Glucose-dependent insulinotropic polypeptide (GIP) alleviates ferroptosis in aging-induced brain damage through the Epac/Rap1 signaling pathway.

Glucose-dependent insulinotropic polypeptide (GIP), a 42-aminoacid hormone, exerts multifaceted effects in physiology, most notably in metabolism, obesity, and inflammation. Its significance extends to neuroprotection, promoting neuronal proliferation, maintaining physiological homeostasis, and inhibiting cell death, all of which play a crucial role in the context of neurodegenerative diseases. Through intricate signaling pathways involving its cognate receptor (GIPR), a member of the G protein-coupled receptors, GIP maintains cellular homeostasis and regulates a defense system against ferroptosis, an essential process in aging. Our study, utilizing GIP-overexpressing mice and in vitro cell model, elucidates the pivotal role of GIP in preserving neuronal integrity and combating age-related damage, primarily through the Epac/Rap1 pathway. These findings shed light on the potential of GIP as a therapeutic target for the pathogenesis of ferroptosis in neurodegenerative diseases and aging.

Raepenol™ Cream, a Complex of Natural Compounds, Promotes Wound Healing and Relieves Pruritus In Vivo.

BACKGROUND/AIM: Skin wound healing is a physiological process restoring the structural and functional integrity of injured skin. During this process, wound management preventing bacterial infection and complications is important for the regeneration of skin layers and adnexa, as well as the protective function of the skin. Therefore, the development of an effective ointment to promote wound healing without complications is beneficial. MATERIALS AND METHODS: This study developed Raepenol™ cream, comprising a base cream and natural compounds including paeonol, D-panthenol and extract of Centella asiatica, and assessed its therapeutic effect in wound healing. A rat model of skin wound healing and a mouse model of imiquimod-induced pruritus were employed. The effect of Raepenol™ cream was evaluated by wound size and histological analysis, including the integrity of skin structures and inflammatory response. RESULTS: Raepenol™ cream treatment effectively restored the structural integrity of the skin in rats, including wound closure, regeneration of skin adnexa, and reconstitution of collagen, comparable to commercial ointment. Additionally, Raepenol™ cream significantly suppressed pruritus by inhibiting mast cell infiltration or retention in the inflammatory site of mouse ears. CONCLUSION: Raepenol™ cream effectively promoted wound healing and relieved pruritus in animal models. These results suggest that it could be a promising option for wound care and pruritus relief, offering potential advantages over current ointments.

Protective Effects of Imatinib on a DSS-induced Colitis Model Through Regulation of Apoptosis and Inflammation.

BACKGROUND/AIM: Inflammatory bowel disease (IBD) is characterized by dysregulated immune responses and a multifactorial etiology. While imatinib has demonstrated efficacy in the treatment of immune-related diseases, its potential effects in IBD treatment remain underexplored. MATERIALS AND METHODS: This study aimed to investigate the therapeutic effects of imatinib in colitis treatment. A dextran sulfate sodium (DSS)-induced colitis model was used to mimic IBD in mice. Imatinib was administered orally to mice simultaneously with DSS treatment. The effects of imatinib on DSS-induced colitis were evaluated by analyzing colitis-related pathology, including the disease activity index (DAI), histological lesions, inflammatory markers, and tight junction integrity. Additionally, western blot analysis and quantitative real-time polymerase chain reaction were used to assess inflammatory markers, tight-junction proteins, and cell death. RESULTS: In the DSS-induced colitis model, imatinib treatment exerted protective effects by attenuating weight loss, restoring colon length, reducing spleen weight, and improving the DAI score and histological lesions. Additionally, imatinib reduced the level of proinflammatory cytokines, including TNF-α, IL-6, and IL-1ß. Furthermore, imatinib treatment restored tight-junction integrity and decreased the expression of apoptosis marker proteins. CONCLUSION: Overall, imatinib treatment significantly alleviated the symptoms of DSS-induced colitis by influencing the expression of proinflammatory cytokines, tight junction proteins, and apoptotic markers in mice. These findings highlight imatinib as a potential therapeutic candidate for IBD.

Silibinin Mitigates Vanadium-induced Lung Injury via the TLR4/MAPK/NF-κB Pathway in Mice.

