cAMP Response Element-binding Protein Signaling Research Articles

#1400 Acidosis-induced inflammatory response in tubule cells and fibroblasts is amplified by tubule-fibroblast crosstalk and mediated via p38 signaling

Abstract Background and Aims Tubulointerstitial kidney disease, associated with micromilieu changes such as acidification and inflammation, impacts tubule cells and fibroblasts. Micromilieu homeostasis influences intracellular signaling and intercellular crosstalk. Furthermore, cell-cell communication modulates the interstitial microenvironment. In the early stages of kidney failure, fibroblasts undergo a transition to an inflammatory phenotype driven by rapid and long-lasting p38 or CREB (cAMP response element-binding protein) signaling. This phenotypic shift involves an increased secretion of cytokines such as IL-6, TNF, or COX-2 metabolites, thereby changing the microenvironment. Additionally, the phenotype switch is characterized by remodelling of the cytoskeleton and alterations in cell-cell contacts. The objective of our study was to evaluate the impact of acidosis on inflammatory responses in proximal tubule cells and fibroblasts in the context of cellular crosstalk. Furthermore, we aimed to investigate the involvement of p38 and CREB signaling. Method HK-2 (human proximal tubule) and CCD-1092Sk (human fibroblasts), in mono and coculture, were exposed to acidic or control media for 3 or 48 h. Protein expression levels of inflammation markers (IL-6, TNF, TGF-ß, and COX-2), dedifferentiation markers (N-cadherin, vinculin, ß-catenin, and vimentin), as well as phospho- and total p38 and CREB, were determined through western blot analysis. The impact of p38 activation was assessed using pharmacological interventions. Furthermore, the influence of IL-6 incubation on the expression of phospho-p38 was investigated Results In tubule cells acidosis led, independent of culture conditions, to an increase of IL-6 after 3h and a decrease of vimentin and COX-2 after 48h. Moreover, acidosis caused an increase of TNF solely in coculture after 3h. Only in monoculture, ß-Catenin expression decreased in tubule cells during acidosis. In fibroblasts acidosis led to an increase of TNF, COX-2, vimentin, vinculin, N-cadherin and a decrease of TGF-ß expression exclusively in co-culture after 48 h. Independent of incubation or culture conditions acidosis induced a strong increase of IL-6 protein expression in fibroblasts. In co-culture, acidosis enhanced phosphorylation of p38 phosphorylation only after 3 h and that of CREB appeared after 3h and was persistent after 48h. In fibroblasts, acidosis enhanced phosphorylation of p38 in a sustained and very strong manner. Moreover, acidosis caused an increased phosphorylation of CREB independent of culture conditions and incubation time. Inhibition of p38 under co-culture conditions reduced acidosis-induced changes in fibroblasts significantly. In monoculture, incubation with IL-6 under acidic conditions caused an increase in p38 phosphorylation after 3 hours in tubule cells and after 48 hours in fibroblasts. Conclusion Our data indicate that acidosis-induced pathophysiological changes are significantly amplified by tubule-fibroblast crosstalk. The synergy between cellular crosstalk and acidosis triggers the activation of the p38, CREB, and IL-6 signaling pathways, leading to a phenotype switch in fibroblasts that promotes inflammation and fibrosis. If these findings hold true in vivo, the synergistic interplay between tubule-fibroblast crosstalk and acidosis emerges as a crucial factor in the development of kidney failure.

Activation of Akt–cAMP response element-binding protein (CREB) signaling as an adaptive response to an electrophilic metabolite of morphine

Activation of Akt–cAMP response element-binding protein (CREB) signaling as an adaptive response to an electrophilic metabolite of morphine

Schwann cell–derived extracellular vesicles as a potential therapy for retinal ganglion cell degeneration

