Cannabinoid 2 receptor activation protects against diabetic cardiomyopathy through inhibition of AGE/RAGE-induced oxidative stress, fibrosis, and inflammasome activation.

Oxidative stress, fibrosis, and inflammasome activation from AGE-RAGE interaction contribute to diabetic cardiomyopathy (DCM) formation and progression. Our study revealed the impact of ß-caryophyllene (BCP) on activating CB2 receptors against diabetes complications and investigated the underlying cell signaling pathways in mice. The murine model of DCM was developed by feeding high-fat diet with streptozotocin injections. After the development of diabetes, the animals received a 12-week oral BCP treatment at a dosage of 50 mg/kg/body weight. BCP treatment showed significant improvement in glucose tolerance, insulin resistance, and enhanced serum insulin levels in diabetic animals. BCP treatment effectively reversed the heart remodeling and restored the phosphorylated troponin I and SERCA2a expression. Ultrastructural examination showed reduced myocardial cell injury in DCM mice treated with BCP. The preserved myocytes were found associated with reduced expression of AGE/RAGE in DCM mice hearts. BCP treatment mitigated oxidative stress by inhibiting expression of NOX4 and activating PI3K/AKT/Nrf2 signaling. BCP suppressed cardiac fibrosis and endothelial-to-mesenchymal transition (EndMT) in DCM mice by inhibiting TGF-ß/Smad signaling. Further, BCP treatment suppressed NLRP3 inflammasome activation in DCM mice and alleviated cellular injury to the pancreatic tissues evidenced by significant elevation of the number of insulin-positive cells. To demonstrate CB2 receptor dependent mechanism of BCP, another group of DCM mice were pretreated with AM630, a CB2 receptor antagonist AM630 and AM630 was observed to abrogate the beneficial effects of BCP in DCM mice. Taken together, BCP showed the potential to protect the myocardium and pancreas of DCM mice mediating CB2 receptor dependent mechanisms. Significance Statement 1. ß-caryophyllene (BCP), a cannabinoid type 2 receptor (CB2R) agonist. 2. BCP attenuates diabetic cardiomyopathy via activating CB2R in mice 3. CB2R activation by BCP shows strong protection against fibrosis and inflammasome activation 4. It regulates AGE/RAGE and PI3K/Nrf2/Akt signaling in mice.

Extracellular Vesicular miRNA in Pancreatic Cancer: From Lab to Therapy.

Pancreatic cancer is a prevalent lethal gastrointestinal cancer that generally does not show any symptoms until it reaches advanced stages, resulting in a high mortality rate. People at high risk, such as those with a family history or chronic pancreatitis, do not have a universally accepted screening protocol. Chemotherapy and radiotherapy demonstrate limited effectiveness in the management of pancreatic cancer, emphasizing the urgent need for innovative therapeutic strategies. Recent studies indicated that the complex interaction among pancreatic cancer cells within the dynamic microenvironment, comprising the extracellular matrix, cancer-associated cells, and diverse immune cells, intricately regulates the biological characteristics of the disease. Additionally, mounting evidence suggests that EVs play a crucial role as mediators in intercellular communication by the transportation of different biomolecules, such as miRNA, proteins, DNA, mRNA, and lipids, between heterogeneous cell subpopulations. This communication mediated by EVs significantly impacts multiple aspects of pancreatic cancer pathogenesis, including proliferation, angiogenesis, metastasis, and resistance to therapy. In this review, we delve into the pivotal role of EV-associated miRNAs in the progression, metastasis, and development of drug resistance in pancreatic cancer as well as their therapeutic potential as biomarkers and drug-delivery mechanisms for the management of pancreatic cancer.

Structure-based virtual screening methods for the identification of novel phytochemical inhibitors targeting furin protease for the management of COVID-19.

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, is a highly contagious respiratory disease with widespread societal impact. The symptoms range from cough, fever, and pneumonia to complications affecting various organs, including the heart, kidneys, and nervous system. Despite various ongoing efforts, no effective drug has been developed to stop the spread of the virus. Although various types of medications used to treat bacterial and viral diseases have previously been employed to treat COVID-19 patients, their side effects have also been observed. The way SARS-CoV-2 infects the human body is very specific, as its spike protein plays an important role. The S subunit of virus spike protein cleaved by human proteases, such as furin protein, is an initial and important step for its internalization into a human host. Keeping this context, we attempted to inhibit the furin using phytochemicals that could produce minimal side effects. For this, we screened 408 natural phytochemicals from various plants having antiviral properties, against furin protein, and molecular docking and dynamics simulations were performed. Based on the binding score, the top three compounds (robustaflavone, withanolide, and amentoflavone) were selected for further validation. MM/GBSA energy calculations revealed that withanolide has the lowest binding energy of -57.2 kcal/mol followed by robustaflavone and amentoflavone with a binding energy of -45.2 kcal/mol and -39.68 kcal/mol, respectively. Additionally, ADME analysis showed drug-like properties for these three lead compounds. Hence, these natural compounds robustaflavone, withanolide, and amentoflavone, may have therapeutic potential for the management of SARS-CoV-2 by targeting furin.

Dietary anti-inflammatory and anti-bacterial medicinal plants and its compounds in bovine mastitis associated impact on human life.

