Unveiling the molecular mechanisms: dietary phytosterols as guardians against cardiovascular diseases.

Until recently, the main pharmaceuticals used to control cholesterol and prevent cardiovascular disease (CVD) were statin-related drugs, known for their historical side effects. Therefore, there is growing interest in exploring alternatives, such as nutritional and dietary components, that could play a central role in CVD prevention. This review aims to provide a comprehensive understanding of how natural phytosterols found in various diets combat CVDs. We begin with a description of the overall approach, then we explore in detail the different direct and indirect mechanisms that contribute to reducing cardiovascular incidents. Phytosterols, including stigmasterol, ß-sitosterol, ergosterol, and fucosterol, emerge as promising molecules within nutritional systems for protection against CVDs due to their beneficial effects at different levels through direct or indirect cellular, subcellular, and molecular mechanisms. Specifically, the mentioned phytosterols exhibit the ability to diminish the generation of various radicals, including hydroperoxides and hydrogen peroxide. They also promote the activation of antioxidant enzymes such as superoxide dismutase, catalase, and glutathione, while inhibiting lipid peroxidation through the activation of Nrf2 and Nrf2/heme oxygenase-1 (HO-1) signaling pathways. Additionally, they demonstrate a significant inhibitory capacity in the generation of pro-inflammatory cytokines, thus playing a crucial role in regulating the inflammatory/immune response by inhibiting the expression of proteins involved in cellular signaling pathways such as JAK3/STAT3 and NF-κB. Moreover, phytosterols play a key role in reducing cholesterol absorption and improving the lipid profile. These compounds can be used as dietary supplements or included in specific diets to aid control cholesterol levels, particularly in individuals suffering from hypercholesterolemia.

Transcutaneous auricular vagus nerve stimulation modifies cortical excitability in middle-aged and older adults.

There is a growing interest in the clinical application of transcutaneous auricular vagus nerve stimulation (taVNS). However, its effect on cortical excitability, and whether this is modulated by stimulation duration, remains unclear. We evaluated whether taVNS can modify excitability in the primary motor cortex (M1) in middle-aged and older adults and whether the stimulation duration moderates this effect. In addition, we evaluated the blinding efficacy of a commonly reported sham method. In a double-blinded randomized cross-over sham-controlled study, 23 healthy adults (mean age 59.91 ± 6.87 years) received three conditions: active taVNS for 30 and 60 min and sham for 30 min. Single and paired-pulse transcranial magnetic stimulation was delivered over the right M1 to evaluate motor-evoked potentials. Adverse events, heart rate and blood pressure measures were evaluated. Participant blinding effectiveness was assessed via guesses about group allocation. There was an increase in short-interval intracortical inhibition (F = 7.006, p = .002) and a decrease in short-interval intracortical facilitation (F = 4.602, p = .014) after 60 min of taVNS, but not 30 min, compared to sham. taVNS was tolerable and safe. Heart rate and blood pressure were not modified by taVNS (p > .05). Overall, 96% of participants detected active stimulation and 22% detected sham stimulation. taVNS modifies cortical excitability in M1 and its effect depends on stimulation duration in middle-aged and older adults. taVNS increased GABAAergic inhibition and decreased glutamatergic activity. Sham taVNS protocol is credible but there is an imbalance in beliefs about group allocation.

Chemistry, Biological Activities, and Pharmacological Properties of Gastrodin: Mechanism Insights.

Gastrodin, a bioactive compound derived from the rhizome of the orchid Gastrodia elata, exhibits a diverse range of biological activities. With documented neuroprotective, anti-inflammatory, antioxidant, anti-apoptotic, and anti-tumor effects, gastrodin stands out as a multifaceted therapeutic agent. Notably, it has demonstrated efficacy in protecting against neuronal damage and enhancing cognitive function in animal models of Alzheimer's disease, Parkinson's disease, and cerebral ischemia. Additionally, gastrodin showcases immunomodulatory effects by mitigating inflammation and suppressing the expression of inflammatory cytokines. Its cytotoxic activity involves the inhibition of angiogenesis, suppression of tumor growth, and induction of apoptosis. This comprehensive review seeks to elucidate the myriad potential effects of Gastrodin, delving into the intricate molecular mechanisms underpinning its pharmacological properties. The findings underscore the therapeutic potential of gastrodin in addressing various conditions linked to neuroinflammation and cancer.

