Molecular Docking of Bacterial Protein Modulators and Pharmacotherapeutics of Carica papaya Leaves as a Promising Therapy for Sepsis: Synchronising In Silico and In Vitro Studies.

Sepsis is a serious health concern globally, which necessitates understanding the root cause of infection for the prevention of proliferation inside the host's body. Phytochemicals present in plants exhibit antibacterial and anti-proliferative properties stipulated for sepsis treatment. The aim of the study was to determine the potential role of Carica papaya leaf extract for sepsis treatment in silico and in vitro. We selected two phytochemical compounds, carpaine and quercetin, and docked them with bacterial proteins, heat shock protein (PDB ID: 4PO2), surfactant protein D (PDB ID: 1PW9), and lactobacillus bacterial protein (PDB ID: 4MKS) against imipenem and cyclophosphamide. Quercetin showed the strongest interaction with 1PW9 and 4MKS proteins. The leaves were extracted using ethanol, methanol, and water through Soxhlet extraction. Total flavonoid content, DPPH assay, HPTLC, and FTIR were performed. In vitro cytotoxicity of ethanol extract was screened via MTT assay on the J774 cell line. Ethanol extract (EE) possessed the maximum number of phytocomponents, the highest amount of flavonoid content, and the maximum antioxidant activity compared to other extracts. FTIR analysis confirmed the presence of N-H, O-H, C-H, C=O, C=C, and C-Cl functional groups in ethanol extract. Cell viability was highest (100%) at 25 µg/mL of EE. The present study demonstrated that the papaya leaves possessed antibacterial and cytotoxic activity against sepsis infection.

Mechanistic and Etiological Similarities in Diabetes Mellitus and Alzheimer's Disease: Antidiabetic Drugs as Optimistic Therapeutics in Alzheimer's Disease.

BACKGROUND: Diabetes mellitus and Alzheimer's disease are two common diseases that majorly affect the elderly population. Patients in both cases are increasing day by day. They are considered two independent diseases, but recent evidence suggests that they have a lot in common. OBJECTIVE: In this review, we focused on the connection between Alzheimer's disease and diabetes and highlighted the importance of antidiabetic drugs against Alzheimer's disease. METHODS: Common pathways such as obesity, vascular diseases, oxidative stress, mitochondrial dysfunction, mutation of the ApoE4 gene, and Sirtuin gene were found to manipulate both diseases. Antidiabetic drugs are found to have promising effects on Alzheimer's disease, acting by reducing insulin resistance, neuronal protection, and reducing amyloid-beta plaques. Some anti-diabetic drugs have shown promising results in vivo and in vitro studies. RESULTS: No review present focuses on the structural features of the antidiabetic molecules against Alzheimer's disease, their crosslinking pathophysiology, the role of natural bioactive molecules, in silico advancements followed by preclinical and clinical studies, and current advancements. Hence, we concentrated on the factors mentioned in the objectives. CONCLUSION: Alzheimer's disease can be considered a form of 'type-3 diabetes,' and repurposing the anti-diabetic drug will open up new paths of research in the field of Alzheimer's disease drug discovery.

Structure-Activity Relationship Insight of Naturally Occurring Bioactive Molecules and Their Derivatives Against Non-Small Cell Lung Cancer: A Comprehensive Review.

BACKGROUND: Non-small cell lung cancer (NSCLC) is a deadly disease that affects millions globally and its treatment includes surgery, chemotherapy, and radiotherapy. Chemotherapy and radiotherapy have many disadvantages, which include potential harmful side effects. Due to the widespread use of drugs in lung cancer, drug treatment becomes challenging due to multidrug resistance and adverse reactions. According to the recent findings, natural products (NPs) and their derivatives are being used to inhibit and suppress cancer cells. OBJECTIVE: Our objective is to highlight the importance of phytochemicals for treating NSCLC by focusing on the structural features essential for the desired activity with fewer side effects compared to synthetic molecules. METHODS: This review incorporated data from the most recent literature, including in vitro, in vivo, nanoformulation-based recent advancements, and clinical trials, as well as the structure-activity relationship (SAR), described for a variety of possible natural bioactive molecules in the treatment of NSCLC. RESULTS: The analysis of data from recent in vitro, in vivo studies and ongoing clinical trials are highlighted. The SAR studies of potential NPs signify the presence of several common structural features that can be used to guide future drug design and development. CONCLUSION: The role of NPs in the battle against NSCLC can be effective, as evidenced by their structural diversity and affinity toward various molecular targets. The main purpose of the review is to gather information about NPs used in the treatment of NSCLC.

Structural Activity Relationship based Medicinal Perspectives of Pyrimidine Derivatives as Anti-Alzheimer's Agents: A Comprehensive Review.

