Myeloid lineage skewing due to exacerbated NF-κB signaling facilitates osteopenia in Scurfy mice

Immune surveillance through Foxp3+ regulatory T cells plays a crucial role in bone homeostasis. Scurfy, the mouse model of autoimmune IPEX syndrome, bears a loss-of-function mutation in Foxp3 that leads to multi-organ inflammation. Herein, we report that scurfy mice exhibit severe bone loss mediated by accelerated osteoclastogenesis. Mechanistically, Foxp3 deficiency results in the upregulation of NF-κB in T helper cells through the loss of repressive Foxp3/NEMO interaction, thereby unleashing NF-κB-mediated over-production of pro-osteoclastogenic cytokines. Flow cytometry analysis shows marked increase in lin(-)Sca-1(+)c-kit(+) hematopoietic stem cells (LSK HSCs) and granulocyte/macrophage progenitors (GMPs) in bone marrow of scurfy mice with corresponding exacerbated osteoclastogenic potential, implying that osteoclast progenitors are affected at a very primitive stage in this disorder. Scurfy LSK HSCs exhibit greater sensitivity to M-CSF and contain abundant PU.1+ Sf LSK HSCs compared with WT. Accordingly, genetic or pharmacological inhibition of M-CSF or mTOR signaling, but not IL-17 signaling, attenuates osteoclastogenesis and osteopenia in scurfy. Thus, our study suggests that Foxp3 deficiency leads to osteopenia owing to dysregulated NF-κB activity and subsequent cytokine-mediated hyper-proliferation of myeloid precursors, and positions the NF-κB pathway as a potential target for therapeutic intervention for this disorder

RasGRP1 is a causal factor in the development of l-DOPA-induced dyskinesia in Parkinson's disease.

The therapeutic effects of l-3,4-dihydroxyphenylalanine (l-DOPA) in patients with Parkinson's disease (PD) severely diminishes with the onset of abnormal involuntary movement, l-DOPA-induced dyskinesia (LID). However, the molecular mechanisms that promote LID remain unclear. Here, we demonstrated that RasGRP1 [(guanine nucleotide exchange factor (GEF)] controls the development of LID. l-DOPA treatment rapidly up-regulated RasGRP1 in the striatum of mouse and macaque model of PD. The lack of RasGRP1 in mice (RasGRP1-/- ) dramatically diminished LID without interfering with the therapeutic effects of l-DOPA. Besides acting as a GEF for Ras homolog enriched in the brain (Rheb), the activator of the mammalian target of rapamycin kinase (mTOR), RasGRP1 promotes l-DOPA-induced extracellular signal-regulated kinase (ERK) and the mTOR signaling in the striatum. High-resolution tandem mass spectrometry analysis revealed multiple RasGRP1 downstream targets linked to LID vulnerability. Collectively, the study demonstrated that RasGRP1 is a critical striatal regulator of LID

Laparoscopic versus open colorectal surgery in the acute setting (LaCeS trial): a multicentre randomized feasibility trial

AbstractBackgroundApproximately 30,000 people per annum undergo major, emergency abdominal, gastrointestinal surgery, of which 36% (~10,800) are carried out for emergency colorectal pathology. Approximately 14% of all patients requiring emergency surgery undergo laparoscopic surgery. AimsThe aims of the LaCeS feasibility trial (Laparoscopic versus Open Colorectal Surgery in the Acute Setting) were to assess the feasibility, safety and acceptability of performing a large-scale definitive phase III randomised controlled trial with a comparison of emergency laparoscopic with open surgery for acute colorectal pathology. MethodsLaCeS was designed as a prospective, multicentre, single blind, parallel group, pragmatic, randomised controlled feasibility trial with an integrated qualitative study. Randomisation was performed centrally with patients being randomised on a 1:1 basis between laparoscopic or open surgery. ResultsA total of 64 patients were recruited across 5 centres. The overall average steady state recruitment rate was 1.2 patients/month. Baseline compliance for clinical and HrQoL data was 99.8% and 93.8% respectively. The conversion rate from laparoscopic to open surgery was 39.4% (95% CI 22.9% – 57.9%). The 30 day post-operative complication rate was 27.3% (95% CI 13.3- 45.5) in the laparoscopic arm and 41.9% (95% CI 24.6 – 60.9) in the open arm. DiscussionThe LaCeS feasibility trial has demonstrated that it is possible to evaluate laparoscopic surgery in the emergency colorectal setting within the context of a randomised controlled trial. LaCeS has demonstrated that it is possible to recruit to a surgical trial in the emergency setting, with good compliance to trial procedures and processes, and overall acceptability by patients and clinicians. The safety data obtained for laparoscopic emergency colorectal surgery indicate an acceptable safety profile, particularly when considering it to that observed in the open arm.Trial Registration ISRCTN15681041 https://doi.org/10.1186/ISRCTN15681041.Funding body: National Institute of Health Research – Research for Patient Benefi

In vitro neuroprotective potential of four medicinal plants against rotenone-induced toxicity in SH-SY5Y neuroblastoma cells