BACKGROUND/AIM: Silibinin, has been investigated for its potential benefits and mechanisms in addressing vanadium pentoxide (V2O5)-induced pulmonary inflammation. This study explored the anti-inflammatory activity of silibinin and elucidate the mechanisms by which it operates in a mouse model of vanadium-induced lung injury. MATERIALS AND METHODS: Eight-week-old male BALB/c mice were exposed to V2O5 to induce lung injury. Mice were pretreated with silibinin at doses of 50 mg/kg and 100 mg/kg. Histological analyses were performed to assess cell viability and infiltration of inflammatory cells. The expression of pro-inflammatory cytokines (TNF-α, IL-6, IL-1ß) and activation of the MAPK and NF-[Formula: see text]B signaling pathways, as well as the NLRP3 inflammasome, were evaluated using real-time PCR, western blot analysis, and immunohistochemistry. Whole blood analysis was conducted to measure white blood cell counts. RESULTS: Silibinin treatment significantly improved cell viability, reduced inflammatory cell infiltration, and decreased the expression of pro-inflammatory cytokines in V2O5-induced lung injury. It also notably suppressed the activation of the MAPK and NF-[Formula: see text]B signaling pathways, along with a marked reduction in NLRP3 inflammasome expression levels in lung tissues. Additionally, silibinin-treated groups exhibited a significant decrease in white blood cell counts, including neutrophils, lymphocytes, and eosinophils. CONCLUSION: These findings underscore the potent anti-inflammatory effects of silibinin in mice with V2O5-induced lung inflammation, highlighting its therapeutic potential. The study not only confirms the efficacy of silibinin in mitigating inflammatory responses but also provides a foundational understanding of its role in modulating key inflammatory pathways, paving the way for future therapeutic strategies against pulmonary inflammation induced by environmental pollutants.

Increased ER stress by depletion of PDIA6 impairs primary ciliogenesis and enhances sensitivity to ferroptosis in kidney cells.

Primary cilia are crucial for cellular balance, serving as sensors for external conditions. Nephronophthisis and related ciliopathies, which are hereditary and degenerative, stem from genetic mutations in cilia-related genes. However, the precise mechanisms of these conditions are still not fully understood. Our research demonstrates that downregulating PDIA6, leading to cilia removal, makes cells more sensitive to ferroptotic death caused by endoplasmic reticulum (ER) stress. The reduction of PDIA6 intensifies the ER stress response, while also impairing the regulation of primary cilia in various cell types. PDIA6 loss worsens ER stress, hastening ferroptotic death in proximal tubule epithelial cells, HK2 cells. Counteracting this ER stress can mitigate PDIA6 depletion effects, restoring both the number and length of cilia. Moreover, preventing ferroptosis corrects the disrupted primary ciliogenesis due to PDIA6 depletion in HK2 cells. Our findings emphasize the role of PDIA6 in primary ciliogenesis, and suggest its absence enhances ER stress and ferroptosis. These insights offer new therapeutic avenues for treating nephronophthisis and similar ciliopathies.

hMAGEA2 Accelerates the Progression of Prostate Cancer via the EFNA3-Erk1/2 Signaling Pathway.

BACKGROUND/AIM: Human melanoma-associated antigen A2 (hMAGEA2) family members play several roles in many types of cancer and have been explored as potential prognostic markers. In this study, we investigated the molecular mechanism underlying hMAGEA2-mediated tumorigenesis of prostate cancer. MATERIALS AND METHODS: Immunohistochemistry and western blot were used to assess protein expression whereas microarray and quantitative reverse transcription-PCR determined mRNA expression. CCK-8 assay was used to determine cell proliferation. Colony formation assay was used to examine tumorigenesis. Migration and invasion were examined using a transwell assay. Propidium iodide (PI)/Annexin V double staining was performed to measure apoptosis. Transcriptional activity was measured using Dual-luciferase reporter assay. RESULTS: hMAGEA2 was highly over-expressed in human prostate cancer tissues compared to benign prostatic hyperplasia tissues. To elucidate its biological function in prostate cancer, we established two stable hMAGEA2-knockdown prostate cancer cell lines, PC3M and 22RV1, and found that they presented significantly decreased proliferation, anchorage-independent colony formation, migration, and invasion. As hMAGEA2 knockdown suppressed prostate cancer cell growth, we examined its potential influence on tumor apoptosis. hMAGEA2-knockdown cell lines displayed early apoptosis. Moreover, knockdown of hMAGEA2 resulted in the down-regulation of EFNA3 expression. Luciferase assay showed that hMAGEA2 bound to the EFNA promoter region and regulated its transcription. Down-regulation of EFNA3 expression led to decreased Ras/Braf/MEK/Erk1/2 phosphorylation and, consequently, inhibited prostate cancer progression. CONCLUSION: hMAGEA2 promotes prostate cancer growth, metastasis, and tumorigenesis by regulating the EFNA3-Erk1/2 signaling pathway, indicating its potential as a therapeutic marker for prostate cancer.

