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Aims/hypothesisCD40 expressed in Müller cells is a central driver of diabetic retinopathy. CD40 causes phospholipase Cγ1 (PLCγ1)-dependent ATP release in Müller cells followed by purinergic receptor (P2X7)-dependent production of proinflammatory cytokines in myeloid cells. In the diabetic retina, CD40 and P2X7upregulate a broad range of inflammatory molecules that promote development of diabetic retinopathy. The molecular event downstream of CD40 that activates the PLCγ1–ATP–P2X7–proinflammatory cytokine cascade and promotes development of diabetic retinopathy is unknown. We hypothesise that disruption of the CD40-driven molecular events that trigger this cascade prevents/treats diabetic retinopathy in mice.MethodsB6 and transgenic mice with Müller cell-restricted expression of wild-type (WT) CD40 or CD40 with mutations in TNF receptor-associated factor (TRAF) binding sites were made diabetic using streptozotocin. Leucostasis was assessed using FITC-conjugated concanavalin A. Histopathology was examined in the retinal vasculature. Expression of inflammatory molecules and phospho-Tyr783 PLCγ1 (p-PLCγ1) were assessed using real-time PCR, immunoblot and/or immunohistochemistry. Release of ATP and cytokines were measured by ATP bioluminescence and ELISA, respectively.ResultsHuman Müller cells with CD40 ΔT2,3 (lacks TRAF2,3 binding sites) were unable to phosphorylate PLCγ1 and release ATP in response to CD40 ligation, and could not induce TNF-α/IL-1β secretion in bystander myeloid cells. CD40–TRAF signalling acted via Src to induce PLCγ1 phosphorylation. Diabetic mice in which WT CD40 in Müller cells was replaced by CD40 ΔT2,3 failed to exhibit phosphorylation of PLCγ1 in these cells and upregulate P2X7and TNF-α in microglia/macrophages.P2x7(also known asP2rx7),Tnf-α(also known asTnf),Il-1β(also known asIl1b),Nos2,Icam-1(also known asIcam1) andCcl2mRNA were not increased in these mice and the mice did not develop retinal leucostasis and capillary degeneration. Diabetic B6 mice treated intravitreally with a cell-permeable peptide that disrupts CD40–TRAF2,3 signalling did not exhibit either upregulation of P2X7and inflammatory molecules in the retina or leucostasis.Conclusions/interpretationCD40–TRAF2,3 signalling activated the CD40–PLCγ1–ATP–P2X7–proinflammatory cytokine pathway. Src functioned as a link between CD40–TRAF2,3 and PLCγ1. Replacing WT CD40 with CD40 ΔT2,3 impaired activation of PLCγ1 in Müller cells, upregulation of P2X7in microglia/macrophages, upregulation of a broad range of inflammatory molecules in the diabetic retina and the development of diabetic retinopathy. Administration of a peptide that disrupts CD40–TRAF2,3 signalling reduced retinal expression of inflammatory molecules and reduced leucostasis in diabetic mice, supporting the therapeutic potential of pharmacological inhibition of CD40–TRAF2,3 in diabetic retinopathy.Graphical abstract

Purpose: The aim of the present study was to enhance the oral bioavailability of curcumin using different surfactant and vehicle for preparing proniosomal gel. Methods: Curcumin comes under BCS Class IV which is having low solubility and low permeability and poor bioavailability. Buccal drug delivery can bypass such problems and leads to increase in bioavailability. Proniosomes offer excellent potential for improved drug delivery through versatile routes, by overcome the permeation barriers. Trial batches of proniosomal gel are prepared by coacervation phase separation method using different concentration of surfactant (Span 20, Span 40, Span 60, and Span 80) with cholesterol, soyalecithin, and vehicles such as 0.1% glycerol solution or pH 6.8. The formulated systems were characterized to find out the effects of surfactant on vesicle size, % entrapment efficiency, and % drug release and permeation at 6 h. Stability studies for proniosomal gel were carried out for 4 weeks. Results and Conclusion: It suggested that formulation (F2) containing Span 20 and phosphate buffer pH 6.8 has high entrapment efficiency, drug release, and permeation as compare to the other formulations and it can enhance the delivery of curcumin through oral route and can improve the bioavailability of drug.