Optic neuropathy is the leading cause of irreversible blindness and is characterized by progressive degeneration of retinal ganglion cells (RGCs). Several studies have demonstrated that transplantation of Schwann cells (SCs) is a promising candidate therapy for optic neuropathy and that intravitreally transplanted cells exert their effect via paracrine actions. Extracellular vesicle (EV)-based therapies are increasingly recognized as a potential strategy for cell replacement therapy. In this study, we aimed to investigate the neuroprotective and regenerative effects of SC-EVs following optic nerve injury. We found that SC-EVs were internalized by RGCs in vitro and in vivo without any transfection reagents. Intriguingly, SC-EVs significantly enhanced the survival and axonal growth of primary RGCs in a coculture system. In a rat optic nerve crush model, SC-EVs mitigated RGC degeneration, prevented RGC loss, and preserved the thickness of the ganglion cell complex, as demonstrated by the statistically significant improvement in RGC counts and thickness measurements. Mechanistically, SC-EVs activated the cAMP-response element binding protein (CREB) signaling pathway and regulated reactive gliosis in ONC rats, which is crucial for RGC protection and axonal regeneration. These findings provide novel insights into the neuroprotective and regenerative properties of SC-EVs, suggesting their potential as a cell-free therapeutic strategy and natural biomaterials for neurodegenerative diseases of the central nervous system.

Xiegan-Liangxue-Jiedu Decoction Alleviated Psoriasis and Depressionlike Behavior in a Mouse Model: Role of the AC–cAMP–PKA–CREB Signaling Pathway

Objectives Psoriasis vulgaris is an immune-mediated inflammatory skin disease that is associated with depression. In this study, we investigated the effect of Xiegan–Liangxue–Jiedu (XGLXJD) decoction, a traditional Chinese medicine formula, on psoriasis based on network pharmacology, molecular docking, and animal experiments. Materials and Methods A protein–protein interaction (PPI) network was constructed using the overlapping targets of XGLXJD decoction and psoriasis. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using Metascape database. High-performance liquid chromatography (HPLC) was used to investigate the main compounds of XGLXJD decoction. Molecular docking was performed to predict the potential interaction between the main compounds and proteins of interest. A C57 mouse model of psoriasis was established via continuous exposure to imiquimod. Seven days later, the XGLXJD decoction was orally administered at increasing doses for 6 days. The psoriasis area and severity index were calculated. Hematoxylin and eosin staining was used to examine skin morphology. Enzyme-linked immunosorbent assay (ELISA) was used to determine the serum levels of adenylyl cyclase (AC), cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), interleukin-17 (IL-17), and tumor necrosis factor-α (TNF-α). Sucrose preference test and forced swimming test were used to assess depression-like behavior. Immunohistochemical (IHC) staining and immunofluorescence were used to investigate the cAMP-response element binding protein (CREB) signaling pathway. Results Overall, 162 overlapping targets were generated. A total of 398 biological processes, 84 molecular functions, and 47 cellular components were identified via GO analysis, whereas 140 pathways were identified via KEGG pathway analysis. The most notable signaling pathways were cAMP as well as downstream IL-17 and TNF-α signaling pathways. HPLC analysis revealed that the main compounds of XGLXJD decoction were paeoniflorin, isorhamnetin, quercetin, luteolin, kaempferol, and baicalein. The molecular docking assay indicated that the docking energies of the main compounds of XGLXJD decoction to the top hub genes were less than −5 kcal/mol. ELISA revealed that the administration of XGLXJD decoction decreased the levels of pro-inflammatory cytokines (TNF-α and IL-17). Furthermore, the AC, cAMP, and PKA levels were enhanced after its administration. IHC staining demonstrated that the administration of XGLXJD decoction activated the AC–cAMP–PKA–CREB signaling pathway in skin. In addition, it enhanced sucrose preference and forced swimming time percentage. It also enhanced the expression of cAMP and PKA in the hippocampus. Conclusion XGLXJD decoction alleviated psoriasis and depression-like behavior. The AC–cAMP–PKA–CREB signaling pathway may play a crucial role in mediating this effect.

Silver Carp (Hypophthalmichthys molitrix) Scale Collagen Peptides-1 (SCPs1) Inhibit Melanogenesis through Downregulation of the cAMP-CREB Signaling Pathway.