TASL mediates keratinocyte differentiation by regulating intracellular calcium levels and lysosomal function.

Maintaining epidermal homeostasis relies on a tightly organized process of proliferation and differentiation of keratinocytes. While past studies have primarily focused on calcium regulation in keratinocyte differentiation, recent research has shed light on the crucial role of lysosome dysfunction in this process. TLR adaptor interacting with SLC15A4 on the lysosome (TASL) plays a role in regulating pH within the endo-lysosome. However, the specific role of TASL in keratinocyte differentiation and its potential impact on proliferation remains elusive. In our study, we discovered that TASL deficiency hinders the proliferation and migration of keratinocytes by inducing G1/S cell cycle arrest. Also, TASL deficiency disrupts proper differentiation process in TASL knockout human keratinocyte cell line (HaCaT) by affecting lysosomal function. Additionally, our research into calcium-induced differentiation showed that TASL deficiency affects calcium modulation, which is essential for keratinocyte regulation. These findings unveil a novel role of TASL in the proliferation and differentiation of keratinocytes, providing new insights into the intricate regulatory mechanisms of keratinocyte biology.

HSPA9 reduction exacerbates symptoms and cell death in DSS-Induced inflammatory colitis.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition that is influenced by various factors, including environmental factors, immune responses, and genetic elements. Among the factors that influence IBD progression, macrophages play a significant role in generating inflammatory mediators, and an increase in the number of activated macrophages contributes to cellular damage, thereby exacerbating the overall inflammatory conditions. HSPA9, a member of the heat shock protein 70 family, plays a crucial role in regulating mitochondrial processes and responding to oxidative stress. HSPA9 deficiency disrupts mitochondrial dynamics, increasing mitochondrial fission and the production of reactive oxygen species. Based on the known functions of HSPA9, we considered the possibility that HSPA9 reduction may contribute to the exacerbation of colitis and investigated its relevance. In a dextran sodium sulfate-induced colitis mouse model, the downregulated HSPA9 exacerbates colitis symptoms, including increased immune cell infiltration, elevated proinflammatory cytokines, decreased tight junctions, and altered macrophage polarization. Moreover, along with the increased mitochondrial fission, we found that the reduction in HSPA9 significantly affected the superoxide dismutase 1 levels and contributed to cellular death. These findings enhance our understanding of the intricate mechanisms underlying colitis and contribute to the development of novel therapeutic approaches for this challenging condition.

Imatinib inhibits oral squamous cell carcinoma by suppressing the PI3K/AKT/mTOR signaling pathway.

Oral squamous cell carcinoma (OSCC) is a prevalent oral and maxillofacial cancer with high mortality as OSCC cells readily invade tissues and metastasize to cervical lymph nodes. Although imatinib exhibits potential anticancer and remarkable clinical activities that therapeutically affect several cancer types, its specific impact on OSCC has yet to be fully explored. Therefore, this study investigated the potential anticancer effect of imatinib on OSCC cells and the underlying mechanisms. The Cell Counting Kit-8 was used to determine the impact of imatinib on cell viability. Then, morphological cell proliferation analysis was conducted to examine how imatinib impacted OSCC cell growth. Moreover, OSCC cell migration was determined through wound-healing assays, and colony formation abilities were investigated through the soft agar assay. Lastly, the effect of imatinib on OSCC cell apoptosis was verified with flow cytometry, and its inhibitory mechanism was confirmed through Western blot. Our results demonstrate that imatinib effectively inhibited OSCC cell proliferation and significantly curtailed OSCC cell viability in a time- and concentration-dependent manner. Furthermore, imatinib suppressed migration and colony formation while promoting OSCC cell apoptosis by enhancing p53, Bax, and PARP expression levels and reducing Bcl-2 expression. Imatinib also inhibited the PI3K/AKT/mTOR signaling pathway and induced OSCC cell apoptosis, demonstrating the potential of imatinib as a treatment for oral cancer.