Identification of new potent NLRP3 inhibitors by multi-level in-silico approaches.

Nod-like receptor protein 3 (NLRP-3), is an intracellular sensor that is involved in inflammasome activation, and the aberrant expression of NLRP3 is responsible for diabetes mellitus, its complications, and many other inflammatory diseases. NLRP3 is considered a promising drug target for novel drug design. Here, a pharmacophore model was generated from the most potent inhibitor, and its validation was performed by the Gunner-Henry scoring method. The validated pharmacophore was used to screen selected compounds databases. As a result, 646 compounds were mapped on the pharmacophore model. After applying Lipinski's rule of five, 391 hits were obtained. All the hits were docked into the binding pocket of target protein. Based on docking scores and interactions with binding site residues, six compounds were selected potential hits. To check the stability of these compounds, 100 ns molecular dynamic (MD) simulations were performed. The RMSD, RMSF, DCCM and hydrogen bond analysis showed that all the six compounds formed stable complex with NLRP3. The binding free energy with the MM-PBSA approach suggested that electrostatic force, and van der Waals interactions, played a significant role in the binding pattern of these compounds. Thus, the outcomes of the current study could provide insights into the identification of new potential NLRP3 inflammasome inhibitors against diabetes and its related disorders.

Herbal remedies in the management of hyperuricemia and gout: A review of in vitro, in vivo and clinical evidences.

Gout, or hyperuricemia is a multifactorial and multi-faceted metabolic disease that is quite difficult to manage and/or treat. Conventional therapies such as non-steroidal anti-inflammatory drugs (NSAIDs) such as allopurinol, corticosteroids and colchicine amongst others, have helped in its management and treatment to some extent. This study aimed to compile and analyze the different herbal remedies used in the management of hyperuricemia and gout. A literature search was conducted from key databases (PubMed, ScienceDirect, Cochrane Library, Google Scholar) using relevant keywords via the PRISMA model. Smilax riparia A.DC. from Traditional Chinese Medicine is used in many countries for its therapeutic effect on lowering serum urate levels. No single study was able to establish the efficacy of a specific traditionally used herb via in vitro, in vivo, and clinical studies. Patients were found to use a panoply of natural remedies, mainly plants to treat hyperuricemia and gout, which have been validated to some extent by in vitro, in vivo, and clinical studies. Nonetheless, further research is needed to better understand the ethnopharmacological relationship of such herbal remedies.

Innovative Encapsulation Strategies for Food, Industrial, and Pharmaceutical Applications.

Bioactive metabolites obtained from fruits and vegetables as well as many drugs have various capacities to prevent or treat various ailments. Nevertheless, their efficiency, in vivo, encounter many challenges resulting in lower efficacy as well as different side effects when high doses are used resulting in many challenges for their application. Indeed, demand for effective treatments with no or less unfavorable side effects is rising. Delivering active molecules to a particular site of action within the human body is an example of targeted therapy which remains a challenging field. Developments of nanotechnology and polymer science have great promise for meeting the growing demands of efficient options. Encapsulation of active ingredients in nano-delivery systems has become as a vitally tool for protecting the integrity of critical biochemicals, improving their delivery, enabling their controlled release and maintaining their biological features. Here, we examine a wide range of nano-delivery techniques, such as niosomes, polymeric/solid lipid nanoparticles, nanostructured lipid carriers, and nano-emulsions. The advantages of encapsulation in targeted, synergistic, and supportive therapies are emphasized, along with current progress in its application. Additionally, a revised collection of studies was given, focusing on improving the effectiveness of anticancer medications and addressing the problem of antimicrobial resistance. To sum up, this paper conducted a thorough analysis to determine the efficacy of encapsulation technology in the field of drug discovery and development.