INTRODUCTION: According to the WHO report 2022, 2.21 million new cases and 1.80 million deaths were reported for lung cancer in the year 2020. Therefore, there is an urgent need to explore novel, safe, and effective therapeutic interventions for lung cancer. METHOD: Hence, in the present study, we explored the anticancer potential of vincamine by using network pharmacology, molecular docking, and in vitro approaches. Network pharmacology studies demonstrated that the most common targets of vincamine are G-protein coupled receptors, cytosolic proteins, and enzymes. Among these targets, two targets, ALK and ERBB2 protein, were common between vincamine and non-small cell lung cancer. RESULT: We discovered a link between these two targets and their companion proteins, as well as cancer-related pathways. In addition, a docking investigation between the ligand for vincamine and two targeted genes revealed a strong affinity toward these targeted proteins. Further, the in vitro study demonstrated that vincamine treatment for 72 h led to dose-dependent (0-500 μM) cytotoxicity on the A549 lung cancer cell line with an IC50 value of 291.7 μΜ. The wound-healing assay showed that vincamine treatment (150 and 300 μM) significantly inhibited cell migration and invasion. Interestingly, acridine orange/ethidium bromide dual staining demonstrated that vincamine treatment induces apoptosis in A549 cells. Additionally, the dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay showed an increased level of reactive oxygen species (ROS) after the vincamine treatment, indicating ROS-mediated apoptosis in A549 cells. CONCLUSION: Altogether, based on our findings, we hypothesize that vincamine-induced apoptosis of lung cancer cells via ALK and ERBB2 protein modulation may be an attractive futuristic strategy for managing lung cancer in combination with chemotherapeutic agents to obtain synergistic effects with reduced side effects.

Curcumin is a principle compound obtained from turmeric, that is, Curcuma longa which is Indian rhizomatous medicinal plant from the family Zingiberaceae. Curcumin is yellow pigment commonly used as a spice in food processing industry. Curcumin, Demethoxycurcumin, and Bisdemethoxycurcumin are the major active constituents of the turmeric and are collectively known as curcuminoids. In recent studies, it has been demonstrated that curcumin has a variety of biological activities, pharmacological performances, provide protection, and promotion of health. This paper reviews the current research progress on its versatile bioactivity, such as antioxidant, anti-inflammatory, and immune-regulatory activities, cancers, diabetes, liver, and cardiovascular systems. The curcumin belongs to biopharmaceutical classification system Class IV that indicates low solubility and low permeability. The systemic bioavailability of orally administered curcumin is low in humans and only traces of it have been found in the liver. Here, we emphasized its broad therapeutic activity in treating life-threatening diseases by improving solubility as well as permeability with the help of novel drug delivery system.

We describe here reactions in which a carbonyl oxygen atom initiates cascade reactions by nucleophilic attack on a covalently attached benzyne. The benzynes are produced by thermal cyclization of triynes via hexadehydro-Diels-Alder reaction. The initially produced oxocarbenium/aryl carbanionic zwitterion is protonated in situ by an external protic nucleophile (NuH) of appropriate acidity. The resulting ion pair (oxocarbenium(+)/Nu(−)) collapses through several different mechanistic manifolds, adding to the diversity of structure classes that can be generated.

In this manuscript, we introduce the concept of modified α-admissible contraction with the help of a simulation function and use this concept to establish some coincidence and common fixed-point theorems in metric space. An illustrative example that yields the main result is given. Also, several existing results within the frame of metric space are established. The main theorem was applied to derive the coincidence and common fixed-point results for α-admissible 𝒵-contraction.

Tesla's full self-driving (FSD) computer is the world's first purpose-built computer for the highly demanding workloads of autonomous driving. It is based on a new System on a Chip (SoC) that integrates industry standard components such as CPUs, ISP, and GPU, together with our custom neural network accelerators. The FSD computer is capable of processing up to 2300 frames per second, a 21× improvement over Tesla's previous hardware and at a lower cost, and when fully utilized, enables a new level of safety and autonomy on the road.

o-Benzynes can be utilized to construct heterocyclic motifs using various nucleophilic and cycloaddition trapping reactions. Acridines have been synthesized by capture of C,N-diarylimines with benzynes generated by classical methods (i.e., from ortho-elimination of precursor arene compounds), although in poor yields. We report here that these imines can be trapped by benzynes generated by the hexadehydro-Diels-Alder (HDDA) reaction in an efficient manner to produce 1,4-dihydroacridine products. These dihydroacridines were subsequently aromatized using MnO2 to provide structurally complex acridines.

