The Neuroprotective Effects of Agmatine on Parkinson's Disease: Focus on Oxidative Stress, Inflammation and Molecular Mechanisms.

Agmatine (AGM), a naturally occurring polyamine derived from L-arginine, has shown significant potential for neuroprotection in Parkinson's Disease (PD) due to its multifaceted biological activities, including antioxidant, anti-inflammatory, and anti-apoptotic effects. This review explores the therapeutic potential of AGM in treating PD, focusing on its neuroprotective mechanisms and evidence from preclinical studies. AGM has been demonstrated to mitigate the neurotoxic effects of rotenone (ROT) by improving motor function, reducing oxidative stress markers, and decreasing levels of pro-inflammatory cytokines in animal models. Additionally, AGM protects against the loss of TH + neurons, crucial for dopamine synthesis. The neuroprotective properties of AGM are attributed to its ability to modulate several key pathways implicated in PD pathogenesis, such as inhibition of NMDA receptors, activation of Nrf2, and suppression of the HMGB1/ RAGE/ TLR4/ MyD88/ NF-κB signaling cascade. Furthermore, the potential of agmatine to promote neurorestoration is highlighted by its role in enhancing neuroplasticity elements such as CREB, BDNF, and ERK1/2. This review highlights agmatine's promising therapeutic potential in PD management, suggesting that it could offer both symptomatic relief and neuroprotective benefits, thereby modifying the disease course and improving the quality of life for patients. Further research is warranted to translate these preclinical findings into clinical applications.

Lipid metabolism reprogramming in renal cell carcinomas.

This study investigates the intricate mechanisms underlying the correlation between elevated consumption of harmful fats and the onset of kidney malignancies. The rise in global obesity rates has been accompanied by an increased prevalence of renal cancers, prompting an exploration into the molecular pathways and biological processes linking these phenomena. Through an extensive review of current literature and clinical studies, we identify potential key factors contributing to the carcinogenic influence of harmful fats on renal tissues. Our analysis highlights the role of adipose tissue-derived factors, inflammatory mediators, and lipid metabolism dysregulation in fostering a microenvironment conducive to renal tumorigenesis. Furthermore, we delve into the impact of harmful fats on signaling pathways associated with cell proliferation, apoptosis evasion, and angiogenesis within the renal parenchyma. This review underscores the importance of elucidating the molecular intricacies linking lipid metabolism and kidney malignancies, offering a foundation for future research and the development of targeted preventive and therapeutic interventions. The findings discussed herein contribute to our understanding of the complex relationship between lipid mediators and renal cancer, providing a basis for public health strategies aimed at mitigating the impact of harmful fats on kidney health.

Biologically based strategies for overcoming in vivo barriers with functional nano-delivery systems.

Nanomedicine has been developed to reduce or eliminate the side effects and toxicity upon systemic therapy of chemotherapeutic agents and to improve their therapeutic efficacy. However, the translation of non-sized or nano-encapsulated drugs is hampered by the low penetration and accumulation of engineered nanoparticles (NPs) in sites of tumors as well as their poor pharmacokinetics. This may be due to the synthetic structure of NPs and also complicated and unknown characteristics of the solid tumor microenvironment (TME). As a result, the TME is being better identified, and the interactions between NPs and the TME or human body are being discovered or predicted. These findings have led to the development of more biocompatible, intelligent, and controllable bio-based nanoformulations that could overcome current barriers and provide sufficient drug delivery to the TME, as discussed in this paper. These formulations are designed to (i) modify the surface of NPs to improve blood circulation while reducing their off-target accumulation and side effects in vivo, (ii) pass through the tumor vasculature by modulating or targeting angiogenesis, (iii) promote NPs distribution in solid tumor regions by applying biological/physical stimuli or extracellular matrix remodeling, and (iv) overcome the cell membrane barrier and other compartments of the cell by specific cell targeting to release the payload drug into the cytoplasm or nucleoplasm.

Dosimetric effect of collimator rotation on intensity modulated radiotherapy and volumetric modulated arc therapy for rectal cancer radiotherapy.

