Preservation of vision after CaMKII-mediated protection of retinal ganglion cells.

Retinal ganglion cells (RGCs) are the sole output neurons that transmit visual information from the retina to the brain. Diverse insults and pathological states cause degeneration of RGC somas and axons leading to irreversible vision loss. A fundamental question is whether manipulation of a key regulator of RGC survival can protect RGCs from diverse insults and pathological states, and ultimately preserve vision. Here, we report that CaMKII-CREB signaling is compromised after excitotoxic injury to RGC somas or optic nerve injury to RGC axons, and reactivation of this pathway robustly protects RGCs from both injuries. CaMKII activity also promotes RGC survival in the normal retina. Further, reactivation of CaMKII protects RGCs in two glaucoma models where RGCs degenerate from elevated intraocular pressure or genetic deficiency. Last, CaMKII reactivation protects long-distance RGC axon projections in vivo and preserves visual function, from the retina to the visual cortex, and visually guided behavior.

Mechanistic Understanding of Dexamethasone-Mediated Protection against Remdesivir-Induced Hepatotoxicity.

Remdesivir (RDV), a broad-spectrum antiviral agent, is often used together with dexamethasone (DEX) for hospitalized COVID-19 patients requiring respiratory support. Potential hepatic adverse drug reaction is a safety concern associated with the use of RDV. We previously reported that DEX cotreatment effectively mitigates RDV-induced hepatotoxicity and reduces elevated serum alanine aminotransferase and aspartate aminotransferase levels in cultured human primary hepatocytes (HPH) and hospitalized COVID-19 patients, respectively. Yet, the precise mechanism behind this protective drug-drug interaction remains largely unknown. Here, we show that through the activation of p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling, RDV induces apoptosis (cleavage of caspases 8, 9, and 3), autophagy (increased autophagosome and LC3-II), and mitochondrial damages (decreased membrane potential, respiration, ATP levels, and increased expression of Bax and the released cytosolic cytochrome C) in HPH. Importantly, cotreatment with DEX partially reversed RDV-induced apoptosis, autophagy, and cell death. Mechanistically, DEX deactivates/dephosphorylates p38, JNK, and ERK1/2 signaling by enhancing the expression of dual specificity protein phosphatase 1 (DUSP1), a mitogen-activated protein kinase (MAPK) phosphatase, in a glucocorticoid receptor (GR)-dependent manner. Knockdown of GR in HPH attenuates DEX-mediated DUSP1 induction, MAPK dephosphorylation, as well as protection against RDV-induced hepatotoxicity. Collectively, our findings suggest a molecular mechanism by which DEX modulates the GR-DUSP1-MAPK regulatory axis to alleviate the adverse actions of RDV in the liver. SIGNIFICANCE STATEMENT: The research uncovers the molecular mechanisms by which dexamethasone safeguards against remdesivir-associated liver damage in the context of COVID-19 treatment.

Exploiting urine-derived induced pluripotent stem cells for advancing precision medicine in cell therapy, disease modeling, and drug testing.

The field of regenerative medicine has witnessed remarkable advancements with the emergence of induced pluripotent stem cells (iPSCs) derived from a variety of sources. Among these, urine-derived induced pluripotent stem cells (u-iPSCs) have garnered substantial attention due to their non-invasive and patient-friendly acquisition method. This review manuscript delves into the potential and application of u-iPSCs in advancing precision medicine, particularly in the realms of drug testing, disease modeling, and cell therapy. U-iPSCs are generated through the reprogramming of somatic cells found in urine samples, offering a unique and renewable source of patient-specific pluripotent cells. Their utility in drug testing has revolutionized the pharmaceutical industry by providing personalized platforms for drug screening, toxicity assessment, and efficacy evaluation. The availability of u-iPSCs with diverse genetic backgrounds facilitates the development of tailored therapeutic approaches, minimizing adverse effects and optimizing treatment outcomes. Furthermore, u-iPSCs have demonstrated remarkable efficacy in disease modeling, allowing researchers to recapitulate patient-specific pathologies in vitro. This not only enhances our understanding of disease mechanisms but also serves as a valuable tool for drug discovery and development. In addition, u-iPSC-based disease models offer a platform for studying rare and genetically complex diseases, often underserved by traditional research methods. The versatility of u-iPSCs extends to cell therapy applications, where they hold immense promise for regenerative medicine. Their potential to differentiate into various cell types, including neurons, cardiomyocytes, and hepatocytes, enables the development of patient-specific cell replacement therapies. This personalized approach can revolutionize the treatment of degenerative diseases, organ failure, and tissue damage by minimizing immune rejection and optimizing therapeutic outcomes. However, several challenges and considerations, such as standardization of reprogramming protocols, genomic stability, and scalability, must be addressed to fully exploit u-iPSCs' potential in precision medicine. In conclusion, this review underscores the transformative impact of u-iPSCs on advancing precision medicine and highlights the future prospects and challenges in harnessing this innovative technology for improved healthcare outcomes.

