An electronic energy compensation method for flattening the energy response of SiPM-GGAG:Ce,B based gamma detector.

The energy response of gross gamma dose rate monitors needs to be flat in order to prevent overestimation of dose at low gamma energies. In this paper, a discriminator threshold modulation based electronic energy compensation algorithm has been proposed for SiPM-scintillator based gamma detectors. Theoretical simulation studies were carried out in order to optimize the parameters of the periodic ramp voltage used for modulation of the discriminator threshold of a SiPM-GGAG:Ce,B based gamma dose rate monitor. A customized threshold modulation circuit and signal processing electronics were developed for this gamma detector. For experimentally optimizing the parameters, the energy response studies of the detector, with and without the discriminator threshold modulation, were carried out. With the optimized parameters for a periodic ramp threshold, the count rates for 241Am (60 keV) and 60Co (1173 and 1332 keV) were observed to be within ±30% of the count rate obtained for 137Cs (662 keV). Using the electronic energy compensation techniques presented in this paper, a flat energy response of the SiPM-scintillator gamma detector for the energy range of 60 keV to 1.5 MeV could be achieved.

Protease activated receptor-1 regulates mixed lineage kinase-3 to drive triple-negative breast cancer tumorigenesis.

Triple-negative breast cancer (TNBC) is difficult to treat breast cancer subtype due to lack or insignificant expressions of targetable estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2). Therefore, finding a targetable protein or signaling pathway in TNBC would impact patient care. Here, we report that a member of the Mixed Lineage Kinase (MLK) family, MLK3, is an effector of G-protein-coupled protease-activated receptors 1 (PAR1) and targeting MLK3 by a small-molecule inhibitor prevented PAR1-mediated TNBC tumorigenesis. In silico and immunohistochemistry analysis of human breast tumors showed overexpression of PAR1 and MLK3 in TNBC tumors. Treating α-thrombin and PAR1 agonist increased MLK3 and JNK activities and induced cell migration in TNBC cells. The PAR1 positive/high (PAR1+/hi) population of TNBC cells showed aggressive tumor phenotype with increased MLK3 signaling. Moreover, combined inhibition of the PAR1 and MLK3 mitigated the TNBC tumor burden in preclinical TNBC models. Our data suggests that activation of the PAR1-MLK3 axis promotes TNBC tumorigenesis. Therefore, combinatorial therapy targeting MLK3 and PAR1 could effectively reduce TNBC tumor burden.

Effect of Flaxseed on Pain Relief and Quality of Life in Patients With Mastalgia: A Single Arm Interventional Study.

Objective: Mastalgia, a common complaint among women, denotes breast discomfort that can manifest as cyclical or non-cyclical. Reassurance, mechanical support and various non-pharmacological treatments, like flaxseeds, have been seen to have a good effect in treating mastalgia. Thus, the aim of this study was to investigates the efficacy of flaxseed in alleviating pain associated with mastalgia and its impact on the overall health-related quality of life among female patients. Materials and Methods: Conducted at a tertiary care center in Northern India over 18 months, it employed a single-arm interventional design. The participants included females aged 18 years and older presenting with breast pain at the Department of General Surgery. The intervention involved daily consumption of 30 g of milled flaxseed for each participant, administered over a period of six months. Pain severity was assessed using the visual analogue scale (VAS) before supplementation and at follow-up intervals up to six months. Concurrently, the Short Form-12 (SF-12) items Health Survey measured health-related quality of life, encompassing both physical and mental health domains. Statistical analysis employed parametric (paired t-test) and non-parametric tests (chi-square, McNemar) where appropriate, with statistical significance set at p<0.05. Results: Two hundred women with mastalgia were included with a significant reduction in mean VAS scores from 6.03±0.83 at baseline to 2.19±0.66 at six months post-intervention (p = 0.0001). This reduction in pain intensity demonstrated a positive correlation with duration of flaxseed supplementation, notably declining after the initial three months. The mean difference in physical and mental SF-12 score at first visit and at 6 months after intervention was significant (p = 0.0001). Conclusion: This study underscores the potential of flaxseed as a therapeutic option for managing mastalgia and enhancing health-related quality of life among affected individuals.