The mechanism of silver carp scale collagen peptides (SCPs1) on melanogenesis and its mechanism of action were examined in mouse melanoma cells (B16). The cell viability and effects of SCPs1 on intracellular tyrosinase (TYR) activity and melanin, reactive oxygen species (ROS), glutathione (GSH) and cyclic adenosine monophosphate (cAMP) content were examined. The regulatory mechanism of SCPs1 on the cAMP response element-binding protein (CREB) signaling pathway was analyzed. The cell viability of the SCPs1 group was >80% (0.01-1 mg/mL) and the inhibitory rate of SCPs1 on B16 cell melanin increased in a dose-dependent manner. The highest inhibitory rate of SCPs1 on melanin content reaching 80.24%. SCPs1 significantly increased the GSH content and decreased the tyrosinase activity, as well as the content of ROS and cAMP. Western blot analysis showed that SCPs1 significantly inhibited melanocortin-1 receptor (MC1R) expression and CREB phosphorylation in the cAMP-CREB signaling pathway, leading to downregulation of microphthalmia-associated transcription factor (MITF) and the expression of TYR, TYR-related protein-1 (TRP-1) and TRP-2. SCPs1 also inhibited the expression of MC1R, MITF, TYR, TRP-1 and TRP-2 at the transcriptional level. Taken together, SCPs1 inhibited melanin synthesis through the downregulation of the cAMP-CREB signaling pathway. Fish-derived collagen peptides could potentially be applied in skin whitening products.

Low-frequency Electrical Stimulation of the Hippocampus Plays a Role in the Treatment of Pharmacoresistant Epilepsy by Blocking the PKA-CREB Pathway.

The objective of this study is to study the mechanism of Low frequency electrical stimulation (LFS) in the treatment of drug-resistant epilepsy by regulating the protein kinase A (PKA)-cAMP response element-binding protein (CREB) signaling pathway upstream of gamma aminobutyric acid A (GABAA) receptor. Primary hippocampal neurons were extracted and cultured from fetal rat brains and randomly divided into the normal control group, PKA-CREB agonist group, and PKA-CREB inhibitor group. Drug-resistant epileptic rats were established and randomly divided into the pharmacoresistant group, LFS group, PKA-CREB agonist combined with hippocampal LFS group, and PKA-CREB inhibitor combined with hippocampal LFS group. The normal rats were in the normal control group and drug-sensitive rats were in the pharmacosensitive group. The seizure frequency of epileptic rats was determined using video surveillance. The expression of PKA, CREB, p-CREB, and GABAA receptor subunits α1 and β2 of each group were detected using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting assays. The in vitro expression levels of PKA, CREB, and p-CREB in the agonist group were significantly higher than those in the normal control group (NRC group), while the expression levels of GABAA receptor subunits α1 and β2 were significantly lower than those in the NRC group. The expression levels of PKA, CREB, and p-CREB in the inhibitor group were significantly lower, while the expression levels of GABAA receptor subunits α1 and β2 were significantly higher than those in the NRC group. The in vivo seizure frequency was significantly lower in the LFS group than in the pharmacoresistant group (PRE group). Compared to the LFS group, the seizure frequency and the expression levels of PKA, CREB, and p-CREB in the rat hippocampus were significantly higher, and the expression levels of GABAA receptor subunits α1 and β2 were significantly lower in the agonist group. The results in the inhibitor group were exactly the opposite of those in the agonist group. The PKA-CREB signaling pathway is involved in the regulation of GABAA receptor subunits α1 and β2. In addition, LFS plays an important role in increasing GABAA receptor expression by regulating the PKA-CREB signaling pathway.

Chemogenetic inhibition of amygdala excitatory neurons impairs rhEPO-enhanced contextual fear memory after TBI

Erythropoietin (EPO) is a hypoxia-responsive cytokine that induces neuroprotective effect in hypoxic-ischaemic, traumatic, excitotoxic and inflammatory injuries. Recently, utilizing a clinically relevant murine model of TBI and delayed hypoxemia, we have found that ongoing recombinant human EPO (rhEPO) administration influenced neurogenesis, neuroprotection, synaptic density and, behavioral outcomes early after TBI, and the impact on long-lasting outcomes 6 months after injury. We also demonstrated that the 1-month behavioral improvement was associated with mitogen-activated protein kinase (MAPK)/cAMP response element-binding protein (CREB) signaling activation and increased of excitatory synaptic density in the amygdala. However, we did not uncover which type of cells were involved in fear memory response enhancement after rhEPO treatment in the setting of TBI with delayed hypoxemia. In this report, using chemogenetic tools in our controlled cortical impact (CCI) model, we were able to inactivate excitatory neurons and eliminate rhEPO-induced fear memory recall enhancement. In summary, these data demonstrate that rhEPO treatment initiated after TBI enhances contextual fear memory in the injured brain via activation of excitatory neurons in the amygdala.