Human constitutive androstane receptor represses liver cancer development and hepatoma cell proliferation by inhibiting erythropoietin signaling.

The constitutive androstane receptor (CAR) is a nuclear receptor that plays a crucial role in regulating xenobiotic metabolism and detoxification, energy homeostasis, and cell proliferation by modulating the transcription of numerous target genes. CAR activation has been established as the mode of action by which phenobarbital-like nongenotoxic carcinogens promote liver tumor formation in rodents. This paradigm, however, appears to be unrelated to the function of human CAR (hCAR) in hepatocellular carcinoma (HCC), which remains poorly understood. Here, we show that hCAR expression is significantly lower in HCC than that in adjacent nontumor tissues and, importantly, reduced hCAR expression is associated with a worse HCC prognosis. We also show overexpression of hCAR in human hepatoma cells (HepG2 and Hep3B) profoundly suppressed cell proliferation, cell cycle progression, soft-agar colony formation, and the growth of xenografts in nude mice. RNA-Seq analysis revealed that the expression of erythropoietin (EPO), a pleiotropic growth factor, was markedly repressed by hCAR in hepatoma cells. Addition of recombinant EPO in HepG2 cells partially rescued hCAR-suppressed cell viability. Mechanistically, we showed that overexpressing hCAR repressed mitogenic EPO-EPO receptor signaling through dephosphorylation of signal transducer and activator of transcription 3, AKT, and extracellular signal-regulated kinase 1/2. Furthermore, we found that hCAR downregulates EPO expression by repressing the expression and activity of hepatocyte nuclear factor 4 alpha, a key transcription factor regulating EPO expression. Collectively, our results suggest that hCAR plays a tumor suppressive role in HCC development, which differs from that of rodent CAR and offers insight into the hCAR-hepatocyte nuclear factor 4 alpha-EPO axis in human liver tumorigenesis.

Phenobarbital in Nuclear Receptor Activation: An Update.

Phenobarbital (PB) is a commonly prescribed anti-epileptic drug that can also benefit newborns from hyperbilirubinemia. Being the first drug demonstrating hepatic induction of cytochrome P450 (CYP), PB has since been broadly used as a model compound to study xenobiotic-induced drug metabolism and clearance. Mechanistically, PB-mediated CYP induction is linked to a number of nuclear receptors, such as the constitutive androstane receptor (CAR), pregnane X receptor (PXR), and estrogen receptor α, with CAR being the predominant regulator. Unlike prototypical agonistic ligands, PB-mediated activation of CAR does not involve direct binding with the receptor. Instead, dephosphorylation of threonine 38 in the DNA-binding domain of CAR was delineated as a key signaling event underlying PB-mediated indirect activation of CAR. Further studies revealed that such phosphorylation sites appear to be highly conserved among most human nuclear receptors. Interestingly, while PB is a pan-CAR activator in both animals and humans, PB activates human but not mouse PXR. The species-specific role of PB in gene regulation is a key determinant of its implication in xenobiotic metabolism, drug-drug interactions, energy homeostasis, and cell proliferation. In this review, we summarize the recent progress in our understanding of PB-provoked transactivation of nuclear receptors with a focus on CAR and PXR. SIGNIFICANCE STATEMENT: Extensive studies using PB as a research tool have significantly advanced our understanding of the molecular basis underlying nuclear receptor-mediated drug metabolism, drug-drug interactions, energy homeostasis, and cell proliferation. In particular, CAR has been established as a cell signaling-regulated nuclear receptor in addition to ligand-dependent functionality. This mini-review highlights the mechanisms by which PB transactivates CAR and PXR.

