Synthesis and biological evaluation of novel (4 or 5-aryl)pyrazolyl-indoles as inhibitors of interleukin-2 inducible T-cell kinase (ITK)

Interleukin-2 inducible T-cell kinase (ITK) is one of five kinases that belong to the Tec kinase family that plays an important role in T-cell and mast cell signaling. Various reports point to a role of ITK in the treatment of allergic asthma. For example, it was shown that mice lacking ITK have reduced airway hyperresponsiveness, inflammation and tracheal responses in an allergic asthma model. In this article, we disclose novel ITK inhibitors based on (4 or 5-aryl)pyrazolyl-indole scaffold that were also found to be selective for ITK over other kinases like IRK, CDK2, GSK3ß and PKA.     

Health benefits of chromones: common ingredients of our daily diet

Phytochemistry Reviews - Chromones are naturally occurring phenolic compounds that are universally present in a healthy human diet. To date, thousands of chromone derivatives, including chromone...     

Per1/Per2–Igf2 axis–mediated circadian regulation of myogenic differentiation

Circadian rhythms regulate cell proliferation and differentiation, but circadian control of tissue regeneration remains elusive at the molecular level. Here, we show that proper myoblast differentiation and muscle regeneration are regulated by the circadian master regulators Per1 and Per2. Depletion of Per1 or Per2 suppressed myoblast differentiation in vitro and muscle regeneration in vivo, demonstrating their nonredundant functions. Both Per1 and Per2 were required for the activation of Igf2, an autocrine promoter of myoblast differentiation, accompanied by Per-dependent recruitment of RNA polymerase II, dynamic histone modifications at the Igf2 promoter and enhancer, and the promoter–enhancer interaction. This circadian epigenetic priming created a preferred time window for initiating myoblast differentiation. Consistently, muscle regeneration was faster if initiated at night, when Per1, Per2, and Igf2 were highly expressed compared with morning. This study reveals the circadian timing as a significant factor for effective muscle cell differentiation and regeneration.     

Sodium nitroprusside enhances biomass and gymnemic acids production in cell suspension of Gymnema sylvestre (Retz.) R.Br. ex. Sm.

Plant Cell, Tissue and Organ Culture (PCTOC) - Gymnemic acids (a group of triterpenoid saponins) found in Gymnema sylvestre (Retz.) R.Br. ex Sm. works as the main hypoglycaemic active components....     

Status of health and conservation classification of tropical coral reefs in Lakshadweep archipelago

Wetlands Ecology and Management - Coral reefs of Lakshadweep perform a range of vital ecosystem functions and sustain the livelihoods of island communities. Coral reefs provide ecosystem services...     

Coronavirus Disease (Covid-19) Associated Mucormycosis (CAM): Case Report and Systematic Review of Literature

Severe coronavirus disease (COVID-19) is currently managed with systemic glucocorticoids. Opportunistic fungal infections are of concern in such patients. While COVID-19 associated pulmonary aspergillosis is increasingly recognized, mucormycosis is rare. We describe a case of probable pulmonary mucormycosis in a 55-year-old man with diabetes, end-stage kidney disease, and COVID-19. The index case was diagnosed with pulmonary mucormycosis 21 days following admission for severe COVID-19. He received 5 g of liposomal amphotericin B and was discharged after 54 days from the hospital. We also performed a systematic review of the literature and identified seven additional cases of COVID-19 associated mucormycosis (CAM). Of the eight cases included in our review, diabetes mellitus was the most common risk factor. Three subjects had no risk factor other than glucocorticoids for COVID-19. Mucormycosis usually developed 10–14 days after hospitalization. All except the index case died. In two subjects, CAM was diagnosed postmortem. Mucormycosis is an uncommon but serious infection that complicates the course of severe COVID-19. Subjects with diabetes mellitus and multiple risk factors may be at a higher risk for developing mucormycosis. Concurrent glucocorticoid therapy probably heightens the risk of mucormycosis. A high index of suspicion and aggressive management is required to improve outcomes.

     

Genomic analysis of a novel species Halomonas shambharensis isolated from hypersaline lake in Northwest India

Molecular Biology Reports - Genome analysis of Halomonas shambharensis, a novel species, was performed to understand the osmoprotectant strategies used by the strain to overcome the salinity stress...     

Amino Acids and mTOR Mediate Distinct Metabolic Checkpoints in Mammalian G1 Cell Cycle

Objective

In multicellular organisms, cell division is regulated by growth factors (GFs). In the absence of GFs, cells exit the cell cycle at a site in G1 referred to as the restriction point (R) and enter a state of quiescence known as G0. Additionally, nutrient availability impacts on G1 cell cycle progression. While there is a vast literature on G1 cell cycle progression, confusion remains – especially with regard to the temporal location of R relative to nutrient-mediated checkpoints. In this report, we have investigated the relationship between R and a series of metabolic cell cycle checkpoints that regulate passage into S-phase.