Risk of Congenital Anomalies with Dolutegravir-Based Anti-retroviral Regimens: A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVES: Dolutegravir has been used as a first-line anti-human immunodeficiency virus drug because of its better efficacy compared with other counterpart medicines. However, making a unanimous decision on its use during pregnancy has become difficult for stakeholders following congenital anomalies reported with its use. The objective of this systematic review and meta-analysis was to study the risk of congenital anomalies in newborns exposed to dolutegravir-based-regimens compared with those exposed to non-dolutegravir-based regimens during the antenatal period. METHODS: An extensive literature search was performed in MEDLINE (through PubMed), EMBASE, Cochrane Database of Systematic Reviews, Google Scholar, and ClinicalTrials.gov until 30 November, 2023. Studies reporting data on congenital anomalies following antenatal use of dolutegravir were included. Risk of bias for randomized controlled trials, non-randomized controlled trials, and observational studies was assessed using RoB2, ROBINS-I, and ROBINS-E tools, respectively. A meta-analysis was performed in 'RevMan 5.4.1' using a random-effects model. Heterogeneity was assessed by the 'Q' statistic and I2 value. A sensitivity analysis was performed for higher heterogeneity/high-risk studies. The study protocol was registered in PROSPERO [CRD42023446374] a priori. RESULTS: Of 26 eligible studies, 12 (six randomized controlled trials and six observational studies with a pooled sample of 32,617) were included in a meta-analysis and 14 in a qualitative synthesis only. The meta-analysis does not show a statistically significant difference in the risk of congenital anomalies between newborns exposed antenatally to dolutegravir-based regimen(s) and those exposed to non-dolutegravir-based regimens [risk ratio 1.10; 95% confidence interval 0.79-1.53; p = 0.59]. Heterogeneity was moderate (I2 = 47%). Pooled results for randomized controlled trials and observational studies separately and the sensitivity analysis for heterogeneity provided similar results. CONCLUSIONS: The risk of congenital anomalies was not significantly different between dolutegravir-based regimens and non-dolutegravir-based-regimens in newborns exposed during their antenatal period.

Impact of 6-hydroxydopamine on agonist-induced human platelet functional parameters: An explanation for platelet impairment in Parkinson's disease.

Parkinson's disease (PD) is the second-most prevalent neurodegenerative disease worldwide, which worsens with advancing age. It is a common movement disorder and is often associated with several vascular diseases with decreased stroke frequency. Circulating platelets substantially regulate vascular complications, including stroke, and share striking similarities with PD neurons. Although structural alterations in platelets are well-documented in PD, their functional parameters remain unclear. This study aimed to investigate the functional abnormalities in platelets associated with PD by evaluating key functional aspects such as adhesion, activation, secretion, aggregation, and clot retraction. To achieve this, we treated human blood platelets with 6-hydroxydopamine or 6-OHDA, that selectively destroys dopaminergic neurons, thereby creating an in vitro experimental model that closely resembles the pathogenic environment in PD, and examine its impact on platelet functions. In our study, platelet adhesion was assessed and further evaluated by a microplate reader, activation and secretion by a flow cytometer, aggregation by aggregometer, and clot retraction by Sonoclot. Phase-contrast and confocal microscopic studies further verified the results from the above experiments. Our findings showed that 6-OHDA treatment significantly inhibited thrombin (a platelet agonist)-induced functions, including adhesion, activation, aggregation, secretion, and clot retraction in human-washed platelets. In summary, this research provides pioneering evidence that 6-OHDA induces abnormal platelet functions, shedding light on the previously unexplored processes by which 6-OHDA affects platelet activity.