Insights into the enhanced hydrogen adsorption on M/La2O3 (M = Ni, Co, Fe).

Lanthanum oxide (La2O3) possesses superior reactivity during catalytic hydrogenation, but the intrinsic activity of La2O3 toward H2 adsorption and activation remains unclear. In the present work, we fundamentally investigated hydrogen interaction with Ni-modified La2O3. Hydrogen temperature programmed desorption (H2-TPD) on Ni/La2O3 shows enhanced hydrogen adsorption with a new hydrogen desorption peak at a higher temperature position compared to that on the metallic Ni surfaces. By systematically exploring the desorption experiments, the enhanced H2 adsorption on Ni/La2O3 is due to the oxygen vacancies formed at the metal-oxide interfaces. Hydrogen atoms transfer from Ni surfaces to the oxygen vacancies to form lanthanum oxyhydride species (H-La-O) at the metal-oxide interfaces. The adsorbed hydrogen at the metal-oxide interfaces of Ni/La2O3 results in improved catalytic reactivity in CO2 methanation. Furthermore, the enhanced hydrogen adsorption on the interfacial oxygen vacancies is ubiquitous for La2O3-supported Fe, Co, and Ni nanoparticles. Benefiting from the modification effect of the supported transition metal nanoparticles, the surface oxyhydride species can be formed on La2O3 surfaces, which resembles the recently reported oxyhydride observed on the reducible CeO2 surfaces with abundant surface oxygen vacancies. These findings strengthen our understanding of the surface chemistry of La2O3 and shed new light on the design of highly efficient La2O3-based catalysts with metal-oxide interfaces.

Spatiotemporal response of water quality in fragmented mangroves to anthropogenic activities and recommendations for restoration.

Mangroves have received substantial attention for their pivotal role as ecological barriers between land and sea, owing to their capacity to effectively capture considerable quantities of terrestrial pollutants. Mangrove fragmentation has been a widespread global trend. There is limited information on the water quality status of these small scattered mangrove patches in coastal sub-developed areas, coupled with a paucity of efficient and intuitive assessment methodologies. To address this gap, the Water Quality Index (WQI) was introduced to evaluate the spatiotemporal characteristics of mangrove water quality. The major sources of pollution and anthropogenic activities that affect mangrove water quality were identified. The results revealed an average WQI value of 44.1 ± 13.3 for mangrove patches, consistently indicating a "low" water quality classification throughout all seasons. Both the size and natural conditions impact the water quality of mangroves. The large artificial patch (WQI: 56.4 ± 7.61) and the natural patch (WQI: 46.6 ± 13.6) exhibited relatively superior water quality, while the WQI value of a size-equivalent artificial patch compared with the natural patch is 38.6 ± 11.8. Aquaculture was the primary human activity that adversely affected the water quality of mangroves, and the potential sources of pollution were rainfall runoff and river discharge. These findings elucidate the unfavorable water quality characteristics and dominant pollution of fragmented mangroves, and validate the applicability of the WQI method for long-term evaluation of the water quality in mangrove patches. This study provides a basis for decision-making in water quality assessment and management of coastal wetlands and marine ecosystems. Scientific guidance to the management for mangrove protection and restoration was offered, such as regulating aquaculture activities, controlling non-point source pollution, implementing mangrove reforestation by using native species in historical mangrove sites.

Clinical Relevance of the Constitutive Androstane Receptor.

