Expression Of p-ERK Research Articles

Mesencephalic astrocyte-derived neurotrophic factor upregulates CHOP and ATF6 in the rat retina with retinitis pigmentosa

ABSTRACT Purpose In the current work, we investigated the potential protective function of MANF against the degeneration of RP in S334ter-3 rats and the mechanism underlying these effects. Methods The left eye of rat was injected with MANF, and the right eye injected PBS as a control. The levels of those ER stress associated proteins were determined by western blot analysis. Results First, those ER stress associated proteins were detected in S334ter-3 rats. Among these proteins, a decrease in the expression of PERK was only showed from PD 6 to PD 12. Surprisingly, a dramatic increase of ATF6 was induced by injection MANF. Then, the expression of ATF6 protein declined rapidly to the control eye. Furthermore, a remarkable increase in the expression of CHOP was examined at 6 h, which peaked at 12 h and maintained the level until 48 h. At the same time, CHOP was detected in Müller cells but not in photoreceptor; nevertheless, photoreceptor survival clearly improved. The increasing expressions of CHOP and ATF6 in SD rats were similar to the changes in S33ter-3 rats after injection MANF. Conclusions These results indicate that MANF may play an important role in protecting photoreceptor degeneration in RP.

Exacerbated endoplasmic reticulum stress transmitted by endometrial stromal cells alters the conditioning of tolerogenic dendritic cells affecting trophoblast migration.

Endometrial stromal cells acquire a secretory profile associated with endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) related to the onset of a sterile inflammatory response essential for sustaining embryo implantation. However, exacerbated stromal ERS/UPR is associated with reproductive complications. Given the ability of dendritic cells (DCs) to sense stress signals and be conditioned by stromal cells, here we investigated the transmission of ERS (TERS) from stromal cells to monocytes and its impact on tolerogenic DCs conditioning. Blood monocytes were differentiated into DCs (rhGM-CSF+rhIL-4, 5 d) in the presence or absence of conditioned media derived from either thapsigargin-treated (stressed) or nonstressed human endometrial stromal cell line. Soluble factors released by stressed stromal cells impaired CD1a+CD14- DC differentiation and induced a proinflammatory profile, increasing the CD86high cell population, COX-2 expression, and tumor necrosis factor (TNF)-α, interleukin (IL)-8 and IL-1β secretion. Additionally, TERS was observed in these cultures, with increased expression of IRE1α, PERK, and ATF4. Even the splicing of the adaptive UPR marker XBP1 was increased though at low levels, its nuclear translocation was unchanged. These effects on spliced XBP1, coupled with a decreased GRP78/BiP and heightened CHOP expression, suggest the triggering of terminal UPR over adaptive UPR, confirmed by the induction of lytic cell death in stressed cultures. Finally, exacerbated TERS negatively impacted trophoblast migration in a blastocyst-like spheroid in vitro model. These findings suggest that exacerbated stromal ERS can be transmitted to monocytes, altering their differentiation, immune profile, and viability, which could ultimately impair trophoblast migration.

Paricalcitol, an active vitamin D analog, mitigates dexamethasone-induced hepatic injury: Role of autophagy, pyroptosis, and PERK/Nrf2/HO-1 signaling pathway.

Paricalcitol, an active vitamin D analog, mitigates dexamethasone-induced hepatic injury: Role of autophagy, pyroptosis, and PERK/Nrf2/HO-1 signaling pathway.

Pembrolizumab in combination with binimetinib in patients with unresectable locally advanced or metastatic triple-negative breast cancer.

Activation of the RAS/MAPK pathway is associated with reduced tumor-infiltrating lymphocytes and poor outcomes in triple-negative breast cancer (TNBC). Previous studies demonstrated that inhibition of the MAPK pathway with a MEK inhibitor is synergistic with immune checkpoint inhibitors. We conducted a phase I/II trial of pembrolizumab and binimetinib in patients with metastatic TNBC with ≤ 3 prior lines of therapy. There were two dose levels (DL) with binimetinib at 45 mg at DL 0 and 30 mg at DL -1. The recommended phase II dose was the standard dose of pembrolizumab with binimetinib 30 mg twice daily. The objective response rate (ORR) was 30.4%, with a numerically higher ORR in patients without liver metastasis at 45.5%. Among patients who achieved objective responses, 80% had a duration of response > 12 months and ongoing even after stopping treatment (5.4 - 69.0 months). Patients with PD-L1-positive tumors (CPS ≥ 10) were more likely to respond with an ORR of 66.7%. However, clinical benefit was observed in 25% of patients with PD-L1-negative tumors. Consistent with preclinical studies, 4 out of 6 patients with clinical benefit had either increased PD-L1 or decreased p-ERK expressions in serial circulating cancer-associated macrophage-like cells (CAMLs) after starting binimetinib. Pembrolizumab and binimetinib at 30 mg are safe with manageable toxicities. Promising activity was observed in patients without liver metastases. Future larger clinical trials are warranted to further evaluate the efficacy of this chemotherapy-free combination.

