Targeting mitophagy for depression amelioration: a novel therapeutic strategy

Major depressive disorder is a global psychiatric condition characterized by persistent low mood and anhedonia, which seriously jeopardizes the physical and mental well-being of affected individuals. While various hypotheses have been proposed to explicate the etiology of depression, the precise pathogenesis and effective treatment of this disorder remain elusive. Mitochondria, as the primary organelles responsible for cellular energy production, possess the ability to meet the essential energy demands of the brain. Research indicated that the accumulation of damaged mitochondria is associated with the onset of depression. Mitophagy, a type of cellular autophagy, specifically targets and removes excess or damaged mitochondria. Emerging evidence demonstrated that mitophagy dysfunction was involved in the progression of depression, and several pharmacological interventions that stimulating mitophagy exerted excellent antidepressant actions. We provided an overview of updated advancements on the regulatory mechanism of mitophagy and the mitophagy abnormality in depressed patients and animals, as well as in cell models of depression. Meanwhile, various therapeutic strategies to restore mitophagy for depression alleviation were also discussed in this review

Curcumin Reduces Cognitive Deficits by Inhibiting Neuroinflammation through the Endoplasmic Reticulum Stress Pathway in Apolipoprotein E4 Transgenic Mice.

Apolipoprotein E4 (ApoE4) is the main genetic risk factor for Alzheimer's disease (AD), but the exact way in which it causes AD remains unclear. Curcumin is considered to have good therapeutic potential for AD, but its mechanism has not been clarified. This study aims to observe the effect of curcumin on ApoE4 transgenic mice and explore its possible molecular mechanism. Eight-month-old ApoE4 transgenic mice were intraperitoneally injected with curcumin for 3 weeks, and the Morris water maze test was used to evaluate the cognitive ability of the mice. Immunofluorescence staining, immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay (ELISA) were used to examine the brain tissues of the mice. Curcumin reduced the high expression of ApoE4 and the excessive release of inflammatory factors in ApoE4 mice. In particular, the expression of marker proteins of endoplasmic reticulum (ER) stress was significantly increased in ApoE4 mice, while curcumin significantly reduced the increase in the expression of these proteins. Collectively, curcumin alleviates neuroinflammation in the brains of ApoE4 mice by inhibiting ER stress, thus improving the learning and cognitive ability of transgenic mice

Repeat‐associated non‐AUG translation in C9orf72‐ALS/FTD is driven by neuronal excitation and stress

Abstract Nucleotide repeat expansions (NREs) are prevalent mutations in a multitude of neurodegenerative diseases. Repeat‐associated non‐AUG (RAN) translation of these repeat regions produces mono or dipeptides that contribute to the pathogenesis of these diseases. However, the mechanisms and drivers of RAN translation are not well understood. Here we analyzed whether different cellular stressors promote RAN translation of dipeptide repeats (DPRs) associated with the G4C2 hexanucleotide expansions in C9orf72, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We found that activating glutamate receptors or optogenetically increasing neuronal activity by repetitive trains of depolarization induced DPR formation in primary cortical neurons and patient derived spinal motor neurons. Increases in the integrated stress response (ISR) were concomitant with increased RAN translation of DPRs, both in neurons and different cell lines. Targeting phosphorylated‐PERK and the phosphorylated‐eif2α complex reduces DPR levels revealing a potential therapeutic strategy to attenuate DPR‐dependent disease pathogenesis in NRE‐linked diseases

Chrysanthemum extract attenuates hepatotoxicity via inhibiting oxidative stress in vivo and in vitro