Silibinin induces oral cancer cell apoptosis and reactive oxygen species generation by activating the JNK/c-Jun pathway.

Background: Oral cancer is one of the most prevalent malignant tumors worldwide. Silibinin has been reported to exert therapeutic effects in various cancer models. However, its mechanism of action in oral cancer remains unclear. We aimed to examine the molecular processes underlying the effects of silibinin in oral cancer in vitro and in vivo as well as its potential anticancer effects. Next, we investigated the molecular processes underlying both in vitro and in vivo outcomes of silibinin treatment on oral cancer. Methods: To investigate the effects of silibinin on the growth of oral cancer cells, cell proliferation and anchorage-independent colony formation tests were conducted on YD10B and Ca9-22 oral cancer cells. The effects of silibinin on the migration and invasion of oral cancer cells were evaluated using transwell assays. Flow cytometry was used to examine apoptosis, cell cycle distribution, and accumulation of reactive oxygen species (ROS). The molecular mechanism underlying the anticancer effects of silibinin was explored using immunoblotting. The in vivo effects of silibinin were evaluated using a Ca9-22 xenograft mouse model. Results: Silibinin effectively suppressed YD10B and Ca9-22 cell proliferation and colony formation in a dose-dependent manner. Moreover, it induced cell cycle arrest in the G0/G1 phase, apoptosis, and ROS generation in these cells. Furthermore, silibinin inhibited the migration and invasion abilities of YD10B and Ca9-22 cells by regulating the expression of proteins involved in the epithelial-mesenchymal transition. Western blotting revealed that silibinin downregulated SOD1 and SOD2 and triggered the JNK/c-Jun pathway in oral cancer cells. Silibinin significantly inhibited xenograft tumor growth in nude mice, with no obvious toxicity. Conclusions: Silibinin considerably reduced the development of oral cancer cells by inducing apoptosis, G0/G1 arrest, ROS generation, and activation of the JNK/c-Jun pathway. Importantly, silibinin effectively suppressed xenograft tumor growth in nude mice. Our findings indicate that silibinin may be a promising option for the prevention or treatment of oral cancer.

Veratramine Inhibits the Cell Cycle Progression, Migration, and Invasion via ATM/ATR Pathway in Androgen-Independent Prostate Cancer.

Prostate cancer (PC) is the second leading cause of cancer-related death among men. Treatment of PC becomes difficult after progression because PC that used to be androgen-dependent becomes androgen-independent prostate cancer (AIPC). Veratramine, an alkaloid extracted from the root of the Veratrum genus, has recently been reported to have anticancer effects that work against various cancers; however, its anticancer effects and the underlying mechanism of action in PC remain unknown. We investigated the anticancer effects of veratramine on AIPC using PC3 and DU145 cell lines, as well as a xenograft mouse model. The antitumor effects of veratramine were evaluated using the CCK-8, anchorage-independent colony formation, trans-well, wound healing assays, and flow cytometry in AIPC cell lines. Microarray and proteomics analyses were performed to investigate the differentially expressed genes and proteins induced by veratramine in AIPC cells. A xenograft mouse model was used to confirm the therapeutic response and in vivo efficacy of veratramine. Veratramine dose dependently reduced the proliferation of cancer cells both in vitro and in vivo. Moreover, veratramine treatment effectively suppressed the migration and invasion of PC cells. The immunoblot analysis revealed that veratramine significantly downregulated Cdk4/6 and cyclin D1 via the ATM/ATR and Akt pathways, both of which induce a DNA damage response that eventually leads to G1 phase arrest. In this study, we discovered that veratramine exerted antitumor effects on AIPC cells. We demonstrated that veratramine significantly inhibited the proliferation of cancer cells via G0/G1 phase arrest induced by the ATM/ATR and Akt pathways. These results suggest that veratramine is a promising natural therapeutic agent for AIPC.

Enhanced primary ciliogenesis via mitochondrial oxidative stress activates AKT to prevent neurotoxicity in HSPA9/mortalin-depleted SH-SY5Y cells.

