Ablation of kynurenine 3-monooxygenase rescues plasma inflammatory cytokine levels in the R6/2 mouse model of Huntington’s disease

Kynurenine 3-monooxygenase (KMO) regulates the levels of neuroactive metabolites in the kynurenine pathway (KP), dysregulation of which is associated with Huntington’s disease (HD) pathogenesis. KMO inhibition leads to increased levels of neuroprotective relative to neurotoxic metabolites, and has been found to ameliorate disease-relevant phenotypes in several HD models. Here, we crossed KMO knockout mice to R6/2 HD mice to examine the effect of KMO depletion in the brain and periphery. KP genes were dysregulated in peripheral tissues from R6/2 mice and KMO ablation normalised levels of a subset of these. KP metabolites were also assessed, and KMO depletion led to increased levels of neuroprotective kynurenic acid in brain and periphery, and dramatically reduced neurotoxic 3-hydroxykunurenine levels in striatum and cortex. Notably, the increased levels of pro-inflammatory cytokines TNFa, IL1β, IL4 and IL6 found in R6/2 plasma were normalised upon KMO deletion. Despite these improvements in KP dysregulation and peripheral inflammation, KMO ablation had no effect upon several behavioural phenotypes. Therefore, although genetic inhibition of KMO in R6/2 mice modulates several metabolic and inflammatory parameters, these do not translate to improvements in primary disease indicators—observations which will likely be relevant for other interventions targeted at peripheral inflammation in HD

TRPM7 in CHBP-induced renoprotection upon ischemia reperfusion-related injury.

Transient receptor potential melastatin 7 (TRPM7) is a membrane ion channel and kinase. TRPM7 was abundantly expressed in the kidney, and up-regulated by ischemia reperfusion (IR) injury. Our previous studies showed that cyclic helix B peptide (CHBP) improved renal IR-related injury, but its underlying mechanism is not well defined. IR-related injury was established in renal tubular epithelial cells (TCMK-1 and HK-2) via 12 to 24-h hypoxia (H) followed by 2-24 h reoxygenation (R), and in mouse kidneys subjected to 30-min ischemia and 12-h to 7-day reperfusion. TRPM7-like current in TCMK-1 cells, TRPM7 mRNA and protein in the in vitro and in vivo models were increased, but reversed by CHBP. TRPM7 was also positively associated with LDH, HMGB1, caspase-3, Bax/Bcl-2, inflammation, apoptosis, tubulointerstitial damage and renal function respectively. Furthermore, silencing TRPM7 improved injury parameters, renal histology and function in the both models. Specific TRPM7 agonist, bradykinin, exaggerated HR induced injury in TCMK-1 cells, and partially blocked the renoprotection of CHBP as well. In conclusion, TRPM7 is involved not only in IR-related injury, but also CHBP-induced renoprotection, which are through its ion channel and subsequent affects inflammation and apoptosis. Therefore, TRPM7 could be a potential biomarker for IR-induced acute kidney injury

A multi-wavelength analysis of a collection of short-duration GRBs observed between 2012-2015

We investigate the prompt emission and the afterglow properties of short duration gamma-ray burst (sGRB) 130603B and another eight sGRB events during 2012-2015, observed by several multi-wavelength facilities including the GTC 10.4m telescope. Prompt emission high energy data of the events were obtained by INTEGRAL/SPI/ACS, Swift/BAT and Fermi/GBM satellites. The prompt emission data by INTEGRAL in the energy range of 0.1-10 MeV for sGRB 130603B, sGRB 140606A, sGRB 140930B, sGRB 141212A and sGRB 151228A do not show any signature of the extended emission or precursor activity and their spectral and temporal properties are similar to those seen in case of other short bursts. For sGRB130603B, our new afterglow photometric data constraints the pre jet-break temporal decay due to denser temporal coverage. For sGRB 130603B, the afterglow light curve, containing both our new as well as previously published photometric data is broadly consistent with the ISM afterglow model. Modeling of the host galaxies of sGRB 130603B and sGRB 141212A using the LePHARE software supports a scenario in which the environment of the burst is undergoing moderate star formation activity. From the inclusion of our late-time data for 8 other sGRBs we are able to; place tight constraints on the non-detection of the afterglow, host galaxy or any underlying kilonova emission. Our late-time afterglow observations of the sGRB 170817A/GW170817 are also discussed and compared with the sub-set of sGRBs