Constitutive androstane receptor (CAR) (NR1I3), a xenobiotic receptor, has long been considered a master mediator of drug disposition and detoxification. Accumulating evidence indicates that CAR also participates in various physiologic and pathophysiological pathways regulating the homeostasis of glucose, lipid, and bile acids, and contributing to cell proliferation, tissue regeneration and repair, as well as cancer development. The expression and activity of CAR can be regulated by various factors, including small molecular modulators, CAR interaction with other transcription factors, and naturally occurring genetic variants. Given that the influence of CAR has extended beyond the realm of drug metabolism and disposition and has expanded into a potential modulator of human diseases, growing efforts have centered on understanding its clinical relevance and impact on human pathophysiology. This review highlights the current information available regarding the contribution of CAR to various metabolic disorders and cancers and ponders the possible challenges that might arise from pursuing CAR as a potential therapeutic target for these diseases. SIGNIFICANCE STATEMENT: The growing importance of the constitutive androstane receptor (CAR) in glucose and lipid metabolism as well as its potential implication in cell proliferation emphasizes a need to keenly understand the biological function and clinical impact of CAR. This minireview captures the clinical relevance of CAR by highlighting its role in metabolic disorders and cancer development.

Constant hue loci in different color spaces for stimuli in Rec. 2020 color gamut and HDR conditions.

Hue is an important attribute for characterizing a color stimulus, which is also an output in various color spaces. The investigations on the hue linearity and constant hue loci for different color spaces were generally conducted using conventional CRT displays or surface color samples, in which the color stimuli were within small color gamuts and viewed under standard dynamic range conditions. With the development of imaging technologies, the hue linearity and constant hue loci need to be investigated for wide color gamuts and high dynamic range conditions, which is critically important for image processing (e.g., gamut mapping and tone mapping). In this study, we carefully carried out a hue matching experiment using high-power LED devices. The color stimuli almost reached Rec. 2020 color gamut with the luminance above the diffuse white luminance (i.e., a high dynamic range condition). The results suggested that the hue linearity of ICTCP color space was the best among the nine color spaces. Twenty-one constant hue loci were derived for each of these nine color spaces, which can be used for hue correction when performing image processing and to further revise the color spaces.

Effects of Overexpression of Fibroblast Growth Factor 15/19 on Hepatic Drug Metabolizing Enzymes.

Fibroblast growth factors 15 (FGF15) and 19 (FGF19) are endocrine growth factors that play an important role in maintaining bile acid homeostasis. FGF15/19-based therapies are currently being tested in clinical trials for the treatment of nonalcoholic steatohepatitis and cholestatic liver diseases. To determine the physiologic impact of long-term elevations of FGF15/19, a transgenic mouse model with overexpression of Fgf15 (Fgf15 Tg) was used in the current study. The RNA sequencing (RNA-seq) analysis revealed elevations of the expression of several genes encoding phase I drug metabolizing enzymes (DMEs), including Cyp2b10 and Cyp3a11, in Fgf15 Tg mice. We found that the induction of several Cyp2b isoforms resulted in increased function of CYP2B in microsomal metabolism and pharmacokinetics studies. Because the CYP2B family is known to be induced by constitutive androstane receptor (CAR), to determine the role of CAR in the observed inductions, we crossed Fgf15 Tg mice with CAR knockout mice and found that CAR played a minor role in the observed alterations in DME expression. Interestingly, we found that the overexpression of Fgf15 in male mice resulted in a phenotypical switch from the male hepatic expression pattern of DMEs to that of female mice. Differences in secretion of growth hormone (GH) between male and female mice are known to drive sexually dimorphic, STAT5b-dependent expression patterns of hepatic genes. We found that male Fgf15 Tg mice presented with many features similar to GH deficiency, including lowered body length and weight, Igf-1 and Igfals expression, and STAT5 signaling. SIGNIFICANCE STATEMENT: The overexpression of Fgf15 in mice causes an alteration in DMEs at the mRNA, protein, and functional levels, which is not entirely due to CAR activation but associated with lower GH signaling.

Vorinostat Corrects Cognitive and Non-Cognitive Symptoms in a Mouse Model of Fragile X Syndrome.

