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However, these events were reversed in mitophagy enhancers treated mTau-HT22 cells. Cell survival was increased, mRNA and protein levels of mitochondrial fusion, synaptic and mitophagy genes were increased, and mitochondrial fragmentation is reduced in mitophagy enhancers treated mTau-HT22 cells. Further, urolithin A showed strongest protective effects among all enhancers tested in AD. Our combination treatments of urolithin A + EGCG, addition to urolithin A and EGCG individual treatment revealed that combination treatments approach is even stronger than urolithin A treatment. Based on these findings, we cautiously propose that mitophagy enhancers are promising therapeutic drugs to treat mitophagy in patients with AD.Rosacea is a common chronic inflammatory disease that affects the middle of the face. Due to the unclear pathogenesis, the effective treatment options for rosacea remain limited. In this study, weighted gene co-expression network analyses (WGCNA) identified three rosacea-related hub modules, which were involved in immune-, metabolic- and development- related signaling pathways. Next, the key genes from green and brown modules were submitted to CMap database for drug prediction and metformin was identified as a candidate drug for rosacea. Moreover, network pharmacology analysis identified pharmacological targets of metformin and demonstrated that metformin could help in treating rosacea partly by modulating inflammatory and angiogenesis signaling pathways. Finally, we verified the therapeutic role and mechanism of metformin on rosacea in vivo and vitro. We found that metformin treatment significantly improved rosacea-like skin lesions including immune cells infiltration, cytokines/chemokines expression and angiogenesis. Moreover, metformin suppressed LL37- and TNF-α-induced the ROS production and MAPK-NF-κB signal activation in keratinocytes cells. In conclusion, our findings identified and verified metformin as a novel therapeutic candidate for rosacea, and it alleviates the pathological symptoms, possibly by suppressing inflammatory responses, angiogenesis in rosacea.We previously described the most highly expressed enzymes from the gut of the red flour beetle, Tribolium castaneum, as cathepsins L. In the present study, two C1 family-specific cysteine cathepsin L enzymes from the larval midgut were isolated and identified using MALDI-TOF MS analysis. The isolated T. castaneum cathepsins were characterized according to their specificity against chromogenic and fluorogenic peptide substrates, and the most efficiently hydrolyzed substrate was Z-FR-pNA with Arg in the P1 subsite. The specificity of insect digestive cathepsins was compared with human lysosomal cathepsin L, the well-studied peptidase of the C1 family cathepsins. T. castaneum digestive cathepsins efficiently hydrolyzed substrates with small and uncharged amino acid residues at P1 (Ala, Gln) more than human cathepsin L. In particular, these insect digestive cathepsins cleaved with higher efficiency the analogs of immunogenic peptides of gliadins, which contribute to autoimmune celiac disease in susceptible people, and thus insect enzymes may be useful in enzymatic treatments for this disease. A bioinformatic study supported by the proteomic analysis of the primary structures of the isolated cathepsins was used to compare tertiary models. The phylogenetic analysis of coleopteran and human cathepsins from the L subfamily indicated that insect digestive cathepsins grouped separately from lysosomal cathepsins.Insect odorant-binding proteins (OBPs) are a class of small soluble proteins that can be found in various tissues wherein binding and transport of small molecules are required. Thus, OBPs are not only involved in typical olfactory function by specific activities with odorants but also participate in other physiological processes in non-chemosensory tissues. To better understand the complex biological functions of OBPs, it is necessary to study the transcriptional regulation of their expression patterns. In this paper, an apparent gradient expression pattern of Obp19, that was highly and specifically expressed in antennae and played an essential role in the detection of camphene, was defined in the antennae of the Japanese pine sawyer. Further, the transcription factor BarH1, that also presented gradient expression pattern in antennae, was found to regulate expression of Obp19 directly through binding to its upstream DNA sequence. The condition of BarH1 gene silence, the gene expression levels of Obp19 significantly decreased. At the same time, additional olfactory genes also were regulated and thus influence camphene reception. These findings provide us an opportunity to incorporate Obps in the gene regulatory networks of insects, which contribute to a better understanding of the multiplicity and diversity of OBPs and the olfactory mediated behaviors.Previously, Escherichia coli was engineered to produce isobutyl acetate (IBA). Titers greater than the toxicity threshold (3 g/L) were achieved by using layer-assisted production. To avoid this costly and complex method, adaptive laboratory evolution (ALE) was applied to E. selleck kinase inhibitor coli for improved IBA tolerance. Over 37 rounds of selective pressure, 22 IBA-tolerant mutants were isolated. Remarkably, these mutants not only tolerate high IBA concentrations, they also produce higher IBA titers. Using whole-genome sequencing followed by CRISPR/Cas9 mediated genome editing, the mutations (SNPs in metH, rho and deletion of arcA) that confer improved tolerance and higher titers were elucidated. The improved IBA titers in the evolved mutants were a result of an increased supply of acetyl-CoA and altered transcriptional machinery. Without the use of phase separation, a strain capable of 3.2-fold greater IBA production than the parent strain was constructed by combing select beneficial mutations. These results highlight the impact improved tolerance has on the production capability of a biosynthetic system.The number of lipophilic drug candidates in pharmaceutical discovery