INTRODUCTION: Intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) are the main radiotherapy techniques for treating and managing rectal cancer. Collimator rotation is one of the crucial parameters in radiotherapy planning, and its alteration can cause dosimetric variations. This study assessed the effect of collimator rotation on the dosimetric results of various IMRT and VMAT plans for rectal cancer. MATERIALS AND METHODS: Computed tomography (CT) images of 20 male patients with rectal cancer were utilized for IMRT and VMAT treatment planning with various collimator angles. Nine different IMRT techniques (5, 7, and 9 coplanar fields with collimator angles of 0°, 45°, and 90°) and six different VMAT techniques (1 and 2 full coplanar arcs with collimator angles of 0°, 45°, and 90°) were planned for each patient. The dosimetric results of various treatment techniques for target tissue (conformity index [CI] and homogeneity index [HI]) and organs at risk (OARs) sparing (parameters obtained from OARs dose-volume histograms [DVH]) as well as radiobiological findings were analyzed and compared. RESULTS: The 7-fields IMRT technique demonstrated lower bladder doses (V40Gy, V45Gy), unaffected by collimator rotation. The 9-fields IMRT and 2-arcs VMAT (excluding the 90-degree collimator) had the lowest V35Gy and V45Gy. A 90-degree collimator rotation in 2-arcs VMAT significantly increased small bowel and bladder V45Gy, femoral head doses, and HI values. Radiobiologically, the 90-degree rotation had adverse effects on small bowel NTCP (normal tissue complication probability). No superiority was found for a 45-degree collimator rotation over 0 or 30 degrees in VMAT techniques. CONCLUSION: Collimator rotation had minimal impact on dosimetric parameters in IMRT planning but is significant in VMAT techniques. A 90-degree rotation in VMAT, particularly in a 2-full arc technique, adversely affects PTV homogeneity index, bladder dose, and small bowel NTCP. Other evaluated collimator angles did not significantly affect VMAT dosimetrical or radiobiological outcomes.

Exploring ncRNAs in epilepsy: From oxidative stress regulation to therapy.

Epilepsy is a prevalent neurological illness which is linked with high worldwide burdens. Oxidative stress (OS) is recognized to be among the contributors that trigger the advancement of epilepsy, affecting neuronal excitability and synaptic transmission. Various types of non-coding RNAs (ncRNAs) are known to serve vital functions in many disease mechanisms, including epilepsy. The current review sought to understand better the mechanisms through which these ncRNAs regulate epilepsy's OS-related pathways. We investigated the functions of microRNAs in controlling gene expression at the post-translatory stage and their involvement in OS and neuroinflammation. We also looked at the different regulatory roles of long ncRNAs, including molecular scaffolding, enhancer, and transcriptional activator, during OS. Circular RNAs and their capability to act as miRNA decoys and their consequential impact on epilepsy development were also explored. Our review aimed to improve the current understanding of novel therapies for epilepsy based on the role of ncRNAs in OS pathways. We also demonstrated the roles of ncRNAs in epilepsy treatment and diagnosis, explaining that these molecules play vital roles that could be used in therapy as biomarkers.

GAS5 lncRNA: A biomarker and therapeutic target in breast cancer.

Breast cancer is one of the most common causes of cancer-related mortality globally, and its aggressive phenotype results in poor treatment outcomes. Growth Arrest-Specific 5 long non-coding RNA has attracted considerable attention due to its pivotal function in apoptosis regulation and tumor aggressiveness in breast cancer. Gas5 enhances apoptosis by regulating apoptotic proteins, such as caspases and BCL2 family proteins, and the sensitivity of BCCs to chemotherapeutic agents. At the same time, low levels of GAS5 increased invasion, metastasis, and overall tumor aggressiveness. GAS5 also regulates EMT markers, critical for cancer metastasis, and influences tumor cell proliferation by regulating various signaling components. As a result, GAS5 can be restored to suppress tumor development as a possible therapeutic strategy, which might present promising prospects for a patient's treatment. Its activity levels might also be a crucial indicator and diagnostic parameter for prediction. This review highlights the significant role of GAS5 in modulating apoptosis and tumor aggressiveness in breast cancer, emphasizing its potential as a therapeutic target for breast cancer treatment and management.

