Insights from molecular dynamics simulations of TRPV1 channel modulators in pain.

TRPV1 is a nonselective cation channel vital for detecting noxious stimuli (heat, acid, capsaicin). Its role in pain makes it a potential drug target for chronic pain management, migraines, and related disorders. This review updates molecular dynamics (MD) simulation studies on the TRPV1 channel, focusing on its gating mechanism, ligand-binding sites, and implications for drug design. The article also explores challenges in developing modulators, SAR optimization, and clinical trial studies. Efforts have been undertaken to concisely present MD simulation findings, with a focus on their relevance to drug discovery.

Does Socioeconomic Status Have an Association with Cranio-vertebral Anomalies: A Step Toward Healing the Curse!

BACKGROUND: The etiological or causal factors of pediatric craniovertebral junction anomalies (CVJA) are still unknown. The disease bears a major proportion of economic and social burdens over a developing country like ours. This article aims to highlight an important modifiable factor that may prove to have a critical causal relationship with disease incidence. MATERIALS AND METHODS: This is a cross-sectional, single-institutional study, wherein the socioeconomic status (SES) of all the operated pediatric patients of CVJA, between 2014 and 2019, was studied. Variables including the patient's age, sex, residence status (rural or urban), perioperative data, length of stay, follow-up, and the time between revision surgery (if required) and clinical presentation were noted. Data regarding average household and type of family (nuclear or joint) were also enquired. RESULTS: Sixty-six patients (M:F 56:10) with a mean age of 13.14 ± 3.44 years were included. The mean annual family income was 11.1 ± 12.1 thousands. 43.9% belonged to joint family; according to Kuppuswami and Prasad scale, 42.4% of patients belong to lower class, while 20 patients belong to lower middle class, and 14 patients belong to the below poverty line category. Neither the SES of patient nor rural-urban background affected the surgical outcome. The mean follow-up of patients in our study was 42.3 ± 23.0 months and 83.3% had a good outcome. DISCUSSION: Patients operated for CVJ anomaly in the authors' institution mainly come from the lower socioeconomic groups. The present study raises several important questions like nutritional deficiencies in reproductive age group females leading to a cascade of events as a causal factor.

Development of epitope-based peptide vaccine against novel coronavirus 2019 (SARS-COV-2): Immunoinformatics approach.

Recently, a novel coronavirus (SARS-COV-2) emerged which is responsible for the recent outbreak in Wuhan, China. Genetically, it is closely related to SARS-CoV and MERS-CoV. The situation is getting worse and worse, therefore, there is an urgent need for designing a suitable peptide vaccine component against the SARS-COV-2. Here, we characterized spike glycoprotein to obtain immunogenic epitopes. Next, we chose 13 Major Histocompatibility Complex-(MHC) I and 3 MHC-II epitopes, having antigenic properties. These epitopes are usually linked to specific linkers to build vaccine components and molecularly dock on toll-like receptor-5 to get binding affinity. Therefore, to provide a fast immunogenic profile of these epitopes, we performed immunoinformatics analysis so that the rapid development of the vaccine might bring this disastrous situation to the end earlier.

Bacterial Compatibility/Toxicity of Biogenic Silica (b-SiO2) Nanoparticles Synthesized from Biomass Rice Husk Ash.

Biogenic silica (b-SiO2) nanopowders from rice husk ash (RHA) were prepared by chemical method and their bacterial compatibility/toxicity was analyzed. The X-ray diffractometry (XRD) patterns of the b-SiO2 nanopowders indicated an amorphous feature due to the absence of any sharp peaks. Micrographs of the b-SiO2 revealed that sticky RHA synthesized SiO2 nanopowder (S1) had clustered spherical nanoparticles (70 nm diameter), while b-SiO2 nanopowder synthesized from red RHA (S2) and b-SiO2 nanopowder synthesized from brown RHA (S3) were purely spherical (20 nm and 10 nm diameter, respectively). Compared to the S1 (11.36 m2g-1) and S2 (234.93 m2g-1) nanopowders, the S3 nanopowders showed the highest surface area (280.16 m2g-1) due to the small particle size and high porosity. The core level of the X-ray photoelectron spectroscopy (XPS) spectra showed that Si was constituted by two components, Si 2p (102.2 eV) and Si 2s (153.8 eV), while Oxygen 1s was observed at 531.8 eV, confirming the formation of SiO2. The anti-bacterial activity of the b-SiO2 nanopowders was investigated using both gram-positive (Escherichia coli) and gram-negative (Staphylococcus aureus) microorganisms. Compared to S2 and S3 silica nanopowders, S1 demonstrated enhanced antibacterial activity. This study signifies the medical, biomedical, clinical, and biological importance and application of RHA-mediated synthesized b-SiO2.

Advances in nanocarriers enabled brain targeted drug delivery across blood brain barrier.