Bioactive compounds from nature: Antioxidants targeting cellular transformation in response to epigenetic perturbations induced by oxidative stress.

Oxidative stress results from a persistent imbalance in oxidation levels that promotes oxidants, playing a crucial role in the early and sustained phases of DNA damage and genomic and epigenetic instability, both of which are intricately linked to the development of tumors. The molecular pathways contributing to carcinogenesis in this context, particularly those related to double-strand and single-strand breaks in DNA, serve as indicators of DNA damage due to oxidation in cancer cases, as well as factors contributing to epigenetic instability through ectopic expressions. Oxidative stress has been considered a therapeutic target for many years, and an increasing number of studies have highlighted the promising effectiveness of natural products in cancer treatment. In this regard, we present significant research on the therapeutic targeting of oxidative stress using natural molecules and underscore the essential role of oxidative stress in cancer. The consequences of stress, especially epigenetic instability, also offer significant therapeutic prospects. In this context, the use of natural epi-drugs capable of modulating and reorganizing the epigenetic network is beginning to emerge remarkably. In this review, we emphasize the close connections between oxidative stress, epigenetic instability, and tumor transformation, while highlighting the role of natural substances as antioxidants and epi-drugs in the anti-tumoral context.

Evaluation of the General Population's Knowledge Concerning Liver Health: A Cross-Sectional Study.

INTRODUCTION: Liver disease is among the leading causes of global mortality and morbidity. Given their substantial impact on public health, raising awareness about liver diseases is paramount for their prevention and effective management. This study aimed to evaluate the knowledge, awareness, attitudes, and behaviors of Syrians regarding liver health, chronic liver disorders, and their associated serious and irreversible complications. METHODS: We conducted a cross-sectional study encompassing the adult Syrian population between August 25 and September 29, 2023, excluding non-Syrians and individuals below the age of 18 years. A validated questionnaire, adapted from a previous study, was employed, consisting of 31 questions that covered topics related to knowledge and awareness of liver health and diseases (3-point Likert scale), attitudes towards liver screening, diagnosis, and treatment, and awareness of treatment options and vaccination. Statistical analysis including logistic regression was conducted using Statistical Product and Service Solutions (SPSS, version 28; IBM SPSS Statistics for Windows, Armonk, NY), with statistical significance set established at pp-values below 0.05. RESULTS: This study included 941 participants, with an average age of 26.5 years. While two-thirds of respondents demonstrated awareness of hepatitis B and C as viral diseases (663 (70.4%) and 612 (65.4%), respectively), approximately 66 (7%) were unaware of the potential for hepatitis to induce chronic liver inflammation or lead to liver failure. Over half of the participants were knowledgeable about the non-genetic nature of hepatitis B and C, and 579 (61.7%) were informed about the transmission risks associated with these infections. The most common reason cited for not participating in health screening tests was the perception of being in good health (219, 77.4%), and prescription medication was the most frequently sought treatment for hepatitis (543, 83.9%). Bivariate analysis revealed correlations between participant knowledge and sex, socioeconomic status, educational level, and occupation (P < 0.05). Similarly, the study identified significant associations between participant attitudes and age, gender, economic status, job, and educational level (P < 0.05). Moreover, the multivariate analysis demonstrated that gender, occupation, and educational level significantly influenced both participants' knowledge and attitudes. Specifically, males exhibited lower knowledge and less favorable attitudes than females (P = 0.041 and P < 0.001, respectively). CONCLUSION: The Syrian population possessed moderate knowledge of liver health and liver disorders. To bridge this knowledge gap and enhance preventive measures, it is recommended that additional health programs and awareness initiatives be implemented, involving healthcare providers and leveraging their expertise.

Prospective virtual screening combined with bio-molecular simulation enabled identification of new inhibitors for the KRAS drug target.