Breaking Barriers: Nucleic Acid Aptamers in Gastrointestinal (GI) Cancers Therapy.

Conventional cancer therapies can have significant adverse effects as they are not targeted to cancer cells and may damage healthy cells. Single-stranded oligonucleotides assembled in a particular architecture, known as aptamers, enable them to attach selectively to target areas. Usually, they are created by Systematic Evolution of Ligand by Exponential enrichment (SELEX), and they go through a rigorous pharmacological revision process to change their therapeutic half-life, affinity, and specificity. They could thus offer a viable substitute for antibodies in the targeted cancer treatment market. Although aptamers can be a better choice in some situations, antibodies are still appropriate for many other uses. The technique of delivering aptamers is simple and reasonable, and the time needed to manufacture them is relatively brief. Aptamers do not require animals or an immune response to be produced, in contrast to antibodies. When used as a medication, aptamers can directly suppress tumor cells. As an alternative, they can be included in systems for targeted drug delivery that administer medications specifically to tumor cells while reducing toxicity to healthy cells. The most recent and cutting-edge methods for treating gastrointestinal (GI) tract cancer with aptamers will be covered in this review, with a focus on targeted therapy as a means of conquering resistance to traditional medicines.

Shedding Light on the Role of Exosomal PD-L1 (ExoPD-L1) in Cancer Progression: an Update.

Exosomes are the primary category of extracellular vesicles (EVs), which are lipid-bilayer vesicles with biological activity spontaneously secreted from either normal or tansformed cells. They serve a crucial role for intercellular communication and affect extracellular environment and the immune system. Tumor-derived exosomes (TEXs) enclose high levels of immunosuppressive proteins, including programmed death-ligand 1 (PD-L1). PD-L1 and its receptor PD-1 act as crucial immune checkpoint molecules, thus facilitating tumor advancement by inhibiting immune responses. PDL-1 is abundantly present on tumor cells and interacts with PD-1 on activated T cells, resulting in T cell suppression and allowing immune evasion of cancer cells. Various FDA-approved monoclonal antibodies inhibiting the PD-1/PD-L1 interaction are commonly used to treat a diverse range of tumors. Although the achieved results are significant, some individuals have a poor reaction to PD-1/PD-L1 blocking. PD-L1-enriched TEXs may mimic the impact of cell-surface PD-L1, consequently potentiating tumor resistance to PD1/PD-L1 based therapy. In light of this, a strong correlation between circulating exosomal PD-L1 levels and response rate to anti-PD-1/PD-L1 antibody treatment has been evinced. This article inspects the function of exosomal PDL-1 in developing resistance to anti-PD-1/PD-L1 therapy for opening new avenues for overcoming tumor resistance to such modalities and development of more favored combination therapy.

Detailed role of SR-A1 and SR-E3 in tumor biology, progression, and therapy.

The first host defense systems are the innate immune response and the inflammatory response. Among innate immune cells, macrophages, are crucial because they preserve tissue homeostasis and eradicate infections by phagocytosis, or the ingestion of particles. Macrophages exhibit phenotypic variability contingent on their stimulation state and tissue environment and may be detected in several tissues. Meanwhile, critical inflammatory functions are played by macrophage scavenger receptors, in particular, SR-A1 (CD204) and SR-E3 (CD206), in a variety of pathophysiologic events. Such receptors, which are mainly found on the surface of multiple types of macrophages, have different effects on processes, including atherosclerosis, innate and adaptive immunity, liver and lung diseases, and, more recently, cancer. Although macrophage scavenger receptors have been demonstrated to be active across the disease spectrum, conflicting experimental findings and insufficient signaling pathways have hindered our comprehension of the molecular processes underlying its array of roles. Herein, as SR-A1 and SR-E3 functions are often binary, either protecting the host or impairing the pathophysiology of cancers has been reviewed. We will look into their function in malignancies, with an emphasis on their recently discovered function in macrophages and the possible therapeutic benefits of SR-A1 and SR-E3 targeting.