BACKGROUND: Fragile X syndrome (FXS) is caused by mutations in the FMR1 gene. It is a form of heritable intellectual disability and autism. Despite recent advance in elucidating disease mechanisms, there is no efficacious medication. Because de novo drug development is a lengthy process, repurposing the existing FDA-approved drugs offers an opportunity to advance clinical intervention for FXS. Our previous study with transcriptome analysis predicts potential therapeutic effects of vorinostat on FXS. METHODS: We analyzed the vorinostat-induced transcriptome changes and confirmed its similarity to that induced by trifluoperazine, which was previously shown to correct pathological outcomes associated with FXS. To validate the therapeutic efficacy, we examined vorinostat's effect on correcting the key behavioral and cellular symptoms in a mouse model of FXS. RESULTS: We found that vorinostat restores object location memory and passive avoidance memory in the Fmr1 knockout mice. For the non-cognitive behavioral symptoms, vorinostat corrected the autism-associated alterations, including repetitive behavior and social interaction deficits. In the open field test, vorinostat dampened hyperactivity in the center area of the arena. Surprisingly, vorinostat did not correct the abnormally elevated protein synthesis in cultured Fmr1 knockout hippocampal neurons, suggesting that different aspects of pathological outcomes may respond differently to a specific therapeutic intervention. CONCLUSIONS: We used the drug-induced transcriptome signature to predict new application of existing drugs. Our data reveal the therapeutic effects of the FDA-approved drug vorinostat in a mouse model of FXS.

Androgen-induced insulin resistance is ameliorated by deletion of hepatic androgen receptor in females.

Androgen excess is one of the most common endocrine disorders of reproductive-aged women, affecting up to 20% of this population. Women with elevated androgens often exhibit hyperinsulinemia and insulin resistance. The mechanisms of how elevated androgens affect metabolic function are not clear. Hyperandrogenemia in a dihydrotestosterone (DHT)-treated female mouse model induces whole body insulin resistance possibly through activation of the hepatic androgen receptor (AR). We investigated the role of hepatocyte AR in hyperandrogenemia-induced metabolic dysfunction by using several approaches to delete hepatic AR via animal-, cell-, and clinical-based methodologies. We conditionally disrupted hepatocyte AR in female mice developmentally (LivARKO) or acutely by tail vein injection of an adeno-associated virus with a liver-specific promoter for Cre expression in ARfl/fl mice (adLivARKO). We observed normal metabolic function in littermate female Control (ARfl/fl ) and LivARKO (ARfl/fl ; Cre+/- ) mice. Following chronic DHT treatment, female Control mice treated with DHT (Con-DHT) developed impaired glucose tolerance, pyruvate tolerance, and insulin tolerance, not observed in LivARKO mice treated with DHT (LivARKO-DHT). Furthermore, during an euglycemic hyperinsulinemic clamp, the glucose infusion rate was improved in LivARKO-DHT mice compared to Con-DHT mice. Liver from LivARKO, and primary hepatocytes derived from LivARKO, and adLivARKO mice were protected from DHT-induced insulin resistance and increased gluconeogenesis. These data support a paradigm in which elevated androgens in females disrupt metabolic function via hepatic AR and insulin sensitivity was restored by deletion of hepatic AR.

Tuning Dehalogenative Coupling of Br2Py on Bimetallic Templates.