Lung cancer is a disease with a high mortality rate and it is the number one cause of cancer death globally. Approximately 12-14% of non-small cell lung cancers are caused by mutations in KRASG12C. The KRASG12C is one of the most prevalent mutants in lung cancer patients. KRAS was first considered undruggable. The sotorasib and adagrasib are the recently approved drugs that selectively target KRASG12C, and offer new treatment approaches to enhance patient outcomes however drug resistance frequently arises. Drug development is a challenging, expensive, and time-consuming process. Recently, machine-learning-based virtual screening are used for the development of new drugs. In this study, we performed machine-learning-based virtual screening followed by molecular docking, all atoms molecular dynamics simulation, and binding energy calculations for the identifications of new inhibitors against the KRASG12C mutant. In this study, four machine learning models including, random forest, k-nearest neighbors, Gaussian naïve Bayes, and support vector machine were used. By using an external dataset and 5-fold cross-validation, the developed models were validated. Among all the models the performance of the random forest (RF) model was best on the train/test dataset and external dataset. The random forest model was further used for the virtual screening of the ZINC15 database, in-house database, Pakistani phytochemicals, and South African Natural Products database. A total of 100 ns MD simulation was performed for the four best docking score complexes as well as the standard compound in complex with KRASG12C. Furthermore, the top four hits revealed greater stability and greater binding affinities for KRASG12C compared to the standard drug. These new hits have the potential to inhibit KRASG12C and may help to prevent KRAS-associated lung cancer. All the datasets used in this study can be freely available at ( https://github.com/Amar-Ajmal/Datasets-for-KRAS ).

Identification of subtle residual sacroiliac joint flexion and extension malreductions in AO/OTA 61-C1.2 (APC3) pelvic injuries after provisional anterior ring reduction.

PURPOSE: Hemipelvis reduction in the setting of AO/OTA 61-C1.2 (APC3) pelvic injuries can be challenging. A common strategy is to provisionally reduce or fix the anterior ring prior to definitive fixation of the posterior ring. In this scenario, it is difficult to assess whether residual sacroiliac joint (SIJ) widening is due to hemipelvis flexion/extension or lateral displacement. This simulation sought to identify a radiographic marker for posterior ilium flexion or extension malreduction in the setting of a reduced anterior ring. METHODS: Symphyseal and both anterior and posterior SIJ ligaments were cut in 8 cadaveric pelvis. The symphysis was reduced and wired. One centimeter of posterior flexion or extension at the SIJ was created to mimic the clinical scenario of hemipelvis flexion or extension malreduction, and a lateral compressive force was applied. SIJ widening and the direction of anterior or posterior ileal displacement relative to the contralateral joint were assessed via inlet views. SIJ widening and the direction of cranial or caudal ileal displacement were assessed using outlet views. Comparisons between flexion and extension models used Fisher's exact test. RESULTS: On outlet views, all flexed hemipelvis demonstrated caudal ileal translation at the superior SIJ, in contrast to all extended hemipelvis demonstrated cranial translation (p < 0.0005); the scenarios were easily distinguishable. Conversely, inlet imaging was unable to identify the direction of malreduction. Flexion/extension scenarios resulted in similar amounts of SIJ widening. CONCLUSION: Residual flexion and extension hemipelvis malreductions in APC3 injuries after provisional anterior fixation can be differentiated by the direction of ileal displacement at the superior SIJ on the outlet view.

Clinical application of transcutaneous auricular vagus nerve stimulation: a scoping review.

PURPOSE: Transcutaneous auricular vagus nerve stimulation (taVNS) is an emerging non-invasive neuromodulation therapy. This study aimed to explore the therapeutic use of taVNS, optimal stimulation parameters, effective sham protocols, and safety. METHODS: A scoping review was conducted. Five databases and grey literature were searched. The data extracted included stimulation parameters, adverse events (AEs), and therapeutic effects on clinical outcomes. RESULTS: 109 studies were included. taVNS was used across 21 different clinical populations, most commonly in psychiatric, cardiac, and neurological disorders. Overall, 2,214 adults received active taVNS and 1,017 received sham taVNS. Reporting of stimulation parameters was limited and inconsistent. taVNS appeared to have a favourable therapeutic effect across a wide range of clinical populations with varied parameters. Three sham protocols were reported but their effectiveness was documented in only two of the 54 sham-controlled studies. Most reported adverse events were localised to stimulation site. CONCLUSION: There is growing evidence for taVNS therapeutic effect. taVNS appears safe and tolerable. Sham protocols need evaluation. Standardised and comprehensive reporting of both stimulation parameters and adverse events is required. Two different questionnaires have been proposed to evaluate adverse events and the effectiveness of sham methods in blinding participants.