The blood brain barrier (BBB) offers protection to the central nervous system (CNS) by maintaining homeostasis. Besides restricting the entry of harmful xenobiotics and endogenous molecules to CNS, BBB also limits the entry of therapeutic agents. Nanotechnology offers the possibility to deliver small molecules/drugs against CNS disorders across BBB. Recently, due to excellent biocompatibility, functional versatility and unique surface electrostatics properties nanodiamonds are also being explored for their drug delivery potential against BBB. Although, studies has been done to understand the mechanisms involved in drug delivery across BBB, but still, progress in the development of any functional drug delivery systems across BBB is in juvenile stages. For this purpose, the strategic developments of more potent drug delivery systems to CNS via endocytic pathways appears to be the most promising approach. Endocytic pathways are essential for communication and transport of nutrients across BBB in endothelial cells. Moreover, modifications of the nanotherapeutic agents with specific brain capillary endothelial cells targeting molecules or ligands have recently shown impressive results of successful delivery of drugs to the brain via receptor-mediated transcytosis. The current review provides a comprehensive insight in the advancements made in nanocarriers-based successful drug delivery to the CNS and their availability in clinics.

Role of hyaluronic acid and phospholipid in the lubrication of a cobalt-chromium head for total hip arthroplasty.

The tribological performance of total hip arthroplasty has an important influence on its success rate. This study examined the concentration-dependent role of hyaluronic acid (HA) and phospholipid (dipalmitoylphosphatidylcholine, DPPC) in the boundary lubricating ability of retrieved cobalt-chromium femoral heads. The microscale frictional coefficients (µ) were measured by atomic force microscopy using a rectangular silicon cantilever integrated with sharp silicon tips. In the case of HA lubricant, the frictional coefficients decreased significantly at concentrations of 2.0 (0.16 ± 0.03) and 3.5 mg/ml (0.11 ± 0.01) while increased at 5.0 mg/ml (0.15 ± 0.01), compared to that with phosphate buffer saline (0.25 ± 0.03). The concentration-dependent lubrication behavior of DPPC was most effective when DPPC was in the physiological concentration range, showing µ = 0.16 ± 0.01 in polypropylene glycol, and 0.05 ± 0.01, 0.02 ± 0.01, and 0.03 ± 0.01 at a DPPC concentration of 0.05, 0.2, and 3.0 mg/ml, respectively. Results obtained show significant differences between the DPPC concentration groups. Conclusively, the microscale frictional response of the retrieved CoCr femoral head has a significant dependence on the concentrations of HA and DPPC. Moreover, observed optimal concentration of HA and DPPC for effective lubrication is similar to that observed in normal human synovial fluid. Therefore, a retrieval of the synovia may be considered during total hip replacement surgeries in an effort for reduction of friction between head and liner of total hip replacement implants.

Interplay between cartilage and subchondral bone contributing to pathogenesis of osteoarthritis.

Osteoarthritis (OA) is a common debilitating joint disorder, affecting large sections of the population with significant disability and impaired quality of life. During OA, functional units of joints comprising cartilage and subchondral bone undergo uncontrolled catabolic and anabolic remodeling processes to adapt to local biochemical and biological signals. Changes in cartilage and subchondral bone are not merely secondary manifestations of OA but are active components of the disease, contributing to its severity. Increased vascularization and formation of microcracks in joints during OA have suggested the facilitation of molecules from cartilage to bone and vice versa. Observations from recent studies support the view that both cartilage and subchondral bone can communicate with each other through regulation of signaling pathways for joint homeostasis under pathological conditions. In this review we have tried to summarize the current knowledge on the major signaling pathways that could control the cartilage-bone biochemical unit in joints and participate in intercellular communication between cartilage and subchondral bone during the process of OA. An understanding of molecular communication that regulates the functional behavior of chondrocytes and osteoblasts in both physiological and pathological conditions may lead to development of more effective strategies for treating OA patients.

Regulation of Wnt signaling activity for growth suppression induced by quercetin in 4T1 murine mammary cancer cells.

