Davidegelund9843

Dysregulation of autophagy in diabetic kidney disease (DKD) has been reported, but the underlying mechanism and its pathogenic role remain elusive. We show that autophagy was inhibited in DKD models and in human diabetic kidneys. Ablation of autophagy-related gene 7 (Atg7) from kidney proximal tubules led to autophagy deficiency and worse renal hypertrophy, tubular damage, inflammation, fibrosis, and albuminuria in diabetic mice, indicating a protective role of autophagy in DKD. Autophagy impairment in DKD was associated with the downregulation of unc-51-like autophagy-activating kinase 1 (ULK1), which was mediated by the upregulation of microRNA-214 (miR-214) in diabetic kidney cells and tissues. Ablation of miR-214 from kidney proximal tubules prevented a decrease in ULK1 expression and autophagy impairment in diabetic kidneys, resulting in less renal hypertrophy and albuminuria. Furthermore, blockade of p53 attenuated miR-214 induction in DKD, leading to higher levels of ULK1 and autophagy, accompanied by an amelioration of DKD. Compared with nondiabetic samples, renal biopsies from patients with diabetes showed induction of p53 and miR-214, associated with downregulation of ULK1 and autophagy. We found a positive correlation between p53/miR-214 and renal fibrosis, but a negative correlation between ULK1/LC3 and renal fibrosis in patients with diabetes. Together, these results identify the p53/miR-214/ULK1 axis in autophagy impairment in diabetic kidneys, pinpointing possible therapeutic targets for DKD.The state of latency occurs when a microbe's persistence in a host produces host damage without perturbing homeostasis sufficiently to cause clinical symptoms or disease. The mechanisms contributing to latency are diverse and depend on the nature of both the microbe and the host. Latency has advantages for both host and microbe. The host avoids progressive damage caused by interaction with the microbe that may translate into disease, and the microbe secures a stable niche in which to survive. Latency is clinically important because some latent microbes can be transmitted to other hosts, and it is associated with a risk for recrudescent microbial growth and development of disease. In addition, it can predispose the host to other diseases, such as malignancies. Hence, latency is a temporally unstable state with an eventual outcome that mainly depends on host immunity. Latency is an integral part of the pathogenic strategies of microbes that require human (and/or mammalian) hosts, including herpesviruses, retroviruses, Mycobacterium tuberculosis, and Toxoplasma gondii. However, latency is also an outcome of infection with environmental organisms such as Cryptococcus neoformans, which require no host in their replicative cycles. For most microbes that achieve latency, there is a need for a better understanding and more investigation of host and microbial mechanisms that result in this state.Orexin/hypocretin neurons located in the lateral hypothalamus play a critical role in the maintenance of arousal and contribute to the regulation of multiple homeostatic and behavioral processes. In this issue of the JCI, Tan and Hang et al. report that feeding a high-fat diet to mice compromised the function of the orexin system, leading to impairments in reward-seeking and active coping mechanisms. The researchers observed changes at the cellular and circuit levels suggesting that reduced excitability of orexin neurons affects behavior through induction of a hypoarousal state.

Transthyretin (TTR) is a tetrameric, amyloid-β (Aβ)-binding protein, which reduces Aβ toxicity. The TTR/Aβ interaction can be enhanced by a series of small molecules that stabilize its tetrameric form. Hence, TTR stabilizers might act as disease-modifying drugs in Alzheimer's disease.

We monitored the therapeutic efficacy of two TTR stabilizers, iododiflunisal (IDIF), which acts as small-molecule chaperone of the TTR/Aβ interaction, and tolcapone, which does not behave as a small-molecule chaperone, in an animal model of Alzheimer's disease using positron emission tomography (PET).

Female mice (AβPPswe/PS1A246E/TTR+/-) were divided into 3 groups (n = 7 per group) IDIF-treated, tolcapone-treated, and non-treated. The oral treatment (100 mg/Kg/day) was started at 5 months of age. Treatment efficacy assessment was based on changes in longitudinal deposition of Aβ in the hippocampus (HIP) and the cortex (CTX) and determined using PET-[18F]florbetaben. Immunohistochemical analysis was performed at age = 14 months.

Standard uptake values relative to the cerebellum (SUVr) of [18F]florbetaben in CTX and HIP of non-treated animals progressively increased from age = 5 to 11 months and stabilized afterwards. In contrast, [18F]florbetaben uptake in HIP of IDIF-treated animals remained constant between ages = 5 and 11 months and significantly increased at 14 months. In the tolcapone-treated group, SUVr progressively increased with time, but at lower rate than in the non-treated group. No significant treatment effect was observed in CTX. Results from immunohistochemistry matched the in vivo data at age = 14 months.

Our work provides encouraging preliminary results on the ability of small-molecule chaperones to ameliorate Aβ deposition in certain brain regions.

Our work provides encouraging preliminary results on the ability of small-molecule chaperones to ameliorate Aβ deposition in certain brain regions.Knowing that Alzheimer's disease (AD) nucleates in the entorhinal cortex (EC), samples of 12 EC specimens were probed for crystals by a protocol detecting fewer than 1/5000th of those present. Of the 61 crystals found, 31 were expected and 30 were novel. selleck chemical Twenty-one crystals of iron oxides and 10 atherosclerosis-associated calcium pyrophosphate dihydrate crystals were expected and found. The 30 unexpected crystals were NLRP3-inflammasome activating calcium oxalate dihydrate (12) and titanium dioxide (18). Their unusual distribution raises the possibility that some were of AD origination sites.

Increased tau acetylation at K174, K274, K280, and K281 has been observed in the brains of Alzheimer's disease (AD) patients or in transgenic mice, but the role of acetylation in tau propagation is elusive.

To study the effect of tau acetylation in entorhinal cortex on tau transmission and learning and memory.

Stereotactic brain injection, behavioral test, electrophysiological recording, immunohistochemistry, and immunofluorescence were used.

We constructed the hyperacetylation mimics of tau (AAV-Tau-4Q), the non-acetylation tau mutant (AAV-Tau-4R), and the wild-type tau (AAV-Tau-WT). By overexpressing these different tau proteins in the entorhinal cortex (EC) of 2-month-old mice, we found that overexpressing Tau-4Q in EC for 3 or 6 months (to 5 or 8 months of age) neither induces tau propagation to dentate gyrus (DG) nor glial activation in DG, nor spatial memory deficit. However, overexpressing Tau-WT and Tau-4Q in EC for 13.5 months (15.5 months of age) at 2 months promoted tau propagation respectively to granulosa and hilus of DG with glial activation, synaptic dysfunction, and memory deficit, while overexpressing Tau-4R abolished tau propagation with improved cellular pathologies and cognitive functions.