Transcutaneous auricular vagus nerve stimulation (taVNS) showed therapeutic effect across a wide range of clinical populations including depression, epilepsy, and strokeThere is a preliminary indication that daily/weekly dose and overall duration of treatment are important to show therapeutic effectivenessWhen using taVNS as an intervention, the questionnaires proposed in this review should be used to evaluate blinding effectiveness and adverse events.

Association between opioid utilization and patient reported outcome measures following lumbar spine surgery.

BACKGROUND CONTEXT: The patient-reported outcomes measurement information system (PROMIS), created by the National institute of Health, is a reliable and valid survey for patients with lumbar spine pathology. Preoperative opioid use has been shown to be an important predictor variable of self-reported health status in legacy patient reported outcome measures. PURPOSE: To investigate the impact of chronic preoperative opiate use on PROMIS survey scores. STUDY DESIGN: Retrospective database analysis. PATIENT SAMPLE: Between March 2019 and November 2021, 227 patients underwent lumbar decompression ± ≤ 2 level fusion. Fifty-seven patients (25.11%) had chronic preoperative opioid use. OUTCOME MEASURES: Oswestry disability index (ODI) and PROMIS survey scores. METHODS: A retrospective analysis of a prospectively maintained single center patient-reported outcome database was performed with a minimum of 2 year follow-up. PROMIS Anxiety, Depression, Fatigue, Pain Interference (PI), Physical Function (PF), Sleep disturbance (SD), and Social Roles (SR) surveys were recorded at preoperative intake with subsequent follow-up at 6, 12, and 24 months postoperatively. Patients were grouped into chronic opioid users as defined by >6-month duration of use. Differences in mean survey scores were evaluated using Welch t-tests. RESULTS: Two hundred and twenty-seven patients met our inclusion criteria of completed PROMIS surveys at the designated timepoints. A total of 57 (25.11%) were chronic opioid users (COU) prior to surgery. Analysis of patient-reported health outcomes shows that long term opioid use correlated with worse ODI and PROMIS scores at baseline compared to nonchronic users (NOU). At 1 and 2 year follow-up, the COU cohort continued to have significantly worse ODI, PROMIS Fatigue, PF, PI, SD, and SR scores. There is a statistical difference in the magnitude of change in health status between the 2 cohorts at 1 year follow-up in PROMIS Depression (-5.04±7.88 vs. -2.49±8.73, p=.042), PF (6.25±7.11 vs. 9.03±9.04, p=.019), and PI (-7.40±7.37 vs. -10.58±9.87, p=.011) and 2 year follow-up in PROMIS PF (5.58±6.84 vs. 7.99±9.64, p=.041) and PI (-6.71±8.32 vs. -9.62±10.06, p=.032). Mean improvement in PROMIS scores for the COU cohort at 2 year follow-up exceeded minimal clinically important difference (MCID) in all domains except PROMIS Depression, SR and SD. CONCLUSION: Patients with chronic opioid use status have worse baseline PROMIS scores compared with patients who had nonchronic use. However, patients in the COU cohort displayed clinically significant postoperative improvement in multiple PROMIS domains. These results show that patients with chronic opioid use can benefit greatly from surgical intervention and will allow physicians to better set expectations with their patients.

Return to Play Criteria After Adult Lumbar Spinal Fractures: A Review of Current Literature and Expert Recommendations.