Pyrimidine is an aromatic and heterocyclic organic compound containing a 6-membered ring consisting of four carbon and two nitrogen atoms on alternative positions. Pyrimidine scaffolds described their existence in the medicinal chemist's cause for their synthesizing practicability and nonpoisonous nature. However, the reason behind neurological disorders is still an open challenge for scientific research and development organizations. Efficacy voids are widespread before researchers, despite high throughput research in the field of anti-Alzheimer's drugs.Researchers have constantly investigated all the probabilities for restraining the unwanted adverse effects of the anti-Alzheimer's agents and are focusing more extensively to rehabilitate neurological disorders. The scientific literature on drug development has been an aspiration to medicinal chemists and other researchers to facilitate further research. Therefore, this review emphasizes the structure-activity relationship (SAR) based approach and the pharmacological advancements of pyrimidine moiety in the new era of therapeutics as anti-Alzheimer's agents.

Recent Advancement of Pyrazole Scaffold Based Neuroprotective Agents: A Review.

As a source of therapeutic agents, heterocyclic nitrogen-containing compounds and their derivatives are still interesting and essential. Pyrazole, a five-member heteroaromatic ring with two nitrogen atoms, has a major impact in chemical industries as well as pharmaceutical industries. Due to its wide range of biological activities against various diseases, it has been identified as a biologically important heterocyclic scaffold. The treatment of neurological disorders has always been a difficult task in both the past and present. Therefore, identifying therapeutically effective molecules for neurological conditions remains an open challenge in biomedical research and development. For developing novel entities as neuroprotective agents, recently, pyrazole scaffold has attracted medicinal chemists worldwide. The major focus of research in this area is discovering novel molecules as neuroprotective agents with minimal adverse effects and better effectiveness in improving the neurological condition. This review mainly covers recent developments in the neuropharmacological role of pyrazole incorporated compounds, including their structural-activity relationship (SAR), which also further includes IC50 values (in mM as well as in µM), recent patents, and a brief history as neuroprotective agents.

Synthesis, biological evaluation and molecular dynamics studies of oxadiazine derivatives as potential anti-hepatotoxic agents.

Generally, herbal medicines having remarkable popularity for treating liver ailments, but they are still unacceptable because of the deprivation of herbal drug standardization. Therefore, there is a need for promising synthetic drugs to overcome the critical liver problem. We introduce 1, 3, 4-oxadiazine ring in this study to identify better anti-hepatotoxic agents via a suitable synthetic route. These oxadiazine-based derivatives were structurally confirmed by analytical and spectral data and evaluated for their anti-hepatotoxic potential. Further, in vitro hepatotoxicity studies have been done to check the toxicity level in the synthesized compound. Compounds 5a, 5b, 5c and 9d were selected for further biological evaluation according to in vitro results. After that, CCl4-induced animal model was used to evaluate in vivo anti-hepatotoxicity activity. Compound 5a with 52.99%, 59.3%, 79.34% and 5b with 52.16%, 57.65%, 75.10% revealed to be most promising for reduction in level of SGPT, SGOT and ALKP, respectively. Moreover, it was also observed that the compound 5a with 411.01%, 53.39% and 5b with 378.63%, 48.9% level of albumin and total protein were respectively. The induced-fit docking results of the compounds 5a and 5b reveal some essential binding information and exhibited desirable ADME properties, and obeyed Lipinski's rule of five. In addition, molecular dynamics studies for 100 ns further confirm the protein-ligand complex's stability, supporting the in vitro and in vivo data, and help in establishing the SAR of synthesized compounds. Two compounds, 5a and 5 b, exhibited higher anti-hepatotoxic activity than the standard drug silymarin.

The controversial therapeutic journey of chloroquine and hydroxychloroquine in the battle against SARS-CoV-2: A comprehensive review.

Recently, the pandemic outbreak of a novel coronavirus, officially termed as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), indicated by a pulmonary infection in humans, has become one of the most significant challenges for public health. In the current fight against coronavirus disease-2019, the medical and health authorities across the world focused on quick diagnosis and isolation of patients; meanwhile, researchers worldwide are exploring the possibility of developing vaccines and novel therapeutic options to combat this deadly disease. Recently, based on various small clinical observations, uncontrolled case studies and previously reported antiviral activity against SARS-CoV-1 chloroquine (CQ) and hydroxychloroquine (HCQ) have attracted exceptional consideration as possible therapeutic agents against SARS-CoV-2. However, there are reports on little to no effect of CQ or HCQ against SARS-CoV-2, and many reports have raised concerns about their cardiac toxicity. Here, in this review, we examine the chemistry, molecular mechanism, and pharmacology, including the current scenario and future prospects of CQ or HCQ in the treatment of SARS-CoV-2.

Magnetic resonance imaging of lumbar intervertebral discs in elderly patients with minor trauma.