The colonic interleukin-19 aggravates the dextran sodium sulfate/stress-induced comorbidities due to colitis and anxiety.

Comorbidities due to inflammatory bowel disease (IBD) and anxiety are commonly acknowledged; however, their underlying basis is unclear. In the current study, we first conducted a clinical retrospective analysis to identify the enhancive incidence rate of IBD before or after the epidemic of Corona Virus Disease 2019 (COVID-19), with higher Generalized Anxiety Disorder-7 (GAD-7), as well as poorer Gastrointestinal Quality of Life Index (GIQLI). Then, the dextran sodium sulfate (DSS) and chronic unpredictable stress (CUS)-induced IBD and anxiety comorbid models were established with the correlational relations between symptoms of IBD and anxiety-related behaviors. We found dysfunctional up-regulation of a new inflammatory factor interleukin (IL)-19 in the colon of DSS/CUS treated mice. Overexpression of IL-19 in colon induced anxious phenotypes, and accelerated the anxious condition and symptoms of colitis in the DSS/CUS model by promoting the expression of inducible nitric oxide synthase (iNOS), IL-1β, and IL-6 pro-inflammatory factors, and activating signal transducer and activator of transcription 3 (STAT3) signaling pathway in the colon. Furthermore, overexpression of IL-19 in the colon also reduced the expression levels of brain-derived neurotrophic factor (BDNF), extracellular signal-regulated kinase (ERK), and cAMP-response element binding protein (CREB) signaling pathways activity in the hippocampus. These results suggest that IL-19 was a pivotal player in DSS/CUS-induced comorbidities of colitis and anxiety with different signaling pathways for the colon and hippocampus, which provides a candidate gene to explore the pathophysiology of comorbidities due to colitis and anxiety.

Investigation of the keratinocyte transcriptome altered in high-glucose environment: An in-vitro model system for precision medicine

BackgroundImpaired wound healing is a serious diabetes complication compromising patients’ quality of life. However, the pathogenesis of diabetic wounds (DWs) remains incompletely understood. Human epidermal keratinocyte (HEK) is the sentinel cell that initiates healing processes after the epidermal integrity has been disrupted. ObjectiveThis study aimed to investigate the functional roles of HEKs in wound healing and to identify candidate genes, signaling pathways and molecular signatures contributing to the DWs. MethodsHEKs were cultured in normal or high-glucose environment, followed by scratch, to mimic the microenvironment of normal wounds and DWs. Subsequently, we performed RNA sequencing and systematically analyzed the expression profiles by bioinformatics approaches. ResultsHigh-glucose environment altered the keratinocyte transcriptome responses to wounding. In experimental model of DWs, we found that TNF, CYP24A1, NR4A3 and GGT1 were key overexpressed genes in keratinocytes and were implicated in multiple cellular responses. Further analysis showed that wounding in high-glucose environment activated G-protein-coupled receptor (GPCR) signaling, cAMP response element-binding protein (CREB) signaling, and adrenomedullin signaling in keratinocytes, while dysregulated skin development and immune responses as compared to their counterpart in normal glucose settings. ConclusionThis simplified in-vitro model serves as a valuable tool to gain insights into the molecular basis of DWs and to facilitate establishment of personalized therapies in clinical practice

Fermented soybean foods (natto) ameliorate age-related cognitive decline by hippocampal TAAR1-mediated activation of the CaMKII/CREB/BDNF signaling pathway in senescence-accelerated mouse prone 8 (SAMP8).

Natto is a traditional fermented soybean-based food that has been an integral part of Japanese cuisine for several centuries. Although there have been extensive studies on the cognitive benefits of soybeans, only limited studies have examined the effects of natto on cognitive function. This study investigated the potential cognitive benefits of natto in senescence-accelerated mouse-prone 8 (SAMP8) mice. After 12 weeks of oral administering natto fermented for 18 h, the spatial learning and memory performance were improved compared with those in SAMP8 control mice. Furthermore, activation of the brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)/cAMP response element-binding protein (CREB) signaling and N-methyl-D-aspartate receptor (NMDAR)-calcium/calmodulin-dependent protein kinase II (CaMKII) cascade was observed in the hippocampus of SAMP8 mice that were fed natto. Additionally, natto administration upregulated trace amine-associated receptor 1 (TAAR1) as a modulator of NMDAR. These findings suggest that natto ameliorates cognitive decline by activating the TAAR1-mediated CaMKII/CREB/BDNF signaling pathway in the hippocampus of SAMP8 mice.