PURPOSE OF REVIEW: Understanding the management of lumbar spinal fractures and return to play (RTP) criteria is an essential component of care for adult athletes. Appropriate management of lumbar spinal fractures must balance minimizing time away from physical activity while also minimizing risk of reinjury. The purpose of this review is to summarize current recommendations on lumbar spinal fracture management and RTP guidelines and to provide expert opinion on areas of discrepancy in the field. RECENT FINDINGS: There is a paucity of high-level evidence on the management and return to play criteria for adult lumbar spine fractures in athletes. Much of the data and recommendations are based on expert opinion and studies in pediatric or osteoporotic patients, which may not be applicable to adult athletes. These data presented here may be used to aid patient-physician conversations and provide guidance on expectations for patients, coaches, and athletic trainers. In general, we recommend that patients be free of lumbar pain, neurologically intact, and have full strength and motion of the lumbar spine and lower extremities before returning to play. Adequate protective equipment is recommended to be worn at all times during practice and play.

Fluoroscopic images of the sacroiliac joint alone are unable to identify simulated flexion or extension malreduction of the anterior pelvic ring in AO/OTA 61-B2.3 pelvic injuries.

PURPOSE: Reduction of AO/OTA 61-B2.3 (APC2) pelvic fractures is challenging in the setting of anterior ring comminution. The anterior ring is visually much simpler to evaluate for flexion or extension hemipelvis deformity than the posterior ring, except in the setting of comminution, necessitating some other visual reference to judge hemipelvis reduction. We sought to test whether pelvic inlet and outlet fluoroscopy of the contours of the sacroiliac joint could be used in isolation to judge hemipelvis flexion or extension. METHODS: Symphyseal and anterior SIJ ligaments were cut (6 cadaveric pelvis). The symphysis was held malreduced to produce one centimeter flexion and extension deformity: 1 cm was selected to mimic a maximum clinical scenario. The SIJ was assessed using inlet and outlet fluoroscopy. The scaled width of the SIJ was assessed at the joint apertures and midjoint on both inlet and outlet views. Joint widths in flexion and extension were compared against joint widths measured on the reduced SIJ using paired t-tests. RESULTS: There was no statistical difference in the superior (p = 0.227, 0.675), middle (p = 0.203, 0.693), and inferior (p = 0.232, 0.961) SIJ widths between hemipelvis flexion or extension models against reduced SIJ on outlet views. There was no statistical difference in the anterior (p = 0.731, 0.662), middle (p = 0.257, 0.655), and posterior (p = 0.657, 0.363) SIJ widths between flexion or extension models against reduced SIJ on inlet views. CONCLUSION: Inspection of SIJ width on inlet and outlet fluoroscopy cannot detect up to one centimeter of hemipelvis flexion or extension malreduction in the setting of AO/OTA 61-B2.3 (APC2) pelvic fractures with complex anterior injuries.

Synthesis, biochemical and computational evaluations of novel bis-acylhydrazones of 2,2'-(1,1'-biphenyl)-4,4'-diylbis(oxy))di(acetohydrazide) as dual cholinesterase inhibitors.

A series of twenty-seven bis(acylhydrazones) were successfully synthesized with high yields through a multistep process, which entailed the esterification of hydroxyl groups, hydrazination with an excess of hydrazine hydrate, and subsequent reactions with various carbonyl moieties (aldehydes). In the final stage of synthesis, different chemical species including aromatic, heterocyclic, and aliphatic compounds were integrated into the framework. The resulting compounds were characterized using several spectroscopic techniques (1H NMR, 13C NMR, and mass spectrometry). Their anticholinesterase activities were assessed in vitro by examining their interactions with two cholinesterase enzymes: acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Among the synthesized hits, compounds 3, 5, 6, 9-12, and 14 exhibited good to moderate inhibition of AChE. Specifically, 10 (IC50 = 26.3 ± 0.4 µM) and 11 (IC50 = 28.4 ± 0.5 µM) showed good inhibitory activity against AChE, while 9, 12, 3, and 6 exhibited significant inhibition potential against AChE with IC50 values ranging from 35.2 ± 1.1 µM to 64.4 ± 0.3 µM. On the other hand, 5 (IC50 = 22.0 ± 1.1 µM) and 27 (IC50 = 31.3 ± 1.3 µM) displayed significant, and 19 (IC50 = 92.6 ± 0.4 µM) showed moderate inhibitory potential for BChE. Notably, 5 and 27 exhibited dual inhibition of AChE and BChE, with greater potency than the standard drug galantamine. The binding patterns of these molecules within the binding cavities of AChE and BChE were anticipated by molecular docking which showed good correlation with our in vitro findings. Further structural optimization of these molecules may yield more potent AChE and BChE inhibitors.

