Unconventional tonicity-regulated nuclear trafficking of NFAT5 mediated by KPNB1, XPOT and RUVBL2.

NFAT5 is the only known mammalian tonicity-responsive transcription factor with an essential role in cellular adaptation to hypertonic stress. It is also implicated in diverse physiological and pathological processes. NFAT5 activity is tightly regulated by extracellular tonicity, but the underlying mechanisms remain elusive. Here, we demonstrate that NFAT5 enters the nucleus via the nuclear pore complex. We found that NFAT5 utilizes a unique nuclear localization signal (NFAT5-NLS) for nuclear import. siRNA screening revealed that only karyopherin ß1 (KPNB1), but not karyopherin α, is responsible for the nuclear import of NFAT5 via direct interaction with the NFAT5-NLS. Proteomics analysis and siRNA screening further revealed that nuclear export of NFAT5 under hypotonicity is driven by exportin-T (XPOT), where the process requires RuvB-like AAA-type ATPase 2 (RUVBL2) as an indispensable chaperone. Our findings have identified an unconventional tonicity-dependent nucleocytoplasmic trafficking pathway for NFAT5 that represents a critical step in orchestrating rapid cellular adaptation to change in extracellular tonicity. These findings offer an opportunity for the development of novel NFAT5 targeting strategies that are potentially useful for the treatment of diseases associated with NFAT5 dysregulation.

Both ASDAS and ADC are associated with spinal mobility in active axial spondyloarthritis: A comparison between early and later disease.

OBJECTIVE: Using diffusion-weighted imaging (DWI)-derived apparent diffusion coefficient (ADC), we aimed to determine the relationship between intensity of spinal inflammation and mobility in patients with axial spondyloarthritis (SpA) in early and later stages of active disease. The Ankylosing Spondylitis Disease Activity Score (ASDAS) was also used for a more comprehensive evaluation. METHODS: Participants with axial SpA and back pain were recruited from 10 rheumatology centers. Clinical, biochemical and radiological parameters were collected. Short tau inversion recovery (STIR) sequence magnetic resonance imaging (MRI) and DWI of the spine and sacroiliac (SI) joints were performed. ADC maps were generated. Participants were examined for Bath Ankylosing Spondylitis Metrology Index (BASMI). Linear regression models were used to determine associations between BASMI and various clinical, radiological, and MRI parameters in participants with active inflammation on spinal ADC maps. RESULTS: One-hundred and twenty-seven participants were included in the analyses. Multivariate linear regression showed that mean ADC spine (ß = .16; P = .03), ASDAS-C-reactive protein (CRP) (ß = .29, P < .001), and ASDAS-erythrocyte sedimentation rate (ESR) (ß = .25, P < .01) were associated with BASMI. In participants with duration of back pain ≤3 years, mean spine ADC (ß = .37; P = .03), ASDAS-CRP (ß = .44; P = .01), and ASDAS-ESR (ß = .42; P = .01) were associated with BASMI after adjustment for confounding factors. In participants with duration of back pain >3 years, only ASDAS-CRP (ß = .25; P < .01) and ASDAS-ESR (ß = .20; P = .20) were associated with BASMI. CONCLUSION: Intensity of inflammation and clinical disease activity were independently associated with impairment of spinal mobility. The associations were stronger in early (≤3 years) than later disease.

Formulation Development of a Food-Graded Curcumin-Loaded Medium Chain Triglycerides-Encapsulated Kappa Carrageenan (CUR-MCT-KC) Gel Bead Based Oral Delivery Formulation.

In recent years, curcumin has been a major research endeavor in food and biopharmaceutical industries owing to its miscellaneous health benefits. There is an increasing amount of research ongoing in the development of an ideal curcumin delivery system to resolve its limitations and further enhance its solubility, bioavailability and bioactivity. The emergence of food-graded materials and natural polymers has elicited new research interests into enhanced pharmaceutical delivery due to their unique properties as delivery carriers. The current study is to develop a natural and food-graded drug carrier with food-derived MCT oil and a seaweed-extracted polymer called k-carrageenan for oral delivery of curcumin with improved solubility, high gastric resistance, and high encapsulation of curcumin. The application of k-carrageenan as a structuring agent that gelatinizes o/w emulsion is rarely reported and there is so far no MCT-KC system established for the delivery of hydrophobic/lipophilic molecules. This article reports the synthesis and a series of in vitro bio-physicochemical studies to examine the performance of CUR-MCT-KC as an oral delivery system. The solubility of CUR was increased significantly using MCT with a good encapsulation efficiency of 73.98 ± 1.57% and a loading capacity of 1.32 ± 0.03 mg CUR/mL MCT. CUR was successfully loaded in MCT-KC, which was confirmed using FTIR and SEM with good storage and thermal stability. Dissolution study indicated that the solubility of CUR was enhanced two-fold using heated MCT oil as compared to naked or unformulated CUR. In vitro release study revealed that encapsulated CUR was protected from premature burst under simulated gastric environment and released drastically in simulated intestinal condition. The CUR release was active at intestinal pH with the cumulative release of >90% CUR after 5 h incubation, which is the desired outcome for CUR absorption under human intestinal conditions. A similar release profile was also obtained when CUR was replaced with beta-carotene molecules. Hence, the reported findings demonstrate the potencies of MCT-KC as a promising delivery carrier for hydrophobic candidates such as CUR.