Curcumin-Nicotinate Attenuates Hippocampal Synaptogenesis Dysfunction in Hyperlipidemia Rats by the BDNF/TrkB/CREB Pathway: Involving Idol/LDLR Signaling to Eliminate Aβ Deposition

Hyperlipidemia has been demonstrated to evoke Alzheimer disease (AD) pathologies such as Amyloid-β (Aβ) deposition and synaptogenesis dysfunction in the hippocampus. Curcumin gives protection against anti-amyloid properties and synaptogenesis dysfunction. Curcumin-Nicotinate (CurTn), a new type of curcumin derivative, ameliorates cognitive impairment by rescuing autophagic flux in the CA1 hippocampus of diabetic rats. However, whether Curtn possesses an antagonistic effect on AD-related pathologies in the hippocampus induced by hyperlipidemia remains ill-defined. The present study aims to investigate whether CurTn alleviates synaptogenesis dysfunction by promoting the activation of brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB)/cAMP-response element binding protein (CREB) signaling and whether the underlying fundamental mechanism involves the elimination of Aβ deposition due to Idol/low-density lipoprotein receptor (LDLR) signaling in the hippocampus of high-fat diet (HFD)-induced hyperlipidemia rats. The results demonstrated that CurTn not only improved synaptogenesis dysfunction in the hippocampus of HFD rats, as evidenced by the increases in the expressions of synapse-related proteins postsynaptic density protein 95 (PSD-95), synapsin-1, and Glutamate receptor 1 (GluR1), but also activated BDNF/TrkB/CREB signaling, as evidenced by the elevation of the expressions of BDNF, pTrkB, and CREB. Moreover, CurTn modulated the Idol/LDLR pathway in the hippocampus of HFD rats, as evidenced by the decreased expression of Idol and the increased expression of LDLR. Furthermore, CurTn eliminated the deposition of Aβ, as evidenced by the reduction in the content of Aβ40 and Aβ42. These results reveal that CurTn may attenuate synaptogenesis dysfunction by activating BDNF/TrkB/CREB signaling, as the possible result of the modulation of Idol/LDLR signaling to eliminate Aβ deposition in the hippocampus of HFD rats.

Sirt3 mediates the benefits of exercise on bone in aged mice.

Exercise in later life is important for bone health and delays the progression of osteoporotic bone loss. Osteocytes are the major bone cells responsible for transforming mechanical stimuli into cellular signals through their highly specialized lacunocanalicular networks (LCN). Osteocyte activity and LCN degenerate with aging, thus might impair the effectiveness of exercise on bone health; however, the underlying mechanism and clinical implications remain elusive. Herein, we showed that deletion of Sirt3 in osteocytes could impair the formation of osteocyte dendritic processes and inhibit bone gain in response to exercise in vivo. Mechanistic studies revealed that Sirt3 regulates E11/gp38 through the protein kinase A (PKA)/cAMP response element-binding protein (CREB) signaling pathway. Additionally, the Sirt3 activator honokiol enhanced the sensitivity of osteocytes to fluid shear stress in vitro, and intraperitoneal injection of honokiol reduced bone loss in aged mice in a dose-dependent manner. Collectively, Sirt3 in osteocytes regulates bone mass and mechanical responses through the regulation of E11/gp38. Therefore, targeting Sirt3 could be a novel therapeutic strategy to prevent age-related bone loss and augment the benefits of exercise on the senescent skeleton.

Recombinant human erythropoietin induces neuroprotection, activates MAPK/CREB pathway, and rescues fear memory after traumatic brain injury with delayed hypoxemia in mice