Targeting the Wnt/ß-catenin cascade in osteosarcoma: The potential of ncRNAs as biomarkers and therapeutics.

Osteosarcoma (OS) is a bone cancer which stems from several sources and presents with diverse clinical features, making evaluation and treatment difficult. Chemotherapy tolerance and restricted treatment regimens hinder progress in survival rates, requiring new and creative therapeutic strategies. The Wnt/ß-catenin system has been recognised as an essential driver of OS development, providing potential avenues for therapy. Non-coding RNAs (ncRNAs), such as circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and microRNAs (miRNAs), are essential in modulating the Wnt/ß-catenin cascade in OS. MiRNAs control the system by targeting vital elements, while lncRNAs and circRNAs interact with system genes, impacting OS growth and advancement. This paper thoroughly analyses the intricate interplay between ncRNAs and the Wnt/ß-catenin cascade in OS. We examine how uncontrolled levels of miRNAs, lncRNAs, and circRNAs lead to an abnormal Wnt/ß-catenin network, which elevates the development, spread, and susceptibility to the treatment of OS. We emphasise the potential of ncRNAs as diagnostic indicators and avenues for treatment in OS care. The review offers valuable insights for academics and clinicians studying OS aetiology and creating new treatment techniques for the ncRNA-Wnt/ß-catenin cascade. Utilising the oversight roles of ncRNAs in the Wnt/ß-catenin system shows potential for enhancing the outcomes of patients and progressing precision medicine in OS therapy.

Insilico generation of novel ligands for the inhibition of SARS-CoV-2 main protease (3CLpro) using deep learning.

The recent emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the coronavirus disease (COVID-19) has become a global public health crisis, and a crucial need exists for rapid identification and development of novel therapeutic interventions. In this study, a recurrent neural network (RNN) is trained and optimized to produce novel ligands that could serve as potential inhibitors to the SARS-CoV-2 viral protease: 3 chymotrypsin-like protease (3CLpro). Structure-based virtual screening was performed through molecular docking, ADMET profiling, and predictions of various molecular properties were done to evaluate the toxicity and drug-likeness of the generated novel ligands. The properties of the generated ligands were also compared with current drugs under various phases of clinical trials to assess the efficacy of the novel ligands. Twenty novel ligands were selected that exhibited good drug-likeness properties, with most ligands conforming to Lipinski's rule of 5, high binding affinity (highest binding affinity: -9.4 kcal/mol), and promising ADMET profile. Additionally, the generated ligands complexed with 3CLpro were found to be stable based on the results of molecular dynamics simulation studies conducted over a 100 ns period. Overall, the findings offer a promising avenue for the rapid identification and development of effective therapeutic interventions to treat COVID-19.

In the Quest for Potent and Selective Malic Enzyme 3 Inhibitors for the Treatment of Pancreatic Ductal Adenocarcinoma.

The genome of pancreatic ductal adenocarcinoma (PDAC) is associated with frequent deletion of the tumor suppressor gene SMAD family member 4 (SMAD4) with collateral deletion of its chromosomal neighbor malic enzyme 2 (ME2). In SMAD4 -/- /ME2 -/- PDAC cells, ME3 takes over the function of the ME2 enzyme, and hence therapeutic targeting of ME3 is expected to arrest tumor growth. Hitherto no selective small molecule inhibitor of ME3 has been reported in the context of PDAC. Based on the molecular docking studies and structure-activity relationships with the reported ME1 inhibitor, several analogues of 6-piperazin-1-ylpyridin-3-ol amides have been synthesized and screened for their ME inhibition activity. Among them, compound 16b is identified as the most potent and selective ME3 inhibitor with an IC50 of 0.15 µM on ME3, and with 15- and 9-fold selectivity over ME1 and ME2, respectively. In the cell viability assay, compound 16b exhibited an IC50 of 3.5 µM on ME2-null PDAC cells, viz., BxPC-3.

Preparation of Novel Nanoformulation to Enhance Efficacy in the Treatment of Cardiovascular Disease.