The primary cilium, an antenna-like structure on the cell surface, acts as a mechanical and chemical sensory organelle. Primary cilia play critical roles in sensing the extracellular environment to coordinate various developmental and homeostatic signaling pathways. Here, we showed that the depletion of heat shock protein family A member 9 (HSPA9)/mortalin stimulates primary ciliogenesis in SH-SY5Y cells. The downregulation of HSPA9 enhances mitochondrial stress by increasing mitochondrial fragmentation and mitochondrial reactive oxygen species (mtROS) generation. Notably, the inhibition of either mtROS production or mitochondrial fission significantly suppressed the increase in primary ciliogenesis in HSPA9-depleted cells. In addition, enhanced primary ciliogenesis contributed to cell survival by activating AKT in SH-SY5Y cells. The abrogation of ciliogenesis through the depletion of IFT88 potentiated neurotoxicity in HSPA9-knockdown cells. Furthermore, both caspase-3 activation and cell death were increased by MK-2206, an AKT inhibitor, in HSPA9-depleted cells. Taken together, our results suggest that enhanced primary ciliogenesis plays an important role in preventing neurotoxicity caused by the loss of HSPA9 in SH-SY5Y cells.

Rhein Induces Oral Cancer Cell Apoptosis and ROS via Suppresse AKT/mTOR Signaling Pathway In Vitro and In Vivo.

Oral cancer remains the leading cause of death worldwide. Rhein is a natural compound extracted from the traditional Chinese herbal medicine rhubarb, which has demonstrated therapeutic effects in various cancers. However, the specific effects of rhein on oral cancer are still unclear. This study aimed to investigate the potential anticancer activity and underlying mechanisms of rhein in oral cancer cells. The antigrowth effect of rhein in oral cancer cells was estimated by cell proliferation, soft agar colony formation, migration, and invasion assay. The cell cycle and apoptosis were detected by flow cytometry. The underlying mechanism of rhein in oral cancer cells was explored by immunoblotting. The in vivo anticancer effect was evaluated by oral cancer xenografts. Rhein significantly inhibited oral cancer cell growth by inducing apoptosis and S-phase cell cycle arrest. Rhein inhibited oral cancer cell migration and invasion through the regulation of epithelial-mesenchymal transition-related proteins. Rhein induced reactive oxygen species (ROS) accumulation in oral cancer cells to inhibit the AKT/mTOR signaling pathway. Rhein exerted anticancer activity in vitro and in vivo by inducing oral cancer cell apoptosis and ROS via the AKT/mTOR signaling pathway in oral cancer. Rhein is a potential therapeutic drug for oral cancer treatment.

PCNB exposure during early embryogenic development induces developmental delay and teratogenicity by altering the gene expression in Xenopus laevis.

Pentachloronitrobenzene (PCNB) is an organochlorine fungicide commonly used to treat seeds against seedling infections and controlling snow mold on golf courses. PCNB has been demonstrated to be toxic to living organisms, including fish and several terrestrial organisms. However, only phenotypical deformities have been studied, and the effects of PCNB on early embryogenesis, where primary organogenesis occurs, have not been completely studied. In the current study, the developmental toxicity and teratogenicity of PCNB is evaluated by using frog embryo teratogenesis assay Xenopus (FETAX). Our results confirmed the teratogenic potential of PCNB revealing the teratogenic index of 1.29 during early embryogenesis. Morphological studies revealed tiny head, bent axis, reduced inter ocular distance, hyperpigmentation, and reduced total body lengths. Whole mount in situ hybridization and reverse transcriptase polymerase chain reaction were used to identify PCNB teratogenic effects at the gene level. The gene expression analyses revealed that PCNB was embryotoxic to the liver and heart of developing embryos. Additionally, to determine the most sensitive developmental stages to PCNB, embryos were exposed to the compound at various developmental stages, demonstrating that the most sensitive developmental stage to PCNB is primary organogenesis. Taken together, we infer that PCNB's teratogenic potential affects not just the phenotype of developing embryos but also the associated genes and involving the oxidative stress as a possible mechanism of toxicity, posing a hazard to normal embryonic growth. However, the mechanisms of teratogenesis require additional extensive investigation to be defined completely.

Carnitine Protects against MPP+-Induced Neurotoxicity and Inflammation by Promoting Primary Ciliogenesis in SH-SY5Y Cells.