BACKGROUND: Lannea schweinfurthii, Zanthoxylum capense, Scadoxus puniceus and Crinum bulbispermum are used traditionally to treat neurological disorders. The aim of this study was to evaluate the cytoprotective potential of the four plants, after induction of toxicity using rotenone, in SH-SY5Y neuroblastoma cells. METHODS: Cytotoxicity of the plant extracts and rotenone was assessed using the sulforhodamine B (SRB) assay. Fluorometry was used to measure intracellular redox state (reactive oxygen species (ROS) and intracellular glutathione content), mitochondrial membrane potential (MMP) and caspase-3 activity, as a marker of apoptotic cell death. RESULTS: Of the tested plants, the methanol extract of Z. capense was the least cytotoxic; LC(50) 121.3 ± 6.97 μg/ml, while S. puniceus methanol extract was the most cytotoxic; LC(50) 20.75 ± 1.47 μg/ml. Rotenone reduced intracellular ROS levels after 24 h exposure. Pre-treating cells with S. puniceus and C. bulbispermum extracts reversed the effects of rotenone on intracellular ROS levels. Rotenone exposure also decreased intracellular glutathione levels, which was counteracted by pre-treatment with any one of the extracts. MMP was reduced by rotenone, which was neutralized by pre-treatment with C. bulbispermum ethyl acetate extract. All extracts inhibited rotenone-induced activation of caspase-3. CONCLUSION: The studied plants demonstrated anti-apoptotic activity and restored intracellular glutathione content following rotenone treatment, suggesting that they may possess neuroprotective properties

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Not AvailableThe occurrence of rickets in young male lambs was investigated and amelioration was done with two commercial feed supplements (CFS-I and CFS-II) as a source of vitamins and minerals to see the beneficial effect in clinically affected lambs. Out of 113 male lambs, 18 lambs showed clinical symptoms of rickets such as bowing of legs, swelling of joints, stiff gait, and lameness. The ameliorative study was conducted for 45 days on 12 rickets affected lambs equally divided into two groups with commercial feed supplements as group I and group II. Six healthy lambs were served as control (group III). Clinical recovery after feed supplementation was assessed on the scale basis, and the hemato-biochemical alterations and serum mineral profile were evaluated on 0, 15, 30, and 45th days. The severity of clinical signs was found reduced in both the feed supplementation groups after 30th day in rickets affected animals and recovered completely on 45th day. The hematological values, serum total protein, globulin, calcium, phosphorus and magnesium levels revealed gradual improvement in rickets affected animals during the course of commercial feed supplementations and were comparable to the control animals at the end of experiment. The results of the study indicated that the feed supplementation with CFS-II was found to be more effective than CFS-I in the amelioration of rickets affected lambs.Not Availabl

Microwave Assisted Synthesis of Some Biologically Active Benzothiazolotriazine Derivatives

Synthesis of some biologically active benzothiazolotriazine derivatives by microwave irradiation is reported. 2-Amino-6-substituted benzothiazoles 1 on treatment with benzaldehyde in anhydrous ethanol afforded 2-benzylidenoimino-6-substitutedbenzothiazoles 2 which underwent cyclisation with ammoniumthiocyanate in dioxane to give 2-phenyl benzothiazolo [3,2-α]-s-triazine-4-[3H] thiones 3.These both steps were carried out in microwave. Compound 3 with benzoyl chloride in anhydrous pyridine gave 2-phenyl-3-(benzoyl) benzothiazolo [3,2-α]-s-triazine-4-thiones 4 in good yields. The structure of all these compounds have been supported by their elemental analysis and their spectral data. All synthesized compounds were tested for their antibacterial activity using standard drug

Microwave Assisted Synthesis of Some Biologically Active Benzothiazolotriazine Derivatives

Abstract: Synthesis of some biologically active benzothiazolotriazine derivatives by microwave irradiation is reported. 2-Amino-6-substituted benzothiazoles 1 on treatment with benzaldehyde in anhydrous ethanol afforded 2-benzylidenoimino-6-substitutedbenzothiazoles 2 which underwent cyclisation with ammoniumthiocyanate in dioxane to give 2-phenyl benzothiazolo [3,2-α]-striazine-4-[3H] thiones 3.These both steps were carried out in microwave. Compound 3 with benzoyl chloride in anhydrous pyridine gave 2-phenyl-3-(benzoyl) benzothiazolo [3,2-α]-s-triazine-4-thiones 4 in good yields. The structure of all these compounds have been supported by their elemental analysis and their spectral data. All synthesized compounds were tested for their antibacterial activity using standard drug

Synthesis and Antibacterial Activity of Some New Phenothiazine Derivatives

A series of some new phenothiazine derivatives were synthesized with the objective for evaluation as antimicrobials. The title compounds were prepared by a five step synthesis scheme. 2-Amino-6-substituted benzothiazoles (1) on diazotization afford 6-substituted benzothiazolyl-2-diazonium chlorides (2). Reaction of 2 with cold solution of β-naphthol in dilute NaOH furnishes α-(2-diazo-6-substituted benzothiazolyl)- β-sodionaphthoxides (3) which on acidification with concentrated HCl gives α-(2-diazo-6-substituted benzothiazolyl)-β-naphthols (4). Reaction of 4 with p-substituted anilines gives α-(2-diazo-6-substituted benzothiazolyl)-β-(p-substituted anilino) naphthalenes (5). This synthesis besides by using conventional methods was also attempted using microwave. Fusion of 5 with sulphur in presence of iodine results in α-(2-diazo-6-substituted benzothiazolyl)-6- substituted [2, 3-b] benzophenothiazines(6). The structures of all these compounds have been supported by elemental analysis and their spectral studies. All synthesized compounds were tested for their antibacterial activity using standard drugs