A traveling surface acoustic wave-based micropiezoactuator: A tool for additive- and label-free cell lysis.

We propose a traveling surface acoustic wave (TSAW)-based microfluidic method for cell lysis that enables lysis of any biological entity, without the need for additional additives. Lysis of cells in the sample solution flowing through a poly (dimethyl siloxane) microchannel is enabled by the interaction of cells with TSAWs propagated from gold interdigitated transducers (IDTs) patterned onto a LiNbO3 piezoelectric substrate, onto which the microchannel was also bonded. Numerical simulations to determine the wave propagation intensities with varying parameters including IDT design, supply voltage, and distance of the channel from the IDT were performed. Experiments were then used to validate the simulations and the best lysis parameters were used to maximize the nucleic acid/protein extraction efficiency (>95%) within few seconds. A comparative analysis of our method with traditional chemical, physical and thermal, as well as the current microfluidic methods for lysis demonstrates the superiority of our method. Our lysis strategy can hence be used independently and/or integrated with other nucleic acid-based technologies or point-of-care devices for the lysis of any pathogen (Gram positives and negatives), eukaryotic cells, and tissues at low voltage (3 V) and frequency (33.17 MHz), without the use of amplifiers.

Structural transitions of a semi-flexible polyampholyte.

Polyampholytes (PAs) are charged polymers composed of positively and negatively charged monomers along their backbone. The sequence of the charged monomers and the bending of the chain significantly influence the conformation and dynamical behavior of the PA. Using coarse-grained molecular dynamics simulations, we comprehensively study the structural and dynamical properties of flexible and semi-flexible PAs. The simulation results demonstrate a flexible PA chain, displaying a transition from a coil to a globule in the parameter space of the charge sequence. In addition, the behavior of the mean-square displacement (MSD), denoted as ⟨(Δr(t))2⟩, reveals distinct dynamics, specifically for the alternating and charge-segregated sequences. The MSD follows a power-law behavior, where ⟨(Δr(t))2⟩ ∼ tß, with ß ≈ 3/5 and ß ≈ 1/2 for the alternating sequence and the charge-segregated sequence in the absence of hydrodynamic interactions, respectively. However, when hydrodynamic interactions are incorporated, the exponent ß shifts to ∼3/5 for the charge-segregated sequence and 2/3 for the well-mixed alternating sequence. For a semi-flexible PA chain, varying the bending rigidity and electrostatic interaction strength (Γe) leads to distinct, fascinating conformational states, including globule, bundle, and torus-like conformations. We show that PAs acquire circular and hairpin-like conformations in the intermediate bending regime. The transition between various conformations is identified in terms of the shape factor estimated from the ratios of eigenvalues of the gyration tensor.

Sialadenitis in Antineutrophil Cytoplasmic Antibodies Vasculitis.

Granulomatosis with polyangiitis (GPA) is a pauci-immune vasculitis typically involving upper and lower respiratory tract involvement and crescentic glomerulonephritis. Salivary gland involvement in GPA is rare. When it occurs in GPA, it is commonly seen with sinonasal and lung involvement and rarely with renal involvement. Easy accessibility of salivary glands allows early biopsy and timely treatment. In our case with GPA, salivary gland involvement was unresponsive to cyclophosphamide but remitted with rituximab.

Effect of Mn2+doping and DDAB-assisted postpassivation on the structural and optical properties of CsPb(Cl/Br)3halide perovskite nanocrystals.