Background: ‘Bianliang ziyu’, a famous chrysanthemum variety commonly planted in Kaifeng, China, is often consumed by local residents. However, the hepatoprotective effects of Bianliang ziyu and their underlying mechanisms are not clear. Objective: In this study, we investigated the hepatoprotective and antioxidative effects of Bianliang ziyu extract (BZE) on liver injury and explored its molecular mechanisms. Design: Sprague-Dawley rats were administered BZE by intragastric administration for 8–9 days, and then alcohol or carbon tetrachloride (CCl4) was administered by gavage to induce acute liver injury. The activities of serum alanine aminotransferase, aspartate aminotransferase, superoxide dismutase, and malondialdehyde in the rats were measured, and the liver of each rat was examined for histopathological changes. In vitro, HL-7702 cells were pretreated with BZE for 24 h and then exposed to 30 mmol•L−1 acetaminophen (APAP) for 12 h. The survival rate of the cells and the alanine aminotransferase and aspartate aminotransferase activities were determined. Then, we investigated the effects of BZE on oxidative stress, apoptosis, and the activation of nuclear factor erythroid-2-related factor 2 (Nrf2) signaling in HL-7702 cells induced by APAP. Results: The results showed that BZE prevented alcohol-, CCl4-, and APAP-induced liver injury and suppressed hepatic oxidative stress in vitro and in vivo. BZE was also observed to significantly inhibit the reduction of mitochondrial membrane potential and regulate the expression of Bcl-2, Bax and Caspase-3 in APAP-induced HL-7702 cells. In addition, BZE significantly promoted nuclear translocation and the expression of Nrf2 as well as its downstream gene hemeoxygenase-1 (HO-1) in vitro. Furthermore, the findings showed that Nrf2 siRNA reversed the effects of BZE on cell survival and apoptosis-related protein expression in APAP-induced HL-7702 cells. Conclusions: BZE plays an important role in preventing hepatotoxicity by inhibiting oxidative stress and apoptosis through activation of Nrf2 signaling. BZE could be developed as an effective functional food for protecting the liver

Coprecipitation Synthesis of Large-Pore-Volume γ‑Alumina Nanofibers by Two Serial Membrane Dispersion Microreactors with a Circulating Continuous Phase

A coprecipitation method was developed for the synthesis of fibrous γ-alumina using serial membrane dispersion microreactors with a circulating continuous phase and high concentrations of NaAlO2 and Al2(SO4)3 as reactants. Owing to the ultra-high mixing intensity and reduction of supersaturation due to the large circular phase ratio, a large pore volume and specific surface area and an extremely narrow pore diameter distribution were realized using the high-concentration and high-viscosity precipitation system. The influence of the phase ratio, dispersion order of reactants, Al2(SO4)3 residence time, and the precipitation reaction pH and time were investigated, and the nanofiber formation mechanism was explored employing theoretical calculations. By controlling the Al2(SO4)3 residence time of 3 s, phase ratio of 16, and pH of 8.0, γ-Al2O3 nanofibers with a pore volume of 1.36 cm3/g, a specific surface area of 376 m2/g, and a length/diameter ratio in the range of 30–54 were obtained without any organic reagents. This study provides an economical and readily scalable method for the synthesis of fibrous γ-Al2O3 with excellent pore properties and a large specific surface area, which can potentially be applied as an excellent catalyst support for diesel and bio-oil hydrogenation

PI3K/akt, JAK/STAT and MEK/ERK pathway inhibition protects retinal gaglion cells via different mechanisms after optic nerve injury

Recently we unexpectedly found that PI3K ⁄ akt, JAK ⁄ STAT and MEK ⁄ ERK pathway inhibitors enhanced retinal ganglion cell (RGC) survival after optic nerve (ON) axotomy in adult rat, a phenomenon contradictory to conventional belief that these pathways are prosurvival. In this study we showed that: (i) the RGC protection was pathway inhibition-dependent; (ii) inhibition of PI3K ⁄ akt and JAK ⁄ STAT, but not MEK ⁄ ERK, activated macrophages in the eye, (iii) macrophage removal from the eye using clodronate liposomes significantly impeded PI3K ⁄ akt and JAK ⁄ STAT inhibition-induced RGC survival and axon regeneration whereas it only slightly affected MEK ⁄ ERK inhibition-dependent protection; (iv) in the absence of recruited macrophages in the eye, inhibition of PI3K ⁄ akt or JAK ⁄ STAT did not influence RGC survival; and (v) strong PI3K ⁄ akt, JAK ⁄ STAT and MEK ⁄ ERK pathway activities were located in RGCs but not macrophages after ON injury. In retinal explants, in which supply of blood-derived macrophages is absent, MEK ⁄ ERK inhibition promoted RGC survival whereas PI3K ⁄ akt or JAK ⁄ STAT inhibition had no effect on RGC viability. However, MEK ⁄ ERK inhibition exerted opposite effects on the viability of purified adult RGCs at different concentrations in vitro, suggesting that this pathway may be bifunctional depending on the level of pathway activity. Our data thus demonstrate that inhibition of the PI3K ⁄ akt or JAK ⁄ STAT pathway activated macrophages to facilitate RGC protection after ON injury whereas the two pathways per se did not modulate RGC viability under the injury conditions (in the absence of the pathway activators). In contrast, the MEK ⁄ ERK pathway inhibition protected RGCs via macrophage-independent mechanism(s)