of Prostatectomy or castration, there is reoccurrence of prostate cancer and high incidence of castration resistant prostate cancer is seen in population undergone ADT. It has been observed that Androgen derivation therapy combined with drugs like abiraterone acetate or docetaxel improve overall survival rate in metastatic hormone sensitive prostate cancer (mHSPC) patients. Scientific investigations have revealed that drugs inhibiting poly ADP Ribose polymerase (PARP) are showing promising results in clinical trials in the prostate cancer population with mCRPC and DNA repair abnormalities. Recently, RISUG adv (reversible inhibition of sperm under guidance) has shown significant results against prostate cancer cell lines and MTT assay has validated substantial effects of this drug against PC3 cell lines. Current review paper highlights the advancements in prostate cancer therapeutics and new drug molecules against prostate cancer. It will provide detailed insights on the signaling pathways which need to be targeted to combat metastasized prostate cancer and castration resistant prostate cancer.

Role of exosomes in prostate cancer and male fertility.

Prostate cancer (PCa) is the second most common and fifth most aggressive neoplasm among men worldwide. In the last decade, extracellular vesicle (EV) research has decoded multiple unsolved cancer-related mysteries. EVs can be classified as microvesicles, apoptotic bodies, and exosomes, among others. Exosomes play a key role in cellular signaling. Their internal cargos (nucleic acids, proteins, lipids) influence the recipient cell. In PCa, the exosome is the regulator of cancer progression. It is also a promising theranostics tool for PCa. Moreover, exosomes have strong participation in male fertility complications. This review aims to highlight the exosome theranostics signature in PCa and its association with male fertility.

Clinical Theranostics Trademark of Exosome in Glioblastoma Metastasis.

Glioblastoma (GBM) is an aggressive type of cancer that has led to the death of a large population. The traditional approach fails to develop a solution for GBM's suffering life. Extensive research into tumor microenvironments (TME) indicates that TME extracellular vesicles (EVs) play a vital role in cancer development and progression. EVs are classified into microvacuoles, apoptotic bodies, and exosomes. Exosomes are the most highlighted domains in cancer research. GBM cell-derived exosomes participate in multiple cancer progression events such as immune suppression, angiogenesis, premetastatic niche formation (PMN), ECM (extracellular matrix), EMT (epithelial-to-mesenchymal transition), metastasis, cancer stem cell development and therapeutic and drug resistance. GBM exosomes also carry the signature of a glioblastoma-related status. The exosome-based GBM examination is part of the new generation of liquid biopsy. It also solved early diagnostic limitations in GBM. Traditional therapeutic approaches do not cross the blood-brain barrier (BBB). Exosomes are a game changer in GBM treatment and it is emerging as a potential platform for effective, efficient, and specific therapeutic development. In this review, we have explored the exosome-GBM interlink, the clinical impact of exosomes on GBM biomarkers, the therapeutics signature of exosomes in GBM, exosome-based research challenges, and future directions in GBM. Therefore, the GBM-derived exosomes offer unique therapeutic opportunities, which are currently under preclinical and clinical testing.