Cesium lead halide perovskite (CsPbX3; X = Cl, Br, I) nanocrystals showing intense band-edge emission and high photoluminescence quantum yield are known to be a potential candidate for application in optoelectronic devices. However, controlling toxicity due to the presence of Pb2+in lead-based halide perovskites is a major challenge for the environment that needs to be tackled cautiously. In this work, we have partially replaced Pb2+with Mn2+ions in the CsPb(Cl/Br)3nanocrystals and investigated their impact on the structural and optical properties. The Rietveld refinement shows that CsPbCl2Br nanocrystals possess a cubic crystal structure withPm3̅mspace group, the Mn2+doping results in the contraction of the unit cell. The CsPb(Cl/Br)3: Mn nanocrystals show a substantial change in the optical properties with an additional emission band at ∼588 nm through a d-d transition, changing the emission color from blue to pink. Here, a didodecyldimethylammonium bromide (DDAB) ligand that triggers both anion and ligand exchange in the CsPb(Cl/Br)3: Mn nanocrystals have been used to regulate the exchange reaction and tune the emission color of halide perovskites by changing the peak position and the PL intensities of band-edge and Mn2+defect states. We have also shown that oleic acid helps in the desorption of oleylamine capping from the CsPb(Cl/Br)3: Mn nanocrystal surfaces and DDAB, resulting in the substitution of Cl-with Br-as well as provides capping with shorter branched length ligand which led to increase in the overall PL intensity by many folds.

Active polar ring polymer in shear flow-An analytical study.

We theoretically study the conformational and dynamical properties of semiflexible active polar ring polymers under linear shear flow. A ring is described as a continuous semiflexible Gaussian polymer with a tangential active force of a constant density along its contour. The linear but non-Hermitian equation of motion is solved using an eigenfunction expansion, which yields activity-independent, but shear-rate-dependent, relaxation times and activity-dependent frequencies. As a consequence, the ring's stationary-state properties are independent of activity, and its conformations and rheological properties are equal to those of a passive ring under shear. The presence of characteristic time scales by relaxation and the activity-dependent frequencies give rise to a particular dynamical behavior. A tank-treading-like motion emerges for long relaxation times and high activities, specifically for stiff rings. In the case of very flexible polymers, the relaxation behavior dominates over activity contributions suppressing tank-treading. Shear strongly affects the crossover from a tank-treading to a relaxation-dominated dynamics, and the ring polymer exhibits tumbling motion at high shear rates. This is reflected in the tumbling frequency, which displays two shear-rate dependent regimes, with an activity-dependent plateau at low shear rates followed by a power-law regime with increasing tumbling frequency for high shear rates.

Molecular insights into the role of mixed lineage kinase 3 in cancer hallmarks.

Mixed-lineage kinase 3 (MLK3) is a serine/threonine kinase of the MAPK Kinase kinase (MAP3K) family that plays critical roles in various biological processes, including cancer. Upon activation, MLK3 differentially activates downstream MAPKs, such as JNK, p38, and ERK. In addition, it regulates various non-canonical signaling pathways, such as ß-catenin, AMPK, Pin1, and PAK1, to regulate cell proliferation, apoptosis, invasion, and metastasis. Recent studies have also uncovered other potentially diverse roles of MLK3 in malignancy, which include metabolic reprogramming, cancer-associated inflammation, and evasion of cancer-related immune surveillance. The role of MLK3 in cancer is complex and cancer-specific, and an understanding of its function at the molecular level aligned specifically with the cancer hallmarks will have profound therapeutic implications for diagnosing and treating MLK3-dependent cancers. This review summarizes the current knowledge about the effect of MLK3 on the hallmarks of cancer, providing insights into its potential as a promising anticancer drug target.

Collective dynamics of active dumbbells near a circular obstacle.

In this article, we present the collective dynamics of active dumbbells in the presence of a static circular obstacle using Brownian dynamics simulation. The active dumbbells aggregate on the surface of a circular obstacle beyond a critical radius. The aggregation is non-uniform along the circumference, and the aggregate size increases with the activity (Pe) and the curvature radius (Ro). The dense aggregate of active dumbbells displays persistent rotational motion with a certain angular speed, which linearly increases with activity. Furthermore, we show a strong polar ordering of the active dumbbells within the aggregate. The polar ordering exhibits long-range correlation, with the correlation length corresponding to the aggregate size. Additionally, we show that the residence time of an active dumbbell on the obstacle surface increases rapidly with area fraction due to many-body interactions that lead to a slowdown of the rotational diffusion. This article further considers the dynamical behavior of a tracer particle in the solution of active dumbbells. Interestingly, the speed of the passive tracer particle displays a crossover from monotonically decreasing to increasing with the size of the tracer particle upon increasing the dumbbells' speed. Furthermore, the effective diffusion of the tracer particle displays non-monotonic behavior with the area fraction; the initial increase in diffusivity is followed by a decrease for a larger area fraction.