Considerable attention has been paid to on-surface Ullmann coupling during the past decade owing to the feasible synthesis of artificial nanostructures. While previous reports mainly concentrated on coupling reactions on single-metal-atom surfaces, herein we present the Ullmann coupling of 2,7-dibromopyrene (Br2Py) on bimetallic surfaces, Bi-Ag(111) and Bi-Au(111), respectively, with scanning tunneling microscopy (STM) and X-ray photoemission spectroscopy (XPS). On the Bi-decorated Ag(111), self-assembly of intact Br2Py is realized due to the reduced activity at the interface. Subsequent annealing promotes the dehalogenation of Br2Py on Bi-Ag(111), while Bi adatoms do not bring any visible influence on coupling reactions. Furthermore, post-deposition of Bi onto preassembled nanostructures on Ag(111) immediately initiates the Ullmann coupling by inducing more Ag adatoms available on the surface, while stepwise annealing afterward leads to complete polymerization and formation of covalent chains with lateral displacement compared to that on the bare Ag(111), probably due to the space hindrance and confinement. For Bi-Au(111) with the modified reconstruction, higher-temperature annealing is required to trigger Ullmann coupling compared to that on Au(111). The exception is that the C-C coupling reaction remains impervious to Bi adatoms, and recovery of the Bi-Au reconstruction is realized after intensive annealing. In principle, bimetallic surfaces herein present intriguing behavior toward the controllable Ullmann coupling, and this report might provide different insights into the comprehensive atomistic elucidation of reaction mechanisms as well as the design of a new platform to effectively regulate Ullmann coupling.

Hepatic CYP2B10 is highly induced by binge ethanol and contributes to acute-on-chronic alcohol-induced liver injury.

BACKGROUND: The chronic-plus-binge model of ethanol consumption, where chronically (8-week) ethanol-fed mice are gavaged a single dose of ethanol (E8G1), is known to induce steatohepatitis in mice. However, how chronically ethanol-fed mice respond to multiple binges of ethanol remains unknown. METHODS: We extended the E8G1 model to three gavages of ethanol (E8G3) spaced 24 h apart, sacrificed each group 9 h after the final gavage, analyzed liver injury, and examined gene expression changes using microarray analyses in each group to identify mechanisms contributing to liver responses to binge ethanol. RESULTS: Surprisingly, E8G3 treatment induced lower levels of liver injury, steatosis, inflammation, and fibrosis as compared to mice after E8G1 treatment. Microarray analyses identified several pathways that may contribute to the reduced liver injury after E8G3 treatment compared to E8G1 treatment. The gene encoding cytochrome P450 2B10 (Cyp2b10) was one of the top upregulated genes in the E8G1 group and was further upregulated in the E8G3 group, but only moderately induced after chronic ethanol consumption, as confirmed by RT-qPCR and western blot analyses. Genetic disruption of Cyp2b10 worsened liver injury in E8G1 and E8G3 mice with higher blood ethanol levels compared to wild-type control mice, while in vitro experiments revealed that CYP2b10 did not directly promote ethanol metabolism. Metabolomic analyses revealed significant differences in hepatic metabolites from E8G1-treated Cyp2b10 knockout and WT mice, and these metabolic alterations may contribute to the reduced liver injury in Cyp2b10 knockout mice. CONCLUSION: Hepatic Cyp2b10 expression is highly induced after ethanol binge, and such upregulation reduces acute-on-chronic ethanol-induced liver injury via the indirect modification of ethanol metabolism.

Gender-specific associations of speech-frequency hearing loss, high-frequency hearing loss, and cognitive impairment among older community dwellers in China.

BACKGROUND AND AIMS: This study aimed atinvestigating the relationship between speech-frequency hearing loss (SFHL), high-frequency hearing loss (HFHL), and cognitive impairment (CI) and then to determine whether there are any differences in gender among older community dwellers in China. METHODS: 1012 adults aged ≥ 60 years (428 males; average age, 72.61 ± 5.51 years) and living in Chongming District, Shanghai were enrolled in the study. We used the audiometric definition of hearing loss (HL) adopted by the World Health Organization (WHO). Speech-frequencies were measured at 0.5 kHz, 1 kHz, 2 kHz, and 4 kHz; high-frequencies were measured at 4 kHz and 8 kHz. Pure tone average (PTA) was measured as hearing sensitivity. Cognitive performance was measured using the mini mental state examination (MMSE). RESULTS: Our studies demonstrated a 37.6% prevalence of HL in males and a 36.0% prevalence of HL in females. Adjusted for confounding variables, the results from a multivariate analysis showed that SFHL was associated with CI in females (OR = 2.922, 95% Confidence Interval = 1.666-5.124) and males (OR = 2.559, 95% Confidence Interval = 1.252-5.232). However, HFHL was associated with CI only in females (OR = 3.490, 95% Confidence Interval = 1.834-6.643). HL was associated with poorer cognitive scores (P < 0.05). "Registration" (P < 0.05) in MMSE was associated with speech- and high-frequency hearing sensitivity. CONCLUSIONS: The associations between HL and CI varied according to gender in older community-dwellers, suggesting that different mechanisms are involved in the etiology of HL. Moreover, hearing sensitivity was negatively associated with cognition scores; therefore, early screening for HL and CI among older community-dwelling adults is advised.