Quercetin is a promising chemopreventive agent against cancer that inhibits tumor progression by inducing cell cycle arrest and promoting apoptotic cell death. Recently, the Wnt/ß-catenin signaling pathway has been implicated in mammary tumorigenesis, where its abnormal activation is associated with the development of breast cancer. Thus, the objective of this study was to examine the biological activities of quercetin against mammary cancer cells, and to determine whether quercetin could regulate the Wnt/ß-catenin signaling pathway. Quercetin showed dose-dependent inhibition of cell growth and induced apoptosis in 4T1 cells. Treatment of 20 µM quercetin suppressed ~50% of basal TopFlash luciferase activity. Moreover, the inhibitory effect of quercetin on the Wnt/ß-catenin signaling pathway was confirmed by the reduced stabilization of the ß-catenin protein. Among various antagonists screened for the Wnt/ß-catenin signaling pathway, the expression of DKK1, 2 and 3 was induced after treatment with 20 µM of quercetin. Stimulation with recombinant DKK1 protein, showed suppressive cell growth of mammary cancer cells instead of quercetin. When 4T1 cells were treated with recombinant Wnt3a or LiCl along with quercetin, both stimulators for the Wnt/ß-catenin signaling pathway were able to restore the suppressed cell viability by quercetin. Thus, our data suggest that quercetin exerts its anticancer activity through the downregulation of Wnt/ß-catenin signaling activity. These results indicate for the first time that quercetin decreases cell viability and induces apoptosis in murine mammary cancer cells, which is possibly mediated by DKK-dependent inhibition of the Wnt/ß-catenin signaling pathway. In conclusion, our findings suggest that quercetin has great potential value as chemotherapeutic agent for cancer treatment, especially in breast cancer controlled by Wnt/ß-catenin signaling activity.

Rspo 1 promotes osteoblast differentiation via Wnt signaling pathway.

R-spondin (Rspo)s proteins are a new group of Wnt/beta-catenin signaling agonists. These signaling molecules are known to be involved in the developmental stages of skeletal system. Recent studies in various murine osteoblast models have proposed that Rspo 1 may interact with Wnt signaling pathway to induce differentiation in osteoblasts. Though findings in murine osteoblasts implicate a synergestic role of Rspo 1 with Wnt signaling, still no study has addressed the similar role in more clinically applicable osteoblast models i.e., human cell lines or primary cells. Therefore, in the present study, we investigated the possible role of Rspo 1 during differentiation process of human in vitro osteoblast cell models like primary osteoblasts or human osteoprogenitor cell line hFOB 1.19 along with murine preosteoblast cell line MC3T3 E-1. Our results showed increase in Rspo 1 at transcript level during differentiating phase of human primary osteoblasts and human FOB 1.19 cells. We also found that Rspo 1 (100 ng/mL) acts additively with Wnt3a to activate Wnt signaling, as confirmed by luciferase activity after transfection of TOPFLASH construct to hFOB 1.19 cells. Similar additive role of Rspo 1 and Wnt3a was apparent in alkaline phosphatase (ALP) activity analysis of human primary cells. Moreover, a reduction in ALP activity was observed with knock-down of Rspo 1 by transfected shRNA in hFOB 1.19 cells. These results suggested the possibility of autocrine regulation by Rspo 1 on the osteogenic activities in human in vitro osteoblast models. Furthermore, these results were corroborated in MC3T3-E1, murine osteoblast cell model. Osteoblastic differentiation was induced by transfection of Rspo 1 which was confirmed by increased ALP staining and qRT-PCR analysis of osteogenic markers, such as Runx2 and osteocalcin. In conclusion, present study highlights the role of Rspo 1 in bone remodeling where it activates Wnt signaling to induce differentiation, as shown in human as well murine in vitro osteoblast cell models.

The effect of TNFα secreted from macrophages activated by titanium particles on osteogenic activity regulated by WNT/BMP signaling in osteoprogenitor cells.

Wear particles are the major cause of osteolysis associated with failure of implant following total joint replacement. During this pathologic process, activated macrophages mediate inflammatory responses to increase osteoclastogenesis, leading to enhanced bone resorption. In osteolysis caused by wear particles, osteoprogenitors present along with macrophages at the implant interface may play significant roles in bone regeneration and implant osteointegration. Although the direct effects of wear particles on osteoblasts have been addressed recently, the role of activated macrophages in regulation of osteogenic activity of osteoblasts has scarcely been studied. In the present study, we examined the molecular communication between macrophages and osteoprogenitor cells that may explain the effect of wear particles on impaired bone forming activity in inflammatory bone diseases. It has been demonstrated that conditioned medium of macrophages challenged with titanium particles (Ti CM) suppresses early and late differentiation markers of osteoprogenitors, including alkaline phosphatase (ALP) activity, collagen synthesis, matrix mineralization and expression of osteocalcin and Runx2. Moreover, bone forming signals such as WNT and BMP signaling pathways were inhibited by Ti CM. Interestingly, TNFα was identified as a predominant factor in Ti CM to suppress osteogenic activity as well as WNT and BMP signaling activity. Furthermore, Ti CM or TNFα induces the expression of sclerostin (SOST) which is able to inhibit WNT and BMP signaling pathways. It was determined that over-expression of SOST suppressed ALP activity, whereas the inhibition of SOST by siRNA partially restored the effect of Ti CM on ALP activity. This study highlights the role of activated macrophages in regulation of impaired osteogenic activity seen in inflammatory conditions and provides a potential mechanism for autocrine regulation of WNT and BMP signaling mediated by TNFα via induction of SOST in osteprogenitor cells.