Effect of the COVID-19 Pandemic on Respiratory Diseases and Their Economic Impacts.

COVID-19 is an airborne respiratory disease that mainly affects the lungs. To date, COVID-19 has infected 580 million people with a mortality of approximately 7 million people worldwide. The emergence of COVID-19 has also affected the infectivity, diagnosis, and disease outcomes of existing diseases such as influenza, TB, and asthma in human populations. These are airborne respiratory diseases with symptoms and mode of transmission similar to those of COVID-19. It was speculated that the protracted nature of the COVID-19 pandemic coupled with vaccination could impact other respiratory diseases and mortality. In this study, we analyzed the impact of COVID-19 on flu, tuberculosis (TB), and asthma. Our analyses suggest that COVID-19 has a potential impact on the mortality of flu, TB, and asthma. These impacts vary across before the COVID-19 era, during the peak period of the pandemic, and after vaccinations/preventive measures were implemented, as well as across different regions of the world. Overall, the spread of flu generally reduced during the pandemic, resulting in a reduced expenditure on flu-related hospitalizations, although there were sporadic spikes at setting times. In contrast, TB deaths generally increased perhaps due to the disruption in access to TB services and reduction in resources. Asthma deaths, on the other hand, only marginally varied. Collectively, the emergence of COVID-19 added extra cost to the overall expenditure on some respiratory infectious diseases, while the cost for other infectious diseases was either reduced or somewhat unaffected.

Lysophosphatidylcholine induces oxidative stress and calcium-mediated cell death in human blood platelets.

Platelets are essential component of circulation that plays a major role in hemostasis and thrombosis. During activation and its demise, platelets release platelet-derived microvesicles, with lysophosphatidylcholine (LPC) being a prominent component in their lipid composition. LPC, an oxidized low-density lipoprotein, is involved in cellular metabolism, but its higher level is implicated in pathologies like atherosclerosis, diabetes, and inflammatory disorders. Despite this, its impact on platelet function remains relatively unexplored. To address this, we studied LPC's effects on washed human platelets. A multimode plate reader was employed to measure reactive oxygen species and intracellular calcium using H2DCF-DA and Fluo-4-AM, respectively. Flow cytometry was utilized to measure phosphatidylserine expression, mitochondrial membrane potential (ΔΨm), and mitochondrial permeability transition pore (mPTP) formation using FITC-Annexin V, JC-1, and CoCl2/calcein-AM, respectively. Additionally, platelet morphology and its ultrastructure were observed via phase contrast and electron microscopy. Sonoclot and light transmission aggregometry were employed to examine fibrin formation and platelet aggregation, respectively. The findings demonstrate that LPC induced oxidative stress and increased intracellular calcium in platelets, resulting in increased phosphatidylserine expression and reduced ΔΨm. LPC triggered caspase-independent platelet death and mPTP opening via cytosolic and mitochondrial calcium, along with microvesiculation and reduced platelet counts. LPC increased the platelet's size, adopting a balloon-shaped morphology, causing membrane fragmentation and releasing its cellular contents, while inducing a pro-coagulant phenotype with increased fibrin formation and reduced integrin αIIbß3 activation. Conclusively, this study reveals LPC-induced oxidative stress and calcium-mediated platelet death, necrotic in nature with pro-coagulant properties, potentially impacting inflammation and repair mechanisms during vascular injury.