The concerted actions of microRNA-29a and interferon-β modulate complete Freund's adjuvant-induced inflammatory pain by regulating the expression of type 1 interferon receptor, interferon-stimulated gene 15, and p-extracellular signal-regulated kinase.

The concerted actions of microRNA-29a and interferon-β modulate complete Freund's adjuvant-induced inflammatory pain by regulating the expression of type 1 interferon receptor, interferon-stimulated gene 15, and p-extracellular signal-regulated kinase.

Effect of the glucagon-like peptide-1 receptor agonists dulaglutide on kidney outcomes in db/db mice.

Effect of the glucagon-like peptide-1 receptor agonists dulaglutide on kidney outcomes in db/db mice.

Electric-field induced sleep promotion and lifespan extension in Gaucher's disease model flies.

Electric-field induced sleep promotion and lifespan extension in Gaucher's disease model flies.

The anti-inflammatory effects of paeonol from Cynanchum paniculatum extracts on LPS-induced macrophage RAW 264.7cells and Helicobacter pylori-infected gastrointestinal mucosal damaged zebrafish.

The anti-inflammatory effects of paeonol from Cynanchum paniculatum extracts on LPS-induced macrophage RAW 264.7cells and Helicobacter pylori-infected gastrointestinal mucosal damaged zebrafish.

PD98059 inhibit the proliferation and differentiation of osteoblasts in the formation of tympanosclerosis via ERK1/2-MAPK signaling pathway.

PD98059 inhibit the proliferation and differentiation of osteoblasts in the formation of tympanosclerosis via ERK1/2-MAPK signaling pathway.

Sigma-1 receptor agonist PRE-084 increases BDNF by activating the ERK/CREB pathway to rescue learning and memory impairment caused by type II diabetes.

Sigma-1 receptor agonist PRE-084 increases BDNF by activating the ERK/CREB pathway to rescue learning and memory impairment caused by type II diabetes.

Impact of Benzo(a)pyrene and Pyrene Exposure on Activating Autophagy and Correlation with Endoplasmic Reticulum Stress in Human Astrocytes.

Benzo(a)pyrene (B(a)P) and pyrene, the most prominent subtypes of polycyclic aromatic hydrocarbons (PAHs), contaminate environments as organic pollutants. They adversely affect body systems, including degeneration of the central nervous system. This study investigated the in vitro toxic effects of B(a)P and pyrene on proliferation, endoplasmic reticulum (ER) stress induction, and autophagy in human astrocytes using U-87 MG human astrocytoma cells as a model. Both B(a)P and pyrene were toxic to U-87 MG cells in a concentration-dependent manner. Astrocytic proliferation was interfered with, enhancing S-phase cell cycle arrest. B(a)P promoted the presence of autophagic vesicles and the expression of autophagic markers LC3, beclin-1, and p62, suggesting activated autophagy. B(a)P enhanced the expression of ER stress markers BiP, PERK, and IRE1. ER stress appeared to be correlated with autophagy induction, as demonstrated by experiments using chloroquine, an autophagy inhibitor. Pyrene enhanced the expression of autophagic markers and ER stress primarily via PERK activation, although autophagic vesicles were not observed. The study demonstrates that B(a)P enhances ER stress-mediated autophagy more evidently than pyrene and affected toxicity to astrocytes. These results provide a basis for understanding the toxic effects of the main PAH substances affecting astrocytes.

Inhibition of hemangioma development by regulating the VEGF/VEGFR autocrine loop via the miR-494/PTEN pathway

