High-Intensity Interval Training and Vitamin D3 Supplementation Decrease CCL-5 and CCR5 Expression In White Adipose Tissue of Diabetic Rats Fed with A High-Fat Diet and Streptozotocin.

Article

作者: Tahmasebi, Worya ; Rahimi, Mohammad Rahman ; Azizi, Mohammad ; Fallahi, Fariba

OBJECTIVEThe purpose of this study was to investigate the effects of 8 weeks of high-intensity interval training (HIIT) and vitamin D3 supplementation on Chemokine (C-C motif) Ligand 5 (CCL-5) and C-C motif chemokine receptor 5 (CCR5) in the white adipose tissue (WAT) of male rats with type 2 diabetes (T2DM).MATERIALS AND METHODSThe experimental study involved 40 male Wistar rats divided into 5 groups (n=8). These groups were healthy control (HC), diabetic control (DC), diabetic+HIIT (DHIIT), diabetic+vitamin D3 (DD3), and diabetic+HIIT+vitamin D3 (DHIITD3). The rats completed 8 weeks of HIIT, consisting of 12 sessions lasting 1 minute each at an intensity of 90-95% of their maximum running speed. Additionally, the rats were administered a weekly dose of 10,000 IU/kg of vitamin D3 for 8 weeks.RESULTSThe levels of CCL-5 (P<0.001) and CCR5 (P=0.003) were found to be higher in the DC group as compared to the HC group. However, when HIIT training and vitamin D3 were administered together, there was a decrease in CCL-5 (P=0.001) and CCR5 (P<0.001) in the DHIITD3 group (P=0.001). Similarly, vitamin D3 alone reduced CCR5 levels in the DD3 group (P< 0.001). Also, the decrease of CCR5 in the DD3 group was higher than in the DHIIT group (P=0.022), and the DHIITD3 group was higher than in the DHIIT group (P<0.001), but there was no difference between the DD3 and DHIITD3 groups (P≥0.05).CONCLUSIONThe results indicate that combining HIIT training with vitamin D3 has a greater effect on reducing the expression of CCL-5 and CCR5 in the white adipose tissue of rats with type 2 diabetes induced by streptozotocin (STZ) and a high-fat diet (HFD), compared to the effects of each one alone. It is recommended that the study be conducted by measuring the variables involved in the mechanisms and the changes in CCL-5 and CCR5.

2023-10-01·International journal of radiation oncology, biology, physics

Interim Analysis of DD3: A Phase IB/II Trial of Dose-Deescalated 3-Fraction SBRT for Centrally Located Lung Cancer.

Article

作者: Hayman, T J ; Peters, G W ; Knowlton, C A ; Park, H S M ; Boateng, K ; Campbell, A M ; Cheng, W