Primary cilia help to maintain cellular homeostasis by sensing conditions in the extracellular environment, including growth factors, nutrients, and hormones that are involved in various signaling pathways. Recently, we have shown that enhanced primary ciliogenesis in dopamine neurons promotes neuronal survival in a Parkinson's disease model. Moreover, we performed fecal metabolite screening in order to identify several candidates for improving primary ciliogenesis, including L-carnitine and acetyl-L-carnitine. However, the role of carnitine in primary ciliogenesis has remained unclear. In addition, the relationship between primary cilia and neurodegenerative diseases has remained unclear. In this study, we have evaluated the effects of carnitine on primary ciliogenesis in 1-methyl-4-phenylpyridinium ion (MPP+)-treated cells. We found that both L-carnitine and acetyl-L-carnitine promoted primary ciliogenesis in SH-SY5Y cells. In addition, the enhancement of ciliogenesis by carnitine suppressed MPP+-induced mitochondrial reactive oxygen species overproduction and mitochondrial fragmentation in SH-SY5Y cells. Moreover, carnitine inhibited the production of pro-inflammatory cytokines in MPP+-treated SH-SY5Y cells. Taken together, our findings suggest that enhanced ciliogenesis regulates MPP+-induced neurotoxicity and inflammation.

SUMOylation and Major Depressive Disorder.

Since the discovery of the small ubiquitin-like modifier (SUMO) protein in 1995, SUMOylation has been considered a crucial post-translational modification in diverse cellular functions. In neurons, SUMOylation has various roles ranging from managing synaptic transmitter release to maintaining mitochondrial integrity and determining neuronal health. It has been discovered that neuronal dysfunction is a key factor in the development of major depressive disorder (MDD). PubMed and Google Scholar databases were searched with keywords such as 'SUMO', 'neuronal plasticity', and 'depression' to obtain relevant scientific literature. Here, we provide an overview of recent studies demonstrating the role of SUMOylation in maintaining neuronal function in participants suffering from MDD.

20 (S)-ginsenoside Rh2 inhibits colorectal cancer cell growth by suppressing the Axl signaling pathway in vitro and in vivo.

Background: Colorectal cancer (CRC) has a high morbidity and mortality worldwide. 20 (S)-ginsenoside Rh2 (G-Rh2) is a natural compound extracted from ginseng, which exhibits anticancer effects in many cancer types. In this study, we demonstrated the effect and underlying molecular mechanism of G-Rh2 in CRC cells in vitro and in vivo. Methods: Cell proliferation, migration, invasion, apoptosis, cell cycle, and western blot assays were performed to evaluate the effect of G-Rh2 on CRC cells. In vitro pull-down assay was used to verify the interaction between G-Rh2 and Axl. Transfection and infection experiments were used to explore the function of Axl in CRC cells. CRC xenograft models were used to further investigate the effect of Axl knockdown and G-Rh2 on tumor growth in vivo. Results: G-Rh2 significantly inhibited proliferation, migration, and invasion, and induced apoptosis and G0/G1 phase cell cycle arrest in CRC cell lines. G-Rh2 directly binds to Axl and inhibits the Axl signaling pathway in CRC cells. Knockdown of Axl suppressed the growth, migration and invasion ability of CRC cells in vitro and xenograft tumor growth in vivo, whereas overexpression of Axl promoted the growth, migration, and invasion ability of CRC cells. Moreover, G-Rh2 significantly suppressed CRC xenograft tumor growth by inhibiting Axl signaling with no obvious toxicity to nude mice. Conclusion: Our results indicate that G-Rh2 exerts anticancer activity in vitro and in vivo by suppressing the Axl signaling pathway. G-Rh2 is a promising candidate for CRC prevention and treatment.

Knockdown of Maged1 inhibits cell cycle progression and causes cell death in mouse embryonic stem cells.