BackgroundInfantile hemangioma (IH) is the most common type of benign vascular tumor found in infants and young children. Hemangioma-derived endothelial cells within the lesion from birth to three months of age are the primary characteristic of IH. (hemangioma-derived endothelial cells, HemECs) proliferated rapidly and formed hemangioma masses, most of which gradually regressed spontaneously within the next 1 to 5 years of age and continued to improve until the age of 6 to 12 years. But 10–15% of IH cases can still result in ulcerative, obstructive, deformity, and even potentially fatal consequences and sequelae. These conditions seriously affect children's physical and mental health as well as their growth and development, necessitating prompt and efficient medical attention of IH is known.ObjectiveThe purpose of this work. HemECs are crucial to the development of IH as a result. Not all of the pathophwork is to examine the impact of OMT on HemECs, with a specific emphasis on its role in cell migration, proliferation, cell cycle regulation, and apoptosis. Additionally, we will research the influence of OMT on the VEGFA/VEGFR-2 signaling pathway in HemECs and assess the impact of OMT on the miR-494/PTEN axis.MethodsThe Cell Counting Kit-8 (CCK-8) assay was employed to evaluate the influence of Oxymatrine (OMT) on the proliferation of Hemangioma Endothelial Cells (HemECs). The Transwell Assay was employed to detect cell invasion and migration. The cell cycle and apoptosis were analyzed through flow cytometry. The impact of OMT on the expression of apoptosis markers (cleaved caspase-3) and proteins associated with the cell cycle (Cyclin D1, Bcl-2, Bax) was examined using Western Blot and Reverse Transcription Polymerase Chain Reaction (RT-PCR).ResultsOMT treatment significantly inhibited the proliferation of HemECs, especially when combined with the miR-494 inhibitor. Additionally, OMT administration raised the proportion of cells entering the G2 phase, accelerated apoptosis, and decreased HemECs' capacity for migration and invasion. The results of Western Blot and RT-PCR demonstrated that OMT decreased the expression levels of Bax and Cleaved Caspase-3 while increasing the expression of Bcl-2 and Cyclin D1. OMT and miR-494 inhibitors have distinct impacts on the phosphorylated versions of VEGFR-2, PTEN, and ERK signaling pathways. OMT may control cell survival and proliferation through the miR-494/PTEN pathway, as evidenced by the fact that PTEN expression was dramatically upregulated in the miR-1297 inhibitor with OMT treatment group, while p-ERK expression was markedly reduced in that group.ConclusionsOMT effectively inhibits the growth, migration, and apoptosis of hemangioma endothelial cells, likely by regulating key proteins involved in the cell cycle and apoptosis. The combination with miR-494 inhibitors enhances its therapeutic effect, suggesting a potential new approach for hemangioma treatment. These findings support the development of OMT-based strategies for hemangiomas and its potential use in cancer therapy.

A novel therapeutic approach targeting PD-L1 in HNSCC and bone marrow-derived mesenchymal stem cells hampers pro-metastatic features in vitro: perspectives for blocking tumor-stroma communication and signaling

BackgroundCurrent conventional treatment regimens for head and neck squamous cell carcinoma (HNSCC), are poorly effective because of the emergence of resistance mechanisms. Many studies have reported how the tumor microenvironment influences tumor response to immune checkpoint inhibitors targeting PD-1/PD-L1. It has been reported that overexpression of PD-L1 correlates with and is involved in cancer progression by promoting epithelial-to-mesenchymal-transition (EMT) program, stemness and tumor cell invasiveness through AKT and MAPK pathways. In this study, we investigated how bone marrow mesenchymal stem cells (BM-MSCs) recruited and educated by HNSCC cells are able to promote tumor cell invasion and EMT program. In addition, we analyzed how the crosstalk between stromal cells and tumor cells can affect PD-L1 expression levels. In this context, we developed and characterized a novel anti-PD-L1 recombinant Fab (rFab’) and tested its ability to potentiate the effect of cisplatin.MethodsBM-MSCs and HNSCC cells co-cultures, cell migration and invasion were performed using Boyden chambers. The effect of treatments on cell viability and growth were analyzed by MTT and clonogenic assay, respectively. The anti-PD-L1 rFab’ was prepared in E. Coli and tested for its binding on HNSCC cells and BM-MSCs by FACS analysis and fluorescence microscopy. PD-L1, p-AKT, p-ERK, N-cadherin and β-catenin expression levels were analyzed by western blotting.ResultsBM-MSCs were induced by tumor cells to migrate, invade and to trans-differentiate in cancer associated fibroblasts (CAFs) as demonstrated by increased expression levels of α-SMA and FAP-α. BM-MSCs contributed to HNSCC invasiveness by increasing p-AKT, p-ERK, N-cadherin and β-catenin expression levels. When BM-MSCs and HNSCC cells were co-cultured the level of PD-L1 expression was enhanced in both cells indicating a reciprocal support in favoring tumor aggressiveness. Tumor cell treatment with rFab’ anti-PD-L1 reduced their viability, growth, migration and invasion and blunted the underlying signaling pathways. In addition, rFab’ anti-PD-L1 was able to potentiate the antitumor effect of cisplatin on HNSCC cells.ConclusionsBM-MSCs recruited and educated by HNSCC cells support tumor cell aggressiveness via PD-L1. A novel rFab’ anti-PD-L1 reduces HNSCC proliferation, migration and invasion and potentiates the cisplatin effect suggesting its potential to be conjugated with drugs for immuno-cytotoxic therapy.