Therapeutic interventions targeting secondary insults, such as delayed hypoxemia, provide a unique opportunity for treatment in severe traumatic brain injury (TBI). Erythropoietin (EPO) is a hypoxia-responsive cytokine with important roles in neurodevelopment, neuroprotection and neuromodulation. We hypothesized that recombinant human erythropoietin (rhEPO) administration would mitigate injury in a combined injury model of TBI and delayed hypoxemia. Utilizing a clinically relevant murine model of TBI and delayed hypoxemia, we characterized how ongoing rhEPO administration influenced neurogenesis, neuroprotection, synaptic density and, behavioral outcomes early after TBI, and the impact on long-lasting outcomes 6 months after injury. We employed novel object recognition (NOR) and fear conditioning to assess long-term memory. At 1-month post-injury, we observed a significant increase in cued-fear memory response in the rhEPO-injured mice compared with vehicle-injured mice. This was associated with neuroprotection and neurogenesis in the hippocampus and mitogen-activated protein kinase (MAPK)/cAMP response element-binding protein (CREB) signaling activation and increased of excitatory synaptic density in the amygdala. Early rhEPO treatment after injury reduced neurodegeneration and increased excitatory synaptic density in the hippocampus and amygdala at 6 months post-injury. However at 6 months post-injury (4 months after discontinuation of rhEPO), we did not observe changes in behavioral assessments nor MAPK/CREB pathway activation. In summary, these data demonstrate that ongoing rhEPO treatment initiated at a clinically feasible time point improves neurological, cognitive, and histological outcomes after TBI in the setting of secondary hypoxemic insults.

Hesperidin Improves Memory Function by Enhancing Neurogenesis in a Mouse Model of Alzheimer's Disease.

Alzheimer’s disease (AD) is an irreversible neurodegenerative disease characterized by memory and cognitive impairments. Neurogenesis, which is related to memory and cognitive function, is reduced in the brains of patients with AD. Therefore, enhancing neurogenesis is a potential therapeutic strategy for neurodegenerative diseases, including AD. Hesperidin (HSP), a bioflavonoid found primarily in citrus plants, has anti-inflammatory, antioxidant, and neuroprotective effects. The objective of this study was to determine the effects of HSP on neurogenesis in neural stem cells (NSCs) isolated from the brain of mouse embryos and five familial AD (5xFAD) mice. In NSCs, HSP significantly increased the proliferation of NSCs by activating adenosine monophosphate (AMP)-activated protein kinase (AMPK)/cAMP-response element-binding protein (CREB) signaling, but did not affect NSC differentiation into neurons and astrocytes. HSP administration restored neurogenesis in the hippocampus of 5xFAD mice via AMPK/brain-derived neurotrophic factor/tropomyosin receptor kinase B/CREB signaling, thereby decreasing amyloid-beta accumulation and ameliorating memory dysfunction. Collectively, these preclinical findings suggest that HSP is a promising candidate for the prevention and treatment of AD.

LYTIC COCKTAIL ATTENUATES CATECHOLAMINE SURGE AFTER SEVERE BURNS BY BLOCKING HISTAMINE H1 RECEPTOR/PKA/CREB/TYROSINE HYDROXYLASE SIGNALING IN CHROMAFFIN CELLS.

Severe burns develop a catecholamine surge, inducing severe damage to the organism, raising the possibility of multisystem organ failure, and even death. The mechanisms of catecholamine surge have not been fully elucidated, and few strategies are generally acceptable to reduce catecholamine surge postburn. Thus, it is valuable to investigate the underlying mechanisms of catecholamine surge postburn to develop targeted interventions to attenuate it. We have found that the lytic cocktail alleviates the surge of catecholamine and organ injury after severe burn; however, the underlying mechanisms were still unclear. Moreover, the lytic cocktail has side effects, such as significant arterial hypotension and breathing depression, limiting its clinical application. This study aims to investigate the therapeutic mechanism of the lytic cocktail in regulating catecholamine levels postburn. We find that promethazine, a classic histamine H1 receptor blocker and a component of the lytic cocktail, can effectively reduce catecholamine surge and organ injury postburn. Our study confirms that blood histamine levels increase after severe burns. We find that histamine can amplify the catecholamine surge by elevating tyrosine hydroxylase expression and catecholamine synthesis in chromaffin cells through the histamine H1 receptor/Protein Kinase A /cAMP-response element binding protein signaling pathway. In summary, for the first time, we find that histamine plays a vital role in catecholamine surge postburn. We also confirm that the lytic cocktail effectively alleviates catecholamine surge and organ injury postburn through promethazine.

Bamboo Lignin Fractions with In Vitro Tyrosinase Inhibition Activity Downregulate Melanogenesis in B16F10 Cells via PKA/CREB Signaling Pathway.