MLK3 promotes prooncogenic signaling in hepatocellular carcinoma via TGFß pathway.

Advanced hepatocellular carcinoma (HCC) is a lethal disease, with limited therapeutic options. Mixed Lineage Kinase 3 (MLK3) is a key regulator of liver diseases, although its role in HCC remains unclear. Analysis of TCGA databases suggested elevated MAP3K11 (MLK3 gene) expression, and TMA studies showed higher MLK3 activation in human HCCs. To understand MLK3's role in HCC, we utlized carcinogen-induced HCC model and compared between wild-type and MLK3 knockout (MLK3-/-) mice. Our studies showed that MLK3 kinase activity is upregulated in HCC, and MLK3 deficiency alleviates HCC progression. MLK3 deficiency reduced proliferation in vivo and MLK3 inhibition reduced proliferation and colony formation in vitro. To obtain further insight into the mechanism and identify newer targets mediating MLK3-induced HCCs, RNA-sequencing analysis was performed. These showed that MLK3 deficiency modulates various gene signatures, including EMT, and reduces TGFB1&2 expressions. HCC cells overexpressing MLK3 promoted EMT via autocrine TGFß signaling. Moreover, MLK3 deficiency attenuated activated hepatic stellate cell (HSC) signature, which is increased in wild-type. Interestingly, MLK3 promotes HSC activation via paracrine TGFß signaling. These findings reveal TGFß playing a key role at different steps of HCC, downstream of MLK3, implying MLK3-TGFß axis to be an ideal drug target for advanced HCC management.

Assessment of Epidemiology and Clinical Profile of Psoriatic Arthritis Patients in India.

BACKGROUND: Psoriasis is an inflammatory skin disease associated with significant comorbidity. However, the characteristics of patients with psoriasis are not well documented in India, and a more detailed understanding is needed to delineate the epidemiologic profile at the regional level for better management of psoriasis. Herein, we reported the clinical profile and demographic pattern of psoriasis to further understand its burden in the Indian setting. METHODS: We conducted a retrospective observational study of patients diagnosed with psoriasis who fulfilled the classification criteria for psoriatic arthritis (CASPAR) criteria. Patients were included from the rheumatology outpatient department of Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute in Mumbai, India. The outcomes included demographic and clinical profiles, patterns of joint involvement, and comorbidities associated with psoriasis. A p-value of <0.05 was considered significant. RESULTS: We enrolled 60 patients, with a mean age of 50.87 years and a higher proportion of females (62%). The majority of patients with less than five joints had associated comorbidities (40 out of 60). Psoriatic arthritis (PsA) occurred in 41 patients [mean ± standard deviation (SD) age of onset-38.88 ± 13.24 years], with the highest occurrence in the 30-50 years (53.3%). The majority of patients with PsA developed it within 2 to ≥5 years of psoriasis occurrence. We did not find any significant correlation between the occurrence of PsA and comorbidities, as well as the duration of PsA and the number of joints (p = 0.152). Pitting and enthesitis were the most common morphological changes noted in almost half of the patients. CONCLUSION: Our study provides an overview of the epidemiologic and clinical characteristics of psoriasis patients in India. These findings could be useful for early diagnosis of PsA and help clinicians in assessing the progression of psoriasis into PsA.

Investigating the role of rotenone on human blood platelets: Molecular insights into abnormal platelet functions in Parkinson's disease.