Imidazole-based epidermal growth factor receptor (EGFR) inhibitors were computationally designed and synthesized. All the compounds were assessed for their anti-proliferative activity against five cancer cell lines, viz., MDA-MB-231 (breast), T47D (breast) and MCF-7 (breast), A549 (lung) and HT-29 (colorectal). Compounds 2c and 2d emerged as better anticancer molecules with no toxicity towards normal cells. 2c and 2d inhibited EGFR enzymatic activity in vitro with IC50 values of 617.33 ± 0.04 nM and 710 ± 0.05 nM, respectively. In order to further improve the potency, we explored an unoccupied area of the ATP binding domain of EGFR and analysed an in silico interaction model of 2c and 2d-EGFR complexes that guided and allowed substitution of the 4-fluorophenyl ring (2c and 2d) with 4-(4-methylpiperazinyl)-3-nitrophenyl at the N-9 position, resulting in compound 3c with a better binding score and potent EGFR inhibitory activity (IC50: 236.38 ± 0.04 nM), which was comparable to the positive control erlotinib (239.91 ± 0.05 nM). 3c exhibited a great improvement in anticancer potency with inhibition of cell growth of all cancer cell lines at very low micromolar concentrations (IC50 = 1.98 to 4.07 μM). Further investigation revealed that 3c also induced an increase in ROS levels in cancer cells in a mitochondrial-independent manner and halted the cell cycle at the sub-G1 phase.

Management of open fractures of tibia is still a matter of debate due to high incidence of infections. Traditionally external fixators have been advocated in managing open tibial fractures. Due to limited efficacy of systemic antibiotics, recently antibiotic coated intramedullary interlocking nails have been developed for the management of open tibia fractures. Therefore, we conducted this prospective randomized study to compare the functional and radiological outcomes of primary ring fixator versus antibiotic coated nail in open diaphyseal tibial fractures.The study included 32 patients with Gustilo-Anderson type II and type IIIA fractures of tibial diaphysis. Out of them 16 patients were managed with Ring External Fixator (Group I) and 16 were managed with OssiproRing fixator as well as antibiotic coated tibial interlocking nail achieved comparable rates of union in the present study. Complication rates were similar in both the groups and the functional and radiological outcomes were comparable in both groups. Results of this study indicate that although ring fixation is an established option for management of open tibial fractures, antibiotic-coated intramedullary nail is also a reliable option in open Grade II and grade IIIA injuries.Level II.

Purpose To report evolution and outcomes of hyperreflective crystalline deposit (HCD) on optical coherence tomography (OCT) in diabetic maculopathy (DM). Methods Patients with DM showing HCD on OCT for the first time between June 2017 and May 2021 were included in the study. Demographic, ophthalmic and OCT features were documented and analysed. Factors leading to the development of HCD and its effect on the functional outcome were analysed and described in this study. Results Sixty cases of HCD were identified in 45 (males −33; females – 12) patients for the first-time during the defined study period. Mean age of the eligible patients was 61.53 ± 8.19 years. Average duration of diabetes was 13.82 ± 7.38 years. Mean visual acuity of these patients was 0.902 ± 0.438 logMAR units (Snellen equivalent = 20/160). Patients with HCD showed subretinal hard exudates, were on anti-cholesterol medications (n = 36, 80%) and showed reduced visual acuity (20/160) if the HCD involved the fovea. The median time taken for the development of HCD was 28 months. Mean follow-up duration of the study was 26.19 ± 27.98 months. Persistence of HCD in all cases (n = 42, 100%) was noted at the last follow-up visit. Conclusion Horizontal, single or multi-layered HCDs on OCT in DM represent intraretinal or subretinal cholesterol crystal precipitates evolving from the hard exudates identical to the “onion ring sign” seen in neovascular AMD. HCDs or CCs depict deranged lipid metabolism, chronic vascular leakage and can lead to substantial visual impairment if the fovea gets involved.

The allosteric regulation of pyruvate kinase M2 (PKM2) affects the switching of the PKM2 protein between the high-activity and low-activity states that allow ATP and lactate production, respectively. PKM2, in its low catalytic state (dimeric form), is chiefly active in metabolically energetic cells, including cancer cells. More recently, PKM2 has emerged as an attractive target due to its role in metabolic dysfunction and other interrelated conditions. PKM2 (dimer) activity can be inhibited by modulating PKM2 dimer-tetramer dynamics using either PKM2 inhibitors that bind at the ATP binding active site of PKM2 (dimer) or PKM2 activators that bind at the allosteric site of PKM2, thus activating PKM2 from the dimer formation to the tetrameric formation. The present perspective focuses on medicinal chemistry approaches to design and discover PKM2 inhibitors and activators and further provides a scope for the future design of compounds targeting PKM2 with better efficacy and selectivity.