Cosmetic ingredients originating from natural resources have garnered considerable attention, and the demand for whitening ingredients is increasing, particularly in Asian countries. Lignin is a natural phenolic biopolymer significantly effective as a natural sunscreen, as its ultraviolet protection efficacy ranges from 250 to 400 nm. However, using different types of lignin as cosmetic ingredients is difficult owing to the heterogeneity of lignin and the lack of in vitro and in vivo safety and efficacy data. Thus, steam-exploded lignin (SEL) was prepared from bamboo, fractionated via successive organic solvent extraction, and sequentially fractionated using ethyl acetate, methanol, and acetone to investigate its potential as a natural whitening material. Gel permeation chromatography showed that the molecular weight of acetone-soluble and acetone-insoluble SEL fractions were the lowest and the highest, respectively. Monomer structures of the four lignin fractions were elucidated using 1H, 13C, and 2D heteronuclear single quantum coherence nuclear magnetic resonance and pyrolysis gas chromatography/mass spectrometry. The antioxidant and tyrosinase inhibition activities of the four fractions were compared. The methanol-soluble SEL fraction (SEL-F2) showed the highest antioxidant activity (except 2,2-diphenyl-1-picrylhydrazyl scavenging activity), and the enzyme inhibition kinetics were confirmed. In this study, the expression pattern of the anti-melanogenic-related proteins by SEL-F2 was confirmed for the first time via the protein kinase A (PKA)/cAMP-response element-binding (CREB) protein signaling pathway in B16F10 melanoma cells. Thus, SEL may serve as a valuable cosmetic whitening ingredient.

Melatonin mitigates traumatic brain injury-induced depression-like behaviors through HO-1/CREB signal in rats

In addition to significant antioxidant properties, melatonin exhibits neuroprotective effects against various neurological diseases including traumatic brain injury (TBI) and ischemic stroke. Several potential mechanisms have been reported in the neuroprotection of melatonin among patients with TBI. Notably, the heme oxygenase-1 (HO-1)/cAMP response element-binding protein (CREB) signaling pathway is implicated in the development of a depressive state. Moreover, the activity of CREB in the nucleus accumbens (NAc) participates in reward and motivation, further contributing to depression induced by TBI. This study aims to explore whether melatonin could mitigate TBI-induced depression by activating of HO-1/CREB signal in a rodent model of weight-drop. As a consequence, melatonin (10 mg/kg) attenuated TBI-induced elevated immobility time in the force swim test, decreased time spent sniffing the novel rat in 3-chambered social test, and downregulated phosphorylated CERB in the NAc. However, a special inhibitor of HO-1 (SnPP) via intracerebroventricular injection partially reversed the neuroprotective effects of melatonin. Furthermore, melatonin decreased the number of summarized intersects in the astrocyte, A1-type astrocytes, IL-6-positive astrocytes in the NAc after TBI exposure, nevertheless, these changes could partially be restored by SnPP. Therefore, our findings demonstrate a novel neuroprotective mechanism for melatonin against TBI which can be a potential neuroprotective agent for the treatment of TBI-induced depression.

A Mixture of Ginkgo biloba L. Leaf and Hericium erinaceus (Bull.) Pers. Fruit Extract Attenuates Scopolamine-Induced Memory Impairments in Mice.

Alzheimer's disease (AD) is a neurodegenerative disease that is characterized by loss of memory and cognitive impairment via dysfunction of the cholinergic nervous system. In cholinergic dysfunction, it is well known that impaired cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) signaling are major pathological markers and are some of the strategies for the development of AD therapy. Therefore, this study is aimed at evaluating whether a mixture comprising Ginkgo biloba L. leaf (GL) and Hericium erinaceus (Bull.) Pers. (HE) fruit extract (GH mixture) alleviated cognitive impairment induced in a scopolamine-induced model. It was discovered that GH reduced neuronal apoptosis and promoted neuronal survival by activating BDNF signaling in an in vitro assay. In addition, the GH (p.o. 240 mg/kg) oral administration group significantly restored the cognitive deficits of the scopolamine-induced mouse group (i.p. 1.2 mg/kg) in the behavior tests such as Y-maze and novel object recognition task (NORT) tests. This mixture also considerably enhanced cholinergic system function in the mouse brain. Furthermore, GH markedly upregulated the expressed levels of extracellular signal-regulated kinase (ERK), CREB, and BDNF protein levels. These results demonstrated that GH strongly exerted a neuroprotective effect on the scopolamine-induced mouse model, suggesting that an optimized mixture of GL and HE could be used as a good material for developing functional foods to aid in the prevention of neurodegenerative diseases, including AD.