Parkinson's disease (PD) is a predominant neuromotor disorder characterized by the selective death of dopaminergic neurons in the midbrain. The majority of PD cases are sporadic or idiopathic, with environmental toxins and pollutants potentially contributing to its development or exacerbation. However, clinical PD patients are often associated with a reduced stroke frequency, where circulating blood platelets are indispensable. Although platelet structural impairment is evident in PD, the platelet functional alterations and their underlying molecular mechanisms are still obscure. Therefore, we investigated rotenone (ROT), an environmental neurotoxin that selectively destroys dopaminergic neurons mimicking PD, on human blood platelets to explore its impact on platelet functions, thus replicating PD conditions in vitro. Our study deciphered that ROT decreased thrombin-induced platelet functions, including adhesion, activation, secretion, and aggregation in human blood platelets. As ROT is primarily responsible for generating intracellular reactive oxygen species (ROS), and ROS is a key player regulating the platelet functional parameters, we went on to check the effect of ROT on platelet ROS production. In our investigation, it became evident that ROT treatment resulted in the stimulation of ROS production in human blood platelets. Additionally, we discovered that ROT induced ROS production by augmenting Ca2+ mobilization from inositol 1,4,5-trisphosphate receptor. Apart from this, the treatment of ROT triggers protein kinase C associated NADPH oxidase-mediated ROS production in platelets. In summary, this research, for the first time, highlights ROT-induced abnormal platelet functions and may provide a mechanistic insight into the altered platelet activities observed in PD patients.

Platelets and inter-cellular communication in immune responses: Dialogue with both professional and non-professional immune cells.

Platelets, derived from bone marrow megakaryocytes, are essential for vascular integrity and play multifaceted roles in both physiological and pathological processes within the vasculature. Despite their small size and absence of a nucleus, platelets are increasingly recognized for their diverse immune functions. Recent research highlights their pivotal role in interactions with various immune cells, including professional cells like macrophages, dendritic cells, natural killer cells, T cells, and B cells, influencing host immune responses. Platelets also engage with non-professional immune cells, contributing to immune responses and structural maintenance, particularly in conditions like inflammation and atherosclerosis. This review underscores the emerging significance of platelets as potent immune cells, elucidating their interactions with the immune system. We explore the mechanisms of platelet activation, leading to diverse functions, such as aggregation, immunity, activation of other immune cells, and pathogen clearance. Platelets have become the predominant immune cells in circulation, involved in chronic inflammation, responses to infections, and autoimmune disorders. Their immunological attributes, including bioactive granule molecules and immune receptors, contribute to their role in immune responses. Unlike professional antigen-presenting cells, platelets process and present antigens through an MHC-I-dependent pathway, initiating T-cell immune responses. This review illuminates the unique features of platelets and their central role in modulating host immune responses in health and disease.

Novel carbamodithioate regulates cellular hypoxia through chemical activation of prolyl hydroxylase-2 for breast cancer chemoprevention.

Inhibition of prolylhydroxylase-2 (PHD-2) in both normoxic and hypoxic cells is a critical component of solid tumours. The present study aimed to identify small molecules with PHD-2 activation potential. Virtually screening 4342 chemical compounds for structural similarity to R59949 and docking with PHD-2. To find the best drug candidate, hits were assessed for drug likeliness, antihypoxic and antineoplastic potential. The selected drug candidate's PHD-2 activation, cytotoxic and apoptotic potentials were assessed using 2-oxoglutarate, MTT, AO/EtBr and JC-1 staining. The drug candidate was also tested for its in-vivo chemopreventive efficacy against DMBA-induced mammary gland cancer alone and in combination with Tirapazamine (TPZ). Virtual screening and 2-oxoglutarate assay showed BBAP-6 as lead compound. BBAP-6 exhibited cytotoxic and apoptotic activity against ER+ MCF-7. In carmine staining and histology, BBAP-6 alone or in combination with TPZ restored normal surface morphology of the mammary gland after DMBA produced malignant alterations. Immunoblotting revealed that BBAP-6 reduced NF-κB expression, activated PHD-2 and induced intrinsic apoptotic pathway. Serum metabolomics conducted with 1H NMR confirmed that BBAP-6 prevented HIF-1α and NF-κB-induced metabolic changes in DMBA mammary gland cancer model. In a nutshell, it can be concluded that BBAP-6 activates PHD-2 and exhibits anticancer potential.