Despite many efforts over the last few decades, cardiac-based drug delivery systems are experiencing major problems, such as the effective delivery of the precise amount of a drug. In the current study, an effort has been made to prepare a nano-herbformulation (NHF) to overcome the major problem of conventional intervention. Copper oxide-based NHF was prepared using plant extract of Alternanthera sessilis and characterized using physicochemical techniques such as Transmission electron microscopy (TEM), X-ray powder diffraction (XRD), Dynamic light scattering (DLS), UV-Vis spectroscopy, and Fourier-transform infrared spectroscopy (FTIR). TEM analysis revealed that spherical NHF obtained of size 20-50 nm. In addition, XRD and FTIR confirmed the presence of phytochemicals with biological properties over the surface of copper oxide-based NHF. It was demonstrated that dose-dependent antiapoptotic activity was shown against DOX-induced cardiomyocytes, where ROS levels were significantly reduced to 0.29% from 37.99%. The results of the flow cytometry analysis using PI and Annexin staining further confirmed the antiapoptotic activity of NHF against DOX-induced cardiomyocytes by ROS scavenging. Thus, NHF might be used for cardiovascular disease treatment.

Preparation of Paclitaxel-Encapsulated Bio-Functionalized Selenium Nanoparticles and Evaluation of Their Efficacy against Cervical Cancer.

The potentiality of nanomedicine in the cancer treatment being widely recognized in the recent years. In the present investigation, the synergistic effects of chitosan-modified selenium nanoparticles loaded with paclitaxel (PTX-chit-SeNPs) were studied. These selenium nanoparticles were tested for drug release analysis at a pH of 7.4 and 5.5, and further characterized using FTIR, DLS, zeta potential, and TEM to confirm their morphology, and the encapsulation of the drug was carried out using UPLC analysis. Quantitative evaluation of anti-cancer properties was performed via MTT analysis, apoptosis, gene expression analysis, cell cycle arrest, and over-production of ROS. The unique combination of phytochemicals from the seed extract, chitosan, paclitaxel, and selenium nanoparticles can be effectively utilized to combat cancerous cells. The production of the nanosystem has been demonstrated to be cost-effective and have unique characteristics, and can be utilized for improving future diagnostic approaches.

Bioaugmentation of Soil with Pseudomonas monteilii Strain Eliminates Inhibition of Okra (Abelmoschus esculentus) Seed Germination by m-Cresol.

Cresols are ubiquitous in nature due to their bulk production and end uses in various industrial processes as well as due to their natural presence. They are highly toxic to both fauna and flora and are included in the list of priority pollutants. In the present study, the effect of m-cresol on germination of ten different crop seeds was tested and the seeds of okra and eggplant were found to be very sensitive, okra being the most vulnerable. Okra seeds lost its viability in the presence of m-cresol, which was proportionate to its concentration as indicated by the standard 2,3,5-tetrazoliumtrichloride (TTC) test. Marked decrease in protease and amylase activities was observed in germinating seeds exposed to the compound. The inhibitory effect of m-cresol on germination was eliminated effectively by bioaugmentation of the soil with the cresol-degrading Pseudomonas monteilii S-CSR-0014. Normal germination and seedling vigor were obtained when the seeds were sown four and eight days after the soil inoculation with the bacterial cells, whereas the seeds sown immediately did not show proper germination. The inoculated bacterium degraded m-cresol efficiently from the spiked soil and exhibited concomitant growth. It can be concluded that m-cresol-contaminated soils could be effectively bioremediated to render the soil suitable for normal seed germination and healthy seedling growth of sensitive crops.

Chemopreventive mechanism of action by oxidative stress and toxicity induced surface decorated selenium nanoparticles.