Hippocampal MSK1 regulates the behavioral and biological responses of mice to chronic social defeat stress: Involving of the BDNF-CREB signaling and neurogenesis

Depression is one of the most common psychiatric diseases in the 21st century, while its pathogenesis is not yet fully understood. Currently, besides to the monoaminergic system, the brain-derived neurotrophic factor (BDNF)-cAMP response element-binding protein (CREB) signaling is one of the most attractive signaling pathways for treating depression. Mitogen and stress-activated kinase (MSK) 1 and 2 are nuclear proteins activated downstream of the ERK1/2 or p38 MAPK pathways, and it has been demonstrated that MSKs are involved in the BDNF-CREB signaling. Here we assumed that MSKs may play a role in depression, and various methods including the chronic social defeat stress (CSDS) model of depression, western blotting, immunofluorescence and virus-mediated gene transfer were used together. It was found that CSDS fully enhanced the expression of both phosphorylated MSK1 and total MSK1 in the hippocampus but not the medial prefrontal cortex (mPFC). CSDS did not influence the expression of phosphorylated MSK2 and total MSK2 in the two brain regions. Genetic over-expression of hippocampal MSK1 fully prevented not only the CSDS-induced depressive-like behaviors but also the CSDS-induced dysfunction in the hippocampal BDNF-CREB signaling and neurogenesis in mice, while genetic knockdown of hippocampal MSK1 aggravated the CSDS-induced depressive-like symptomatology in mice. Our results collectively suggest that although CSDS evidently enhances the activity of hippocampal MSK1, it is not a contributor to the CSDS-induced dysfunction in the brain but a defensive feedback regulator which protects against CSDS. Therefore, hippocampal MSK1 participates in the pathogenesis of depression and is a feasible and potential antidepressant target.

Analysis and Construction of a Molecular Diagnosis Model of Drug-Resistant Epilepsy Based on Bioinformatics.

Background: Epilepsy is a complex chronic disease of the nervous system which influences the health of approximately 70 million patients worldwide. In the past few decades, despite the development of novel antiepileptic drugs, around one-third of patients with epilepsy have developed drug-resistant epilepsy. We performed a bioinformatic analysis to explore the underlying diagnostic markers and mechanisms of drug-resistant epilepsy. Methods: Weighted correlation network analysis (WGCNA) was applied to genes in epilepsy samples downloaded from the Gene Expression Omnibus database to determine key modules. The least absolute shrinkage and selection operator (LASSO) regression and support vector machine-recursive feature elimination (SVM-RFE) algorithms were used to screen the genes resistant to carbamazepine, phenytoin, and valproate, and sensitivity of the three-class classification SVM model was verified through the receiver operator characteristic (ROC) curve. A protein–protein interaction (PPI) network was utilized to analyze the protein interaction relationship. Finally, ingenuity pathway analysis (IPA) was adopted to conduct disease and function pathway and network analysis. Results: Through WGCNA, 72 genes stood out from the key modules related to drug resistance and were identified as candidate resistance genes. Intersection analysis of the results of the LASSO and SVM-RFE algorithms selected 11, 4, and 5 drug-resistant genes for carbamazepine, phenytoin, and valproate, respectively. Subsequent union analysis obtained 17 hub resistance genes to construct a three-class classification SVM model. ROC showed that the model could accurately predict patient resistance. Expression of 17 hub resistance genes in healthy subjects and patients was significantly different. The PPI showed that there are six resistance genes (CD247, CTSW, IL2RB, MATK, NKG7, and PRF1) that may play a central role in the resistance of epilepsy patients. Finally, IPA revealed that resistance genes (PRKCH and S1PR5) were involved in “CREB signaling in Neurons.” Conclusion: We obtained a three-class SVM model that can accurately predict the drug resistance of patients with epilepsy, which provides a new theoretical basis for research and treatment in the field of drug-resistant epilepsy. Moreover, resistance genes PRKCH and S1PR5 may cooperate with other resistance genes to exhibit resistance effects by regulation of the cAMP-response element-binding protein (CREB) signaling pathway.