PURPOSE: Vertebral body fractures due to minor trauma, which commonly occur in the elderly, are a frequently encountered clinical problem. We utilized MRI in patients with acute back pain following minor injury to ensure the earliest possible diagnosis. Lumbar discs adjacent to fractured vertebral bodies were evaluated, using magnetic resonance imaging (MRI), to elucidate how often these discs were injured and how the injured discs were depicted by MRI. MATERIALS AND METHODS: We retrospectively reviewed MR images of 74 discs from 37 elderly patients (>65-year-old) with a single level vertebral fracture (fracture group). Patients with multiple-level fractures, burst fractures and/or major trauma, such as that resulting from a traffic accident, were excluded from this study. We also reviewed MR images of 190 discs from 27 elderly patients diagnosed with lumbar stenosis, who had no previous history of vertebral body fractures (stenosis group). RESULTS: In the fracture group, 23% (17/74) of T1-weighted images exhibited a high-intensity area in the disc, whereas only 3% (5/190) exhibited a high-intensity area in the stenosis group. In some cases, in the T2-weighted images we also found a high-intensity zone in discs that showed low- or iso-intensity. This phenomenon was more frequently observed in the fracture group (47%: 35/74) than in the stenosis group. CONCLUSION: The present study indicates that, in elderly patients, intervertebral discs adjacent to vertebral fractures resulting from minor trauma are often injured. Because hemorrhage is the most likely cause of a high-intensity T1-weighted image, the results indicate that hemorrhage can be induced in a disc adjacent to a vertebral body fractured by even minor trauma.

Short segment pedicle screw instrumentation and augmentation vertebroplasty in lumbar burst fractures: an experience.

To assess the efficacy and feasibility of vertebroplasty and posterior short-segment pedicle screw fixation for the treatment of traumatic lumbar burst fractures. Short-segment pedicle screw instrumentation is a well described technique to reduce and stabilize thoracic and lumbar spine fractures. It is relatively a easy procedure but can only indirectly reduce a fractured vertebral body, and the means of augmenting the anterior column are limited. Hardware failure and a loss of reduction are recognized complications caused by insufficient anterior column support. Patients with traumatic lumbar burst fractures without neurologic deficits were included. After a short segment posterior reduction and fixation, bilateral transpedicular reduction of the endplate was performed using a balloon, and polymethyl methacrylate cement was injected. Pre-operative and post-operative central and anterior heights were assessed with radiographs and MRI. Sixteen patients underwent this procedure, and a substantial reduction of the endplates could be achieved with the technique. All patients recovered uneventfully, and the neurologic examination revealed no deficits. The post-operative radiographs and magnetic resonance images demonstrated a good fracture reduction and filling of the bone defect without unwarranted bone displacement. The central and anterior height of the vertebral body could be restored to 72 and 82% of the estimated intact height, respectively. Complications were cement leakage in three cases without clinical implications and one superficial wound infection. Posterior short-segment pedicle fixation in conjunction with balloon vertebroplasty seems to be a feasible option in the management of lumbar burst fractures, thereby addressing all the three columns through a single approach. Although cement leakage occurred but had no clinical consequences or neurological deficit.

Percutaneous vertebroplasty for osteoporotic fractures.

BACKGROUND: Vertebral augmentation has been widely used to treat vertebral body compression fractures caused by varied pathologies. The lifetime risk of a vertebral body compression fracture is 16% for women and 5% for men, and exponential increase of osteoporotic fractures worldwide. PURPOSE: To determine the efficacy and durability of percutaneous vertebroplasty for the treatment of back pain associated with osteoporotic vertebral fractures. DESIGN: A prospective study. MATERIALS AND METHODS: A prospective evaluation of pain relief in 30 patients, with mean age of 73.7 years, who underwent percutaneous injection of polymethyl methacrylate into 54 vertebrae under fluoroscopic guidance over a period of 35 months was done. Before the procedure and at follow up, patients were asked to quantify their pain on a visual analogue scale. RESULTS: The procedure was technically successful in all the patients. Mean duration of follow up was 21.5 months (6-44 months). Ninety-seven percent of the patients reported a significant relief 24 hours after the procedure. Ninety-two percent reported significant improvement in back pain, previously associated with a compression fracture, as well as improved ambulatory ability. Before vertebroplasty, the VAS score was 8.91+/- 1.82 compared to a score of 2.02+/- 1.95 at follow up. The mean difference in VAS score was significant (p<.0001). One patient had an asymptomatic epidural leak of PMMA, however did not require any further intervention. CONCLUSION: Percutaneous vertebroplasty of symptomatic osteoporotic vertebral compression fractures is a minimally invasive procedure that provides immediate and sustained pain relief in patients with refractory pain.