PURPOSE/OBJECTIVE(S)Prior studies suggested excessive toxicity for central lung tumors treated with 3-fraction stereotactic body radiation therapy (SBRT). This may be related to the high biologically equivalent dose assuming alpha/beta of 10 (BED) of 54 Gy in 3 fractions (BED = 151.2), as 50-60 Gy in 5 fractions (BED = 100.0-132.0) was well-tolerated in RTOG 0813. We initiated a prospective phase IB/II trial to test the hypothesis that a dose-deescalated regimen of 45 Gy in 3 fractions (BED 112.5) would be safe and efficacious in central lung tumors.MATERIALS/METHODSWe enrolled patients with primary or secondary lung tumors ≤5cm in a central but not ultra-central tumor location defined as within 2 cm of (but not abutting) tracheobronchial tree, esophagus, or heart. Patients were either medically inoperable or refused surgical intervention. Co-primary endpoints were safety and efficacy, defined as local control (LC). Secondary endpoints included lobar control, regional control (LRC), distant control (DC), progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). Organ-at-risk dose constraints were consistent with those of RTOG 0236. The Bayesian predictive probability approach was utilized for continuous monitoring after 10 patients were treated and have mature assessment of toxicity, after which interim analysis was planned. We recommended terminating the trial for safety if there was sufficient evidence that the rate of grade ≥3 was greater than 0.25 (predictive probability >0.80).RESULTSAs of the data cut-off date of 1/26/23, the trial was open for 34 months (including a nearly-immediate suspension due to the COVID-19 pandemic). A total of 17 patients have been treated on protocol with a median follow-up of 12 months. No grade ≥3 adverse events attributable to SBRT have occurred to date, though one patient died of unrelated cardiac arrhythmias 1 month after SBRT completion (Table 1). Maximum CTCAE grade 2 adverse events attributable to SBRT occurred in 17.6% of patients. The predictive probability of concluding unacceptably high toxicity rate by the end of the trial based on toxicity data in the current stage is 0.62%. To date, there have been 0 local recurrences, 1 regional recurrence without local recurrence (8 months after SBRT completion, successfully salvaged with definitive chemoradiotherapy without additional toxicities), and 1 distant recurrence without local recurrence (6 months after SBRT in a patient with lung metastasis from colon adenocarcinoma).CONCLUSIONInterim analysis of the DD3 trial suggests that for patients with central but not ultra-central lung tumors, an SBRT regimen of 45 Gy in 3 fractions warrants continued trial accrual and follow-up given no grade ≥3 toxicities or local recurrences in the early follow-up period among the first 17 patients enrolled.

2018-12-01·Journal of Cellular Biochemistry3区 · 生物学

Molecular docking and simulation study for synthesis of alternative dapsone derivative as a newer antileprosy drug in multidrug therapy

3区 · 生物学

Article

作者: Vedithi, Sundeep Chaitanya ; Mahapatra, Namita ; Padhy, Rabindra N. ; Paidesetty, Sudhir K. ; Sahoo, Jyotirmaya ; Swain, Shasank S. ; Dehury, Budheswar ; Hussain, Tahziba

AbstractLeprosy (causative, Mycobacterium leprae) continues to be the persisting public health problem with stable incidence rates, owing to the emergence of dapsone resistance that being the principal drug in the ongoing multidrug therapy. Hence, to overcome the drug resistance, structural modification through medicinal chemistry was used to design newer dapsone derivative(s) (DDs), against folic acid biosynthesis pathway. The approach included theoretical modeling, molecular docking, and molecular dynamic (MD) simulation as well as binding free energy estimation for validation of newly designed seven DDs, before synthesis. Theoretical modeling, docking, and MD simulation studies were used to understand the mode of binding and efficacy of DDs against the wild‐type and mutant dihydropteroate synthases (DHPS). Principal component analysis was performed to understand the conformational dynamics of DHPS‐DD complexes. Furthermore, the overall stability and negative‐binding free energy of DHPS‐DD complexes were deciphered using Molecular Mechanics/Poisson‐Boltzmann Surface Area technique. Molecular mechanics study revealed that DD3 possesses higher binding free energy than dapsone against mutant DHPS. Energetic contribution analysis portrayed that van der Waals and electrostatic energy contributes profoundly to the overall negative free energy, whereas polar solvation energy opposes the binding. Finally, DD3 was synthesized and characterized using Fourier‐transform infrared spectroscopy, UV, liquid chromatography‐mass spectrometry, and proton nuclear magnetic resonance techniques. This study suggested that DD3 could be further promoted as newer antileprosy agent. The principles of medicinal chemistry and bioinformatics tools help to locate effective therapeutics to minimize resources and time in current drug development modules.

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适应症	最高研发状态	国家/地区	公司	日期
自身免疫性疾病	临床前	西班牙	Palau Pharma SA	-
炎症	药物发现	西班牙	Almirall SA	-
炎症	药物发现	西班牙	Draconis Pharma SL	-
炎症	药物发现	西班牙	Proteomika SL	-
炎症	药物发现	西班牙	Esteve Pharmaceuticals S.A.	-