Obturator inlet and iliac oblique technique for safe, convenient, and reliable iliac screw placement.

Background: There are many described techniques for the placement of posterior iliac screws for extension of lumbar posterior spinal instrumentation to the pelvis. However, each one has its limitations. We describe our technique for fluoroscopic guidance of iliac screw placement utilizing the obturator inlet and iliac oblique views as well as a detailed review of how to obtain and interpret these views for safe iliac screw placement. Methods: Retrospective chart review of patients undergoing iliac screw placement utilizing the obturator inlet and iliac oblique views as part of spine instrumentation between January 2019 and March 2022. Screw length and bony breaches are reported utilizing this technique. Results: Twelve patients underwent posterior lumbopelvic fixation with a total of 23 screws placed via either open or percutaneous technique. The mean screw length was 96.5 mm (Range 80-110, standard dev 7.75). There were no recorded breaches or recannulation attempts. Conclusions: We show how this technique is a much more convenient alternative to the placement of iliac screws under the obturator outlet oblique ("teardrop" view) which necessitates that the C-arm is in line with the instruments being placed. These described views can be used to place screws with either open or percutaneous techniques and with either the posterior superior iliac spine (PSIS) or S2 alar iliac (S2AI) starting points.

Efficient microwave synthesis of flurbiprofen derivatives and their enhancement of efficacy in chronic inflammatory pain models and gastro-protective potential in post-operative model.

Present research was designed to synthesize and characterize the flurbiprofen derivatives and to evaluate their analgesic, anti-inflammatory and gastro-protective activities in post-operative and chronic inflammatory pain models. Flurbiprofen derivatives were produced by using three-step processes involving esterification, hydrazide production, and schiff base, each of which modified a different carboxyl group. All the newly synthesized flurbiprofen derivatives (NS5-NS8) were characterized by 1H NMR,13C NMR,19F NMR and HR-ESI-MS, and the post-operative, inflammatory pain and ulcerogenic activities were determined in well-established in-vivo animal models. To evaluate post-operative and inflammatory pain, various doses of compounds [1, 3, 10, and 30 mg/kg (bwt)] were used, while their ulcerogenic potential was assessed at doses of 100 and 150 mg/kg (bwt). The incisional damage linked pain was significantly (p < 0.001) reduced by derivatives at different doses in both the acute and repeated tests with decreased response of phologistic agent-induced inflammation. The stomach histology and biochemical features demonstrate that the synthesized derivatives have no potential to cause ulcerogenicity as compared to aspirin and flurbiprofen. Furthermore, docking shows that the hydrazide moiety of these compounds is crucial in interacting within COX-2 binding site. Therefore, the synthesized compounds exhibit strong analgesic and anti-inflammatory effects and a low risk of causing ulcers. These attributes render them potentially valuable therapeutic agents for the treatment of pathological disorders associated with inflammation and pain.Communicated by Ramaswamy H. Sarma.

Identification of IL-2 inducible tyrosine kinase inhibitors by quantum mechanics and ligand based virtual screening approaches.