Transcriptome Profiling in the Hippocampi of Mice with Experimental Autoimmune Encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), approximates the key histopathological, clinical, and immunological features of MS. Hippocampal dysfunction in MS and EAE causes varying degrees of cognitive and emotional impairments and synaptic abnormalities. However, the molecular alterations underlying hippocampal dysfunctions in MS and EAE are still under investigation. The purpose of this study was to identify differentially expressed genes (DEGs) in the hippocampus of mice with EAE in order to ascertain potential genes associated with hippocampal dysfunction. Gene expression in the hippocampus was analyzed by RNA-sequencing and validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Gene expression analysis revealed 1202 DEGs; 1023 were upregulated and 179 were downregulated in the hippocampus of mice with EAE (p-value < 0.05 and fold change >1.5). Gene ontology (GO) analysis showed that the upregulated genes in the hippocampi of mice with EAE were associated with immune system processes, defense responses, immune responses, and regulation of immune responses, whereas the downregulated genes were related to learning or memory, behavior, and nervous system processes in the GO biological process. The expressions of hub genes from the search tool for the retrieval of interacting genes/proteins (STRING) analysis were validated by RT-qPCR. Additionally, gene set enrichment analysis showed that the upregulated genes in the hippocampus were associated with inflammatory responses: interferon-γ responses, allograft rejection, interferon-α responses, IL6_JAK_STAT3 signaling, inflammatory responses, complement, IL2_STAT5 signaling, TNF-α signaling via NF-κB, and apoptosis, whereas the downregulated genes were related to synaptic plasticity, dendritic development, and development of dendritic spine. This study characterized the transcriptome pattern in the hippocampi of mice with EAE and signaling pathways underpinning hippocampal dysfunction. However, further investigation is needed to determine the applicability of these findings from this rodent model to patients with MS. Collectively, these results indicate directions for further research to understand the mechanisms behind hippocampal dysfunction in EAE.

Hayatine inhibits amino acid-induced mTORC1 activation as a novel mTOR-Rag A/C interaction disruptor.

Abnormal activation of the mechanistic target of rapamycin (mTOR) signaling is commonly observed in many cancers and attracts extensive attention as an oncology drug discovery target, which is encouraged by the success of rapamycin and its analogs (rapalogs) in treatment of mTORC1-hyperactive cancers in both pre-clinic models and clinical trials. However, rapamycin and existing rapalogs have typically short-lasting partial responses due to drug resistance, thereby triggering our interest to investigate a potential mTORC1 inhibitor that is mechanistically different from rapamycin. Here, we report that hayatine, a derivative from Cissampelos, can serve as a potential mTORC1 inhibitor selected from a natural compound library. The unique properties owned by hayatine such as downregulation of mTORC1 activities, induction of mTORC1's translocation to lysosomes followed by autophagy, and suppression on cancer cell growth, strongly emphasize its role as a potential mTORC1 inhibitor. Mechanistically, we found that hayatine disrupts the interaction between mTORC1 complex and its lysosomal adaptor RagA/C by binding to the hydrophobic loop of RagC, leading to mTORC1 inhibition that holds great promise to overcome rapamycin resistance. Taken together, our data shed light on an innovative strategy using structural interruption-based mTORC1 inhibitors for cancer treatment.

Role of the superior salivatory nucleus in parasympathetic control of choroidal blood flow and in maintenance of retinal health.