Mouse embryonic stem cells (mESCs) are characterized by self-renewal and pluripotency and can undergo differentiation into the three germ layers (ectoderm, mesoderm, and endoderm). Melanoma-associated antigen D1 (Maged1), which is expressed in all developing and adult tissues, modulates tissue regeneration and development. In the present study, we examined the expression and function of Maged1 in mESCs. Maged1 protein and mRNA expression increased during mESC differentiation. The pluripotency of mESCs was significantly reduced through extracellular signal-regulated kinase 1/2 phosphorylation upon knockdown of Maged1, and through G1 cell cycle arrest during cell division, resulting in significantly reduced mESC proliferation. Moreover, the diameter of the embryoid bodies was significantly reduced, accompanied by increased levels of ectodermal differentiation markers and decreased levels of mesodermal and endodermal differentiation markers. Maged1-knockdown mESC lines showed significantly reduced teratoma volumes and inhibition of teratoma formation in nude mice. Additionally, we observed increased ectodermal markers but decreased mesodermal and endodermal markers in teratoma tissues. These findings show that Maged1 affects mESC pluripotency, proliferation, cell cycle, and differentiation, thereby contributing to our understanding of the basic molecular biological mechanisms and potential roles of Maged1 as a regulator of various mESC properties.

Protective Effect of GIP against Monosodium Glutamate-Induced Ferroptosis in Mouse Hippocampal HT-22 Cells through the MAPK Signaling Pathway.

The effect of glucose-dependent insulinotropic polypeptide (GIP) on cells under oxidative stress induced by glutamate, a neurotransmitter, and the underlying molecular mechanisms were assessed in the present study. We found that in the pre-treatment of HT-22 cells with glutamate in a dose-dependent manner, intracellular ROS were excessively generated, and additional cell damage occurred in the form of lipid peroxidation. The neurotoxicity caused by excessive glutamate was found to be ferroptosis and not apoptosis. Other factors (GPx-4, Nrf2, Nox1 and Hspb1) involved in ferroptosis were also identified. In other words, it was confirmed that GIP increased the activity of sub-signalling molecules in the process of suppressing ferroptosis as an antioxidant and maintained a stable cell cycle even under glutamate-induced neurotoxicity. At the same time, in HT-22 cells exposed to ferroptosis as a result of excessive glutamate accumulation, GIP sustained cell viability by activating the mitogen-activated protein kinase (MAPK) signalling pathway. These results suggest that the overexpression of the GIP gene increases cell viability by regulating mechanisms related to cytotoxicity and reactive oxygen species production in hippocampal neuronal cell lines.

Ginger-derived compounds exert in vivo and in vitro anti-asthmatic effects by inhibiting the T-helper 2 cell-mediated allergic response.

6-Shogaol (SHO) and 6-gingerol (GIN), naturally derived compounds of ginger (Zingiber officinale Roscoe), have been found to have anti-allergic effects on dermatitis-like skin lesions and rhinitis. Although SHO and GIN have demonstrated a potential in various inflammatory diseases, their efficacy and mechanism in asthma have not been largely examined. Therefore, the present study demonstrated the anti-asthmatic effects of SHO and GIN on the T-helper (Th) 2 cell-mediated allergic response pathway in an ovalbumin (OVA)-induced asthma mouse model. The asthma mouse model was established with an intraperitoneal (i.p.) injection of 50 µg OVA and 1 mg aluminum hydroxide with or without an i.p. injection of SHO and GIN (10 mg/kg) before treatment with OVA. In addition, the current study assessed mast cell degranulation in antigen-stimulated RBL-2H3 cells under different treatment conditions (SHO or GIN at 0, 10, 25, 50 and 100 nM) and determined the mRNA and protein levels of anti-oxidative enzymes [superoxide dismutase (SOD)1, SOD2, glutathione peroxidase-1/2, catalase] in lung tissues. SHO and GIN inhibited eosinophilia in the bronchoalveolar lavage fluids and H&E-stained lung tissues. Both factors also decreased mucus production in periodic acid-Schiff-stained lung tissues and the levels of Th2 cytokines in these tissues. GIN attenuated oxidative stress by upregulating the expression levels of anti-oxidative proteins. In an in vitro experiment, the degranulation of RBL-2H3 rat mast cells was significantly decreased. It was found that SHO and GIN effectively suppressed the allergic response in the mouse model by inhibiting eosinophilia and Th2 cytokine production. Collectively, it was suggested that SHO can inhibit lung inflammation by attenuating the Th2 cell-mediated allergic response signals, and that GIN can inhibit lung inflammation and epithelial cell remodeling by repressing oxidative stress. Therefore, SHO and GIN could be used therapeutically for allergic and eosinophilic asthma.