Interleukin-2-inducible T-cell kinase (ITK) is a crucial intracellular signaling mediator in normal and malignant T-cells and natural killer cells. Selective inhibition of ITK might be useful for treating a variety of disorders including; autoimmune, inflammatory, and neoplastic disorders. Over the past two decades, the clinical management of ITK inhibitors has progressed dramatically. So far, specific inhibitor with no off-target effects against ITK is available. Herein, we aim to discover potential virtual hits to fasten the process of drug design and development against ITK. In this regard, the key chemical characteristics of ITK inhibitors were identified using ligand-based pharmacophore modeling. The validated pharmacophore comprises one hydrogen bond donor and three hydrogen bond acceptors and was utilized as a 3D query in virtual screening using ZINC, Covalent, and in-house databases. A total of 12 hit compounds were chosen on the basis of their critical interactions with the significant amino acids of ITK. The orbital energies such as HOMO and LUMO of the hit compounds were calculated to evaluate the inhibitor's potencies. Further, molecular dynamics simulation demonstrated the stability of ITK upon binding of selected virtual hits. Binding energy using the MMGBSA method showed the potential binding affinity of all the hits with ITK. The research identifies key chemical characteristics with geometric restrictions that lead to ITK inhibition.Communicated by Ramaswamy H. Sarma.

Bioactive substances of cyanobacteria and microalgae: Sources, metabolism, and anticancer mechanism insights.

Cyanobacteria and microalgae contain various phytochemicals, including bioactive components in the form of secondary metabolites, namely flavonoids, phenolic acids, terpenoids, and tannins, with remarkable anticancer effects. This review highlights the recent advances in bioactive compounds, with potential anticancer activity, produced by cyanobacteria and microalgae. Previous in vitro investigations showed that many of these bioactive compounds exhibit potent effects against different human cancer types, such as leukemia and breast cancers. Multiple mechanisms implicated in the antitumor effect of these compounds were elucidated, including their ability to target cellular, subcellular, and molecular checkpoints linked to cancer development and promotion. Recent findings have highlighted various mechanisms of action of bioactive compounds produced by cyanobacteria and microalgae, including induction of autophagy and apoptosis, inhibition of telomerase and protein kinases, as well as modulation of epigenetic modifications. In vivo investigations have demonstrated a potent anti-angiogenesis effect on solid tumors, as well as a reduction in tumor volume. Some of these compounds were examined in clinical investigations for certain types of cancers, making them potent candidates/scaffolds for antitumor drug development.

Technical Factors Contributing to Nonunion in Supracondylar Distal Femur Fractures Treated With Lateral Locked Plating: A Risk-Stratified Analysis.

OBJECTIVE: To identify technical factors associated with nonunion after operative treatment with lateral locked plating. DESIGN: Retrospective cohort study. SETTING: Ten Level I trauma centers. PATIENT SELECTION CRITERIA: Adult patients with supracondylar distal femur fractures (OTA/AO type 33A or C) treated with lateral locked plating from 2010 through 2019. OUTCOME MEASURES AND COMPARISONS: Surgery for nonunion stratified by risk for nonunion. RESULTS: The cohort included 615 patients with supracondylar distal femur fractures. The median patient age was 61 years old (interquartile range: 46 -72years) and 375 (61%) were female. Observed were nonunion rates of 2% in a low risk of nonunion group (n = 129), 4% in a medium-risk group (n = 333), and 14% in a high-risk group (n = 153). Varus malreduction with an anatomic lateral distal femoral angle greater than 84 degrees, was associated with double the odds of nonunion compared to those without such varus [odds ratio, 2.1; 95% confidence interval (CI), 1.1-4.2; P = 0.03]. Malreduction by medial translation of the articular block increased the odds of nonunion, with 30% increased odds per 4 mm of medial translation (95% CI, 1.0-1.6; P = 0.03). Working length increased the odds of nonunion in the medium risk group, with an 18% increase in nonunion per 10-mm increase in working length (95% CI, 1.0-1.4; P = 0.01). Increased proximal screw density was protective against nonunion (odds ratio, 0.71; 95% CI, 0.53-0.92; P = 0.02) but yielded lower mRUST scores with each 0.1 increase in screw density associated with a 0.4-point lower mRUST (95% CI, -0.55 to -0.15; P < 0.001). Lateral plate length and type of plate material were not associated with nonunion. ( P > 0.05). CONCLUSIONS: Malreduction is a surgeon-controlled variable associated with nonunion after lateral locked plating of supracondylar distal femur fractures. Longer working lengths were associated with nonunion, suggesting that bridge plating may be less likely to succeed for longer fractures. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.