The vasodilatory pterygopalatine ganglion (PPG) innervation of the choroid is under the control of preganglionic input from the superior salivatory nucleus (SSN), the parasympathetic portion of the facial motor nucleus. We sought to confirm that choroidal SSN drives a choroid-wide vasodilation and determine if such control is important for retinal health. To the former end, we found, using transscleral laser Doppler flowmetry, that electrical activation of choroidal SSN significantly increased choroidal blood flow (ChBF), at a variety of choroidal sites that included more posterior as well as more anterior ones. We further found that the increases in ChBF were significantly reduced by inhibition of neuronal nitric oxide synthase (nNOS), thus implicating nitrergic PPG terminals in the SSN-elicited ChBF increases. To evaluate the role of parasympathetic control of ChBF in maintaining retinal health, some rats received unilateral lesions of SSN, and were evaluated functionally and histologically. In eyes ipsilateral to choroidal SSN destruction, we found that the flash-evoked scotopic electroretinogram a-wave and b-wave peak amplitudes were both significantly reduced by 10 weeks post lesion. Choroidal baroregulation was evaluated in some of these rats, and found to be impaired in the low systemic arterial blood pressure (ABP) range where vasodilation normally serves to maintain stable ChBF. In retina ipsilateral to SSN destruction, the abundance of Müller cell processes immunolabeled for glial fibrillary acidic protein (GFAP) and GFAP message were significantly upregulated. Our studies indicate that the SSN-PPG circuit mediates parasympathetic vasodilation of choroid, which appears to contribute to ChBF baroregulation during low ABP. Our results further indicate that impairment in this adaptive mechanism results in retinal dysfunction and pathology within months of the ChBF disturbance, indicating its importance for retinal health.

Friend or Foe: Xenobiotic Activation of Nrf2 in Disease Control and Cardioprotection.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that governs a highly conserved pathway central to the protection of cells against various oxidative stresses. However, the biological impact of xenobiotic intervention of Nrf2 in physiological and pathophysiological conditions remains debatable. Activation of Nrf2 in cancer cells has been shown to elevate drug resistance and increase cell survival and proliferation, while inhibition of Nrf2 sensitizes cancer cells to drug treatment. On the other hand, activation of Nrf2 in normal healthy cells has been explored as a rather successful strategy for cancer chemoprevention. Selective activation of Nrf2 in off-target cells has recently been investigated as an approach for protecting off-target tissues from untoward drug toxicity. Specifically, induction of antioxidant response element genes via Nrf2 activation in cardiac cells is being explored as a means to limit the well-documented cardiotoxicity accompanied by cancer treatment with commonly prescribed anthracycline drugs. In addition to cancers, Nrf2 has been implicated in many other diseases including Alzheimer's and Parkinson's Diseases, diabetes, and cardiovascular disease. In this review, we discuss the roles of Nrf2 and its downstream target genes in the treatment of various diseases, and its recently explored potential for increasing the benefit: risk ratio of commonly utilized cancer treatments.

Rational design for high-yield monolayer WS2films in confined space under fast thermal processing.

Tungsten Disulfide (WS2) films, as one of the most attractive members in the family of transition metal dichalcogenides, were synthesized typically on SiO2/Si substrate by confine-spaced chemical vapor deposition method. The whole process could be controlled efficiently by precursor concentration and fast thermal process. To be priority, the effect of fast heating-up to cooling-down process and source ratio-dependent rule for WS2structure have been systematically studied, leading to high-yield and fine structure of monolayer WS2films with standard triangular morphology and average edge length of 92.4µm. The growth time of the samples was regulated within 3 min, and the optimal source ratio of sulfur to tungsten oxide is about 200:3. The whole experimental duration was about 50 min, which is only about quarter in comparison to relevant reports. We assume one type of 'multi-nucleation dynamic process' to provide a potential way for fast synthesis of the samples. Finally, the good performance of as-fabricated field-effect transistor on WS2film was achieved, which exhibits high electron mobility of 4.62 cm2V-1s-1, fast response rate of 42 ms, and remarkable photoresponsivity of 3.7 × 10-3A W-1. Our work will provide a promising robust way for rapid synthesis of high-quality monolayer TMDs films and pave the way for the potential applications of TMDCs.