pipelines has increased in recent years. These drugs often possess physicochemical properties that result in poor oral bioavailability, and their clinical potential may be limited without adequate formulation strategies. Cannabidiol (CBD) is an excellent example of a highly lipophilic compound with poor oral bioavailability, due to low water solubility and extensive first-pass metabolism. An approach that may overcome these limitations is formulation of the drug in self-nanoemulsifying drug delivery systems (SNEDDS). Herein, CBD-SNEDDS formulations were prepared and evaluated in vitro. Promising formulations (F2, F4) were administered to healthy female Sprague-Dawley rats via oral gavage (20 mg/kg CBD). Resulting pharmacokinetic parameters of CBD were compared to those following administration of CBD in two oil-based formulations a medium-chain triglyceride oil vehicle (MCT-CBD), and a sesame oil-based formulation similar in composition to an FDA-approved formulation of CBD, Epidiolex® (SO-CBD). Compared to MCT-CBD, administration of the SNEDDS formulations led to more rapid absorption of CBD (median Tmax values 0.5 h (F2), 1 h (F4), 6 h (MCT-CBD)). Administration of F2 and F4 formulations also improved the systemic exposure to CBD by 2.2 and 2.8-fold compared to MCT-CBD; however, no improvement was found compared to SO-CBD.Long noncoding RNAs (lncRNAs) are associated with tumorigenesis and linked to altered metabolism. Our previous studies have identified an oncogenic function of lncRNA Linc00173 in small cell lung cancer (SCLC), while the detailed mechanisms remain to be fully clarified. We show that Linc00173 plays a critical role for chemoresistance in SCLC through reprogramming glucose metabolism. By phosphorylating Y-Box Binding Protein 1 (YB1), Linc00173 stimulates the translation of YB1 bound glucose metabolic enzymes HK2 and G6PD, which activates glycolysis and the pentose phosphate pathway (PPP). The expression levels of Linc00173 and HK2/G6PD show a positive correlation in 46 tissue samples from SCLC patients. Furthermore, we demonstrated that the inhibitors of HK2 and G6PD, 3-BrPA and RRx-001, exhibit a synergistic antitumor effect with chemotherapy both in vitro and in vivo, including a PDX model. For the first time, we identified the mechanism of Linc00173/YB1 axis-induced glucose metabolic rewiring in SCLC, indicating that glucose metabolic enzymes HK2 and G6PD may be potential therapeutic targets for SCLC treatments.Aromatic l-amino acid decarboxylase deficiency results in decreased neurotransmitter levels and severe motor dysfunction. Twenty-six patients without head control received bilateral intraputaminal infusions of a recombinant adeno-associated virus type 2 vector containing the human aromatic l-amino acid decarboxylase gene (eladocagene exuparvovec) and have completed 1-year evaluations. Rapid improvements in motor and cognitive function occurred within 12 months after gene therapy and were sustained during follow-up for >5 years. An increase in dopamine production was demonstrated by positron emission tomography and neurotransmitter analysis. Patient symptoms (mood, sweating, temperature, and oculogyric crises), patient growth, and patient caretaker quality of life improved. Though improvements were observed in all treated participants, younger age was associated with greater improvement. There were no treatment-associated brain injuries, and most adverse events were related to underlying disease. Post-surgery complications such as cerebrospinal fluid leakage were managed with standard of care. Most patients experienced mild to moderate dyskinesia that resolved in a few months. These observations suggest that eladocagene exuparvovec treatment for aromatic l-amino acid decarboxylase deficiency provides durable and meaningful benefits with a favorable safety profile.Blood-brain barrier (BBB) damage can be a result of central nervous system (CNS) diseases and may be a cause of CNS deterioration. However, there are still many unknowns regarding effective and targeted therapies for maintaining BBB integrity during ischemia/reperfusion (I/R) injury. In this study, we demonstrate that the circular RNA of FoxO3 (circ-FoxO3) promotes autophagy via mTORC1 inhibition to attenuate BBB collapse under I/R. Upregulation of circ-FoxO3 and autophagic flux were detected in brain microvessel endothelial cells in patients with hemorrhagic transformation and in mice models with middle cerebral artery occlusion/reperfusion. In vivo and in vitro studies indicated that circ-FoxO3 alleviated BBB damage principally by autophagy activation. Mechanistically, we found that circ-FoxO3 inhibited mTORC1 activity mainly by sequestering mTOR and E2F1, thus promoting autophagy to clear cytotoxic aggregates for improving BBB integrity. These results demonstrate that circ-FoxO3 plays a novel role in protecting against BBB damage, and that circ-FoxO3 may be a promising therapeutic target for neurological disorders associated with BBB damage.The FDA approved drug Dronabinol was identified in a previous study applying virtual screening using the haemozoin crystal as a target against malaria parasites. The active ingredient of dronabinol is synthetic tetrahydrocannabinol (THC), which is one of the major cannabinoids from Cannabis sativa. Traditional use of cannabis for malaria fever was reported in the world's oldest pharmacopoeia, dating to around 5000 years ago. In this research we report that THC inhibits β-haematin (synthetic haemozoin) and malaria parasite growth. Due the psychoactivity of THC, CBD, the other major naturally occurring cannabinoid that lacks the off-target psychoactive effects of THC, was also tested and inhibited β-haematin but showed only a mild antimalarial activity. To evaluate whether THC inhibit haemozoin formation, we performed a cellular haem fractionation assay that indicated that is not the likely mechanism of action. For the first time, the cannabinoid chemical structure is raised as a new chemical class to be further studied for malaria treatment, aiming to overcome the undesirable psychoactive effects of THC and optimize the antimalarial effects.