HSV-1 inhibits melanogenesis of PIG1 cells through downregulation of VN1R5/ERK pathway.

Herpes simplex virus type 1 (HSV-1) is an ubiquitous pathogen that can infect humans through skin or mucous regions. This study was to explore the effects and underlying mechanism of HSV-1 as examined within the human epidermal melanocyte cell line, PIG1. Our results showed that following HSV-1 infection, PIG1 cells shrank and acquired a rounded shape, while the numbers and lengths of their dendrites decreased and melanogenesis was inhibited. Meanwhile, the HSV-1 receptors (nectin-1, herpes virus entry mediator, paired immunoglobulin-like type 2 receptor alpha) and phospho-extracellular signal-regulating kinase (p-ERK) were all substantially decreased, while vomeronasal type-1 receptor 5 (VN1R5) increased. Results of RNA interference and protein inhibitor assays revealed that knockdown of VN1R5 increased the expression of p-ERK and microphthalmia-associated transcription factor (MITF), while an inhibition of ERK decreased VN1R5 expression. Taken together, our study provides the first evidence that HSV-1 can infect human normal melanocytes and inhibit melanogenesis through VN1R5/ERK pathway.

Baicalin Decreases the LPS-Induced Intestine Inflammatory Responses by ROS/p-ERK/p-P38 Signal Pathways In Vivo and In Vitro.

Background: This study aimed to investigate the role of ROS/MAPK signaling pathways and the effects of baicalin in LPS-induced inflammatory responses in mice and porcine intestinal epithelial cells (IPEC-J2). Methods: In vivo, 18 male C57BL/6J mice were randomly divided into three groups (n = 6): control, LPS (3.5 mg/kg LPS administered intraperitoneally [ip] on day 7), and baicalin (200 mg/kg orally for 7 days, with LPS ip on day 7). On day 8, mice were sacrificed, and jejunal tissues were collected for H&E staining. ROS levels in serum and cytokine protein expressions (TNF-α and IL-6) in the jejunum were measured via ELISA, while intestinal MAPK proteins were analyzed using Western blotting. In vitro, the study involved two experimental setups: NAC (a ROS scavenger) and baicalin. For the NAC experiment, IPEC-J2 cells were divided into three groups: control, LPS, and NAC. In the LPS group, cells were treated with LPS (40 μg/mL) for 1 h. In the NAC group, cells were pretreated with NAC prior to LPS exposure. For the baicalin experiment, IPEC-J2 cells were divided into five groups: control, LPS, and baicalin at low (10 μM), medium (20 μM), and high (40 μM) doses. Cells were pretreated with baicalin for 24 h before LPS exposure. ROS/LDH levels and cytokine expressions in the supernatant were determined via ELISA, and MAPK protein expressions were assessed using Western blotting. Results: In vivo, LPS-induced oxidative stress and inflammatory responses in the intestine, reduced the villus height-to-crypt ratio, and significantly increased protein expressions of p-ERK, p-P38, JNK, and p-JNK (p < 0.05). Baicalin treatment significantly inhibited serum ROS levels (p < 0.01), reduced jejunal cytokine expressions (TNF-α and IL-6, p < 0.05), improved intestinal structural damage, and decreased p-ERK, p-P38, and p-JNK protein expressions (p < 0.05). In vitro, NAC significantly reduced ROS levels (p < 0.01), cytokine expressions (TNF-α and IL-6), and MAPK activation (ERK, JNK, P38, and their phosphorylated forms, p < 0.05). Baicalin also significantly decreased ROS (p < 0.05), TNF-α (p < 0.05), IL-6 (p < 0.05), and MAPK protein expressions (ERK, p-ERK, and p-P38, p < 0.05). Molecular docking demonstrated that baicalin effectively bound to ERK and P38 proteins. Conclusions: Baicalin mitigated LPS-induced inflammatory responses via the ROS/p-ERK/p-P38 signaling pathway in vivo and in vitro.

Repurposing bosentan as an anticancer agent: EGFR/ERK/c-Jun modulation inhibits NSCLC tumor growth.

Drug repurposing of well-established drugs to be targeted against lung cancer has been a promising strategy. Bosentan is an endothelin 1 (ET-1) blocker widely used in pulmonary hypertension. The