Methods

We used double-block experiments to order G1 checkpoints that monitor the presence of GFs, essential amino acids (EEAs), the conditionally essential amino acid glutamine, and inhibition of mTOR. Cell cycle progression was monitored by uptake of [³H]-thymidine and flow cytometry, and analysis of cell cycle regulatory proteins was by Western-blot.

Results

We report here that the GF-mediated R can be temporally distinguished from a series of late G1 metabolic checkpoints mediated by EAAs, glutamine, and mTOR – the mammalian/mechanistic target of rapamycin. R is clearly upstream from an EAA checkpoint, which is upstream from a glutamine checkpoint. mTOR is downstream from both the amino acid checkpoints, close to S-phase. Significantly, in addition to GF autonomy, we find human cancer cells also have dysregulated metabolic checkpoints.

Conclusion

The data provided here are consistent with a GF-dependent mid-G1 R where cells determine whether it is appropriate to divide, followed by a series of late-G1 metabolic checkpoints mediated by amino acids and mTOR where cells determine whether they have sufficient nutrients to accomplish the task. Since mTOR inhibition arrests cells the latest in G1, it is likely the final arbiter for nutrient sufficiency prior to committing to replicating the genome.     

Using the Electronic Medical Record to Identify Community-Acquired Pneumonia: Toward a Replicable Automated Strategy

Background

Timely information about disease severity can be central to the detection and management of outbreaks of acute respiratory infections (ARI), including influenza. We asked if two resources: 1) free text, and 2) structured data from an electronic medical record (EMR) could complement each other to identify patients with pneumonia, an ARI severity landmark.

Methods

A manual EMR review of 2747 outpatient ARI visits with associated chest imaging identified x-ray reports that could support the diagnosis of pneumonia (kappa score  = 0.88 (95% CI 0.82∶0.93)), along with attendant cases with Possible Pneumonia (adds either cough, sputum, fever/chills/night sweats, dyspnea or pleuritic chest pain) or with Pneumonia-in-Plan (adds pneumonia stated as a likely diagnosis by the provider). The x-ray reports served as a reference to develop a text classifier using machine-learning software that did not require custom coding. To identify pneumonia cases, the classifier was combined with EMR-based structured data and with text analyses aimed at ARI symptoms in clinical notes.

Results

370 reference cases with Possible Pneumonia and 250 with Pneumonia-in-Plan were identified. The x-ray report text classifier increased the positive predictive value of otherwise identical EMR-based case-detection algorithms by 20–70%, while retaining sensitivities of 58–75%. These performance gains were independent of the case definitions and of whether patients were admitted to the hospital or sent home. Text analyses seeking ARI symptoms in clinical notes did not add further value.

Conclusion

Specialized software development is not required for automated text analyses to help identify pneumonia patients. These results begin to map an efficient, replicable strategy through which EMR data can be used to stratify ARI severity.     

Niosomal Gel of Lornoxicam for Topical Delivery: In vitro Assessment and Pharmacodynamic Activity

Lornoxicam is a potent oxicam class of non steroidal anti-inflammatory agent, prescribed for mild to moderate pain and inflammation. Niosomal gel of lornoxicam was developed for topical application. Lornoxicam niosomes (Lor-Nio) were fabricated by thin film hydration technique. Bilayer composition of niosomal vesicles was optimized. Lor-Nio dispersion was characterized by DSC, XRD, and FT-IR. Morphological evaluation was performed by scanning electron microscopy (SEM). Lor-Nio dispersion was incorporated into a gel using 2% w/w Carbopol 980 NF. Rheological and texture properties of Lor-Nio gel formulation showed suitability of the gel for topical application. The developed formulation was evaluated for in vitro skin permeation and skin deposition studies, occlusivity test and skin irritation studies. Pharmacodynamic activity of the Lor-Nio gel was performed by carragenan-induced rat paw model. Optimized Lor-Nio comprised of Span 60 and cholesterol in a molar ratio of 3:1 with 30 μM dicetyl palmitate as a stabilizer. It had particle size of 1.125 ± 0.212 μm (d₉₀), with entrapment efficiency of 52.38 ± 2.1%. DSC, XRD, and IR studies showed inclusion of Lor into niosomal vesicles. SEM studies showed spherical closed vesicular structure with particles in nanometer range. The in vitro skin permeation studies showed significant improvement in skin permeation and skin deposition for Lor-Nio gel (31.41 ± 2.24 μg/cm², 30.079 ± 1.2 μg/cm²) over plain lornoxicam gel (7.37 ± 1.27 μg/cm², 6.6 ± 2.52 μg/cm²). The Lor-Nio gel formulation showed enhanced anti-inflammatory activity by exhibiting mean edema inhibition (87.69 ± 1.43%) which was significantly more than the plain lornoxicam gel (53.84 ± 2.21%).KEY WORDS: anti-inflammatory activity, lornoxicam, niosomes, rheology, texture analysis