BACKGROUND: Scientists are working on creating novel materials that can help in the treatment of diverse cancer-related diseases having trademark highlights like the target siting, specificity, improved therapeutic index of radiotherapy and chemotherapeutic treatments. The utilization of novel nanomaterials which are surface adorned with drugs or natural compounds can be used in diverse medical applications and helps in setting up a new platform for its improvement in the chemotherapeutic potentiality. One such nanomaterial is the trace element selenium in its nanoparticulate form that has been proved to be a potential chemotherapeutic agent recently. METHODS: The English language papers were gathered from electronic databases like Sciencedirect, Pub Med, Google Scholar and Scopus, the papers are published from 2001 to 2019. RESULTS: In the initial phase, approximately 200 papers were searched upon, out of which 118 articles were included after screening and critical reviewing. The information included was also tabulated for better knowledge and easy read. These articles contain information on the nanotechnology, inflammation, cancer and selenium as nanoparticles. CONCLUSION: The overview of the paper explains the enhancement of potentiality of anticancer drugs or phytochemicals which restricts its utilization in chemotherapeutic applications by the encapsulation or adsorption of them on selenium nanoparticles proven to accelerate the anticancerous properties with better results when compared with individual components. SeNPs (selenium nanoparticles) have demonstrated chemotherapeutic activity due to pro-oxidant property, where the anti-oxidant enzymes are stimulated to produce reactive active species, which induces oxidative stress, followed by activation of the apoptotic signalling pathway, cell cycle arrest, mitochondrial dysfunction and other pathways that ultimately lead to cell death. Selenium in nanoparticulate form can be used as a micronutrient to human health, thereby having low toxicity, can easily be degraded and also has good biocompatibility.

Antibacterial and antioxidant potential of biosynthesized copper nanoparticles mediated through Cissus arnotiana plant extract.

Environment friendly methods for the synthesis of copper nanoparticles have become a valuable trend in the current scenario. The utilization of phytochemicals from plant extracts has become a unique technology for the synthesis of nanoparticles, as they possess dual nature of reducing and capping agents to the nanoparticles. In the present investigation we have synthesized copper nanoparticles (CuNPs) using a rare medicinal plant Cissus arnotiana and evaluated their antibacterial activity against gram negative and gram positive bacteria. The morphology and characterization of the synthesized CuNPs were studied and done using UV-Visible spectroscopy at a wavelength range of 350-380 nm. XRD studies were performed for analyzing the crystalline nature; SEM and TEM for evaluating the spherical shape within the size range of 60-90 nm and AFM was performed to check the surface roughness. The biosynthesized CuNPs showed better antibacterial activity against the gram-negative bacteria, E. coli with an inhibition zone of 22.20 ±â€¯0.16 mm at 75 µg/ml. The antioxidant property observed was comparatively equal with the standard antioxidant agent ascorbic acid at a maximum concentration of 40 µg/ ml. This is the first study reported on C. arnotiana mediated biosynthesis of copper nanoparticles, where we believe that the findings can pave way for a new direction in the field of nanotechnology and nanomedicine where there is a significant potential for antibacterial and antioxidant activities. We predict that, these could lead to an exponential increase in the field of biomedical applications, with the utilization of green synthesized CuNPs, due to its remarkable properties. The highest antibacterial property was observed with gram-negative strains mainly, E. coli, due to its thin peptidoglycan layer and electrostatic interactions between the bacterial cell wall and CuNPs surfaces. Hence, CuNPs can be potent therapeutic agents in several biomedical applications, which are yet to be explored in the near future.

Selenium nanoparticles: A potent chemotherapeutic agent and an elucidation of its mechanism.

Selenium nanoparticles have at present picked up a vital prospect in the field of medicine, due to their inquisitive properties when compared to other selenium compounds. They are comparatively better as anticancer, non- toxic, and biocompatible operators than selenite (SeO3-2) and selenate (SeO4-2) compounds. The mechanism behind the anticancerous property of SeNps is primarily due to the invasion of the apoptotic pathways and cell cycle arrest, which eventually lead to blockage of other pathways. Conjugation or surface modification of selenium nanoparticles enhances its anticancer adequacy by antibiotics, biomolecules or phytochemical compounds present in microbes or plants. Selenium, being an integral part of enzyme like glutathione peroxidase (GPx) and other seleno-chemical compounds, can enhance the chemotherapeutic activity by acting as a functional division of redox center and inhibiting the tissues from cellular damage by ROS. SeNps can open ways to new regular strategies for treating illnesses like malignancy, and this audit expresses the reasons why these nano measured medications can be the following huge achievement as chemotherapeutic operators.