Bovine mastitis (BM) is the most common bacterial mediated inflammatory disease in the dairy cattle that causes huge economic loss to the dairy industry due to decreased milk quality and quantity. Milk is the essential food in the human diet, and rich in crucial nutrients that helps in lowering the risk of diseases like hypertension, cardiovascular diseases and type 2 diabetes. The main causative agents of the disease include various gram negative, and positive bacteria, along with other risk factors such as udder shape, age, genetic, and environmental factors also contributes much for the disease. Currently, antibiotics, immunotherapy, probiotics, dry cow, and lactation therapy are commonly recommended for BM. However, these treatments can only decrease the rise of new cases but can't eliminate the causative agents, and they also exhibit several limitations. Hence, there is an urgent need of a potential source that can generate a typical and ideal treatment to overcome the limitations and eliminate the pathogens. Among the various sources, medicinal plants and its derived products always play a significant role in drug discovery against several diseases. In addition, they are also known for its low toxicity and minimum resistance features. Therefore, plants and its compounds that possess anti-inflammatory and anti-bacterial properties can serve better in bovine mastitis. In addition, the plants that are serving as a food source and possessing pharmacological properties can act even better in bovine mastitis. Hence, in this evidence-based study, we particularly review the dietary medicinal plants and derived products that are proven for anti-inflammatory and anti-bacterial effects. Moreover, the role of each dietary plant and its compounds along with possible role in the management of bovine mastitis are delineated. In this way, this article serves as a standalone source for the researchers working in this area to help in the management of BM.

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.

Biofilm Inhibition on Medical Devices and Implants Using Carbon Dots: An Updated Review.

Biofilms are an intricate community of microbes that colonize solid surfaces, communicating via a quorum-sensing mechanism. These microbial aggregates secrete exopolysaccharides facilitating adhesion and conferring resistance to drugs and antimicrobial agents. The escalating global concern over biofilm-related infections on medical devices underscores the severe threat to human health. Carbon dots (CDs) have emerged as a promising substrate to combat microbes and disrupt biofilm matrices. Their numerous advantages such as facile surface functionalization and specific antimicrobial properties, position them as innovative anti-biofilm agents. Due to their minuscule size, CDs can penetrate microbial cells, inhibiting growth via cytoplasmic leakage, reactive oxygen species (ROS) generation, and genetic material fragmentation. Research has demonstrated the efficacy of CDs in inhibiting biofilms formed by key pathogenic bacteria such as Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. Consequently, the development of CD-based coatings and hydrogels holds promise for eradicating biofilm formation, thereby enhancing treatment efficacy, reducing clinical expenses, and minimizing the need for implant revision surgeries. This review provides insights into the mechanisms of biofilm formation on implants, surveys major biofilm-forming pathogens and associated infections, and specifically highlights the anti-biofilm properties of CDs emphasizing their potential as coatings on medical implants.

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.

Repurposing of SARS-CoV-2 compounds against Marburg Virus using MD simulation, mm/GBSA, PCA analysis, and free energy landscape.

The significant mortality rate associated with Marburg virus infection made it the greatest hazard among infectious diseases. Drug repurposing using in silico methods has been crucial in identifying potential compounds that could prevent viral replication by targeting the virus's primary proteins. This study aimed at repurposing the drugs of SARS-CoV-2 for identifying potential candidates against the matrix protein VP40 of the Marburg virus. Virtual screening was performed where the control compound, Nilotinib, showed a binding score of -9.99 kcal/mol. Based on binding scores, hit compounds 9549298, 11960895, 44545852, 51039094, and 89670174 were selected that had a lower binding score than the control. Subsequent molecular dynamics (MD) simulation revealed that compound 9549298 consistently formed a hydrogen bond with the residue Gln290. This was observed both in molecular docking and MD simulation poses, indicating a strong and significant interaction with the protein. 11960895 had the most stable and consistent RMSD pattern exhibited in 100 ns simulation, while 9549298 had the most identical RMSD plot compared to the control molecule. MM/PBSA analysis showed that the binding free energy (ΔG) of 9549298 and 11960895 was lower than the control, with -30.84 and -38.86 kcal/mol, respectively. It was observed by the PCA (principal component analysis) and FEL (free energy landscape) analysis that compounds 9549298 and 11960895 had lesser conformational variation. Overall, this study proposed 9549298 and 11960895 as potential binders of VP40 MARV that can cause its inhibition, however it inherently lacks experimental validation. Furthermore, the study proposes in-vitro experiments as the next step to validate these computational findings, offering a practical approach to further explore these compounds' potential as antiviral agents.Communicated by Ramaswamy H. Sarma.

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.

Corrigendum: Unravelling the therapeutic potential of botanicals against chronic obstructive pulmonary disease (COPD): molecular insights and future perspectives.

[This corrects the article DOI: 10.3389/fphar.2022.824132.].

Corrigendum: Phytotherapy for attention deficit hyperactivity disorder (ADHD): a systematic review and meta-analysis.

[This corrects the article DOI: 10.3389/fphar.2022.827411.].

Corrigendum: Cytokinins: a genetic target for increasing yield potential in the CRISPR era.

[This corrects the article DOI: 10.3389/fgene.2022.883930.].

Commercialization potential of PET (polyethylene terephthalate) recycled nanomaterials: A review on validation parameters.

Polyethylene Terephthalate (PET) is a polymer which is considered as one of the major contaminants to the environment. The PET waste materials can be recycled to produce value-added products. PET can be converted to nanoparticles, nanofibers, nanocomposites, and nano coatings. To extend the applications of PET nanomaterials, understanding its commercialization potential is important. In addition, knowledge about the factors affecting recycling of PET based nanomaterials is essential. The presented review is focused on understanding the PET commercialization aspects, keeping in mind market analysis, growth drivers, regulatory affairs, safety considerations, issues associated with scale-up, manufacturing challenges, economic viability, and cost-effectiveness. In addition, the paper elaborates the challenges associated with the use of PET based nanomaterials. These challenges include PET contamination to water, soil, sediments, and human exposure to PET nanomaterials. Moreover, the paper discusses in detail about the factors affecting PET recycling, commercialization, and circular economy with specific emphasis on life cycle assessment (LCA) of PET recycled nanomaterials.

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.

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.

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

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

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.

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.