Perforin is a granular effector pore-forming protein formed in NK cells and Cytotoxic T lymphocytes. These cytotoxic proteins are part of the first-line immune defense in the human body. They ensure apoptosis of pathogen-infected cells or tumor cells in the human body. Activation of receptors on NK cell or T cell triggers secondary proteins in these cells. Further, it leads to Ca

Background: Intertrochanteric fractures (IT) are fragility fractures of hip and mostly associated with senile osteoporosis with trivial trauma or low velocity injuries. Traditionally extramedullary osteosynthesis in form of dynamic hip screw (DHS) was treatment of choice for these fractures in past but recent trends are more in favors of intramedullary osteosynthesis as proximal femoral intramedullary nailing (PFN). Here we studied and compared the radiological and functional evaluation of treatment parameters of these fractures managed with both modalities of treatment. Methods: This prospective randomized study was conducted on 42 patients (21 patients in each group, group A, DHS; group B, PFN) with intertrochanteric fracture managed in two years of duration (July 2014 to June 2016). All the per-operative findings and complications were compared, while radiological assessment with radiographs and functional evaluation with Harris hip score was done at 1, 3 and 6 months post-operative follow-ups. Results: Mean age of patients were 56.14 years (range 25-84), and 56.19 years (range 28-80), in group A and B respectively. We observed that PFN had less mean blood loss (144 ml), less mean limb length shortening (0.5 cm) and gained better mean functional results at 6 months (Harris hip score, 86.9) due to early mobilization while patients managed with DHS had more blood loss (155 ml), more shortening (1.07 cm) and less functional outcomes at 6 months follow-up (scores, 77.2). Intra-operative radiation exposure was more in PFN group, while there was no significant difference in radiological union, neck-shaft angle and implant sliding in both groups. Conclusion: PFN was better than DHS in management of intertrochanteric fractures in terms of per-operative parameters (decreased blood loss, less complications), and as well as in functional outcomes (early weight bearing and mobilization, better Harris hip scores), while other parameters are not significantly different.

Xanthine oxidase (XO) plays a crucial role in the formation of uric acid by oxidative hydroxylation of purines. Herein, we report the design and synthesis of Knoevenagel/tandem Knoevenagel and Michael adducts of cyclohexane-1,3-dione and aryl aldehydes as nonpurine XO inhibitors derived from naturally occurring scaffolds. Density functional theory calculations highlighted the reaction pathways and reasoned the formation of tandem Knoevenagel and Michael adducts. The synthetics were assessed for their XO inhibitory potential, and among them, four compounds (1b, 1g, 2b, and 3a) were found to possess best IC50 values in the range of 3.66–4.98 μM. Interestingly, Knoevenagel adducts exhibited a competitive-type inhibition, whereas tandem Knoevenagel and Michael adducts produced a noncompetitive mode of inhibition. The compounds were capable of reducing the H2O2 levels induced by XO, both in normal and cancer cells with no significant cytotoxicity. Molecular modeling studies highlighted the role of interactions...

We report here various pathways by which six-membered N-heteroaromatic compounds react with benzynes that are generated by the HDDA reaction. The initially formed 1,3-zwitterionic species (a) can collapse intramolecularly to give novel 1 : 1 adducts of the heterocycle and benzyne; (b) can react with an externally added, electrophilic third-component to give functionalized heterocyclic products; or (c) can react with an external protic nucleophile to produce, following collapse of the ion pair resulting from protonation of the zwitterion, a variety of three-component assemblies. Mechanisms for formation of some of the 1 : 1 adducts are supported by DFT methods. The scope of the protic nucleophilic coupling was also expanded to a two-pot operation by using triflic acid as a protic “non-nucleophile”, followed by the addition of a suitably reactive nucleophile.

Purpose To describe the choroidal variations in posterior microphthalmos (PM). Methods In this observational case series, four eyes of two patients diagnosed as PM based on the characteristic clinical features were included. Multimodal retinal imaging with clinical fundus documentation using ultrawide field fundus camera, optical coherence tomography (OCT) and indocyanine green angiography (ICGA) was done for these cases. Results Multimodal imaging of these cases confirmed the variations in the choroid in PM cases. In both cases, on OCT, the retina and choroid were thick. retinal papillomacular fold (RPMF) was noted in all four eyes. On ICGA, the dye transit time from the arm to choroid and retina were within normal limits. Choroidal vasculature in the far retinal periphery was reduced and was noted as hypocyanescent areas anterior to the equator while the density of choroidal vessels was significantly more posterior to the equator. Vortex veins were not visualised in both cases. Conclusion Choroidal structure and vessels undergo alterations in PM. Further validation of these findings is required in a larger cohort of PM cases.

We herein report a new synthetic route for a series of unreported 1,4-dihydropyrazolo[4,3-b]indoles (6-8) via deoxygenation of o-nitrophenyl-substituted N-aryl pyrazoles and subsequent intramolecular (sp

We report here elaboration of a cascade strategy for naphthyne formation using Kobayashi benzynes as diynophiles in a subsequent in situ hexadehydro-Diels-Alder reaction. Density functional theory computations suggest that the strained benzynes act as "super-diynophiles" in this transformation. The reaction requires only mildly basic and ambient temperature conditions and allows for rapid construction of various naphthalenic products. The trapping efficiencies of several arynophiles were determined using the benzyne to naphthyne cyclization as an internal clock reaction.

A series of 30 non-covalent imidazo[1,2-a]quinoxaline-based inhibitors of epidermal growth factor receptor (EGFR) were designed and synthesized. EGFR inhibitory assessment (against wild type) data of compounds revealed 6b, 7h, 7j, 9a and 9c as potent EGFRWT inhibitors with IC50 values of 211.22, 222.21, 193.18, 223.32 and 221.53 nM, respectively, which were comparable to erlotinib (221.03 nM), a positive control. Furthermore, compounds exhibited excellent antiproliferative activity when tested against cancer cell lines harboring EGFRWT, A549, a non-small cell lung cancer (NSCLC), HCT-116 (colon), MDA-MB-231 (breast) and gefitinib-resistant NSCLC cell line H1975 harboring EGFRL858R/T790M. In particular, compound 6b demonstrated significant inhibitory potential against gefitinib-resistant H1975 cells (IC50 = 3.65 μM) as compared to gefitinib (IC50 &gt, 20 μM). Moreover, molecular docking disclosed the binding mode of the 6b to the domain of EGFR (wild type and mutant type), indicating the basis of inhibition. Furthermore, its effects on redox modulation, mitochondrial membrane potential, cell cycle analysis and cell death mode in A549 lung cancer cells were also reported.

Introduction: Pyruvate kinase isozyme M2 (PKM2) was observed to be overexpressed and play a key role in cell growth and cancer cells' metabolism. During the past years, phytochemicals have been developed as new treatment options for chemoprevention and cancer therapy. Natural resources, like shikonin (naphthoquinone) and its derivatives, have emerged to be high potential therapeutics in cancer treatment. Methods: Our study aimed to design novel anti-tumour agents (PKM2 inhibitors) focusing on the shikonin scaffold with a better activity using computational methods. We applied a three-dimensional quantitative structure-activity relationship (3D-QSAR) approach using Field-Based QSAR. Results: The Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) were performed on a series of forty shikonin derivatives, including shikonin, to develop robust models and rationalize the PKM2 inhibitory activity profile by building a correlation between structural features and activity. Conclusion: These predictive computational models will further help the design and synthesis of potent PKM2 inhibitors and their fast biological assessment at a low cost.

To enhance the assimilation of light in the solar thermal area, we need to focus beyond the thermo-physical properties of the nanoparticles, i.e., optical properties of the nanoparticles (NPs) augment the optical characteristics of the solar spectrum; therefore, the concept of plasmonic nanofluids has been introduced. The plasmonic nanoparticles (mainly work on scattering and absorption mechanisms) suspended in a base fluid are known to enhance the thermal and photon efficiency of the volumetric solar thermal collectors compared to the conventional ones. Further, this study aims to review the most recently published works on plasmonic nanofluids that exclusively present its preparation methods, thermophysical properties, and applications in solar collectors. Following, an overview of the potential features of plasmonic nanofluids and their preparation methods are presented. Afterward, the stability and thermophysical properties of such nanofluids are discussed. Then, the application in solar energy collectors, automotive cooling, as well as biomedical applications are overviewed. Finally, some future directions for further research in this field of study are suggested. In this work, we reviewed the work done in the plasmonic field in the last decade, and we have tried to summarize the results based on published data and future outlooks. This work can benefit researchers in this field as there is no comprehensive review of plasmonic nanofluids available. This work is believed to help the researchers to modernize the latest trends and understand the potential research gap in the optical properties of nanofluids to enhance the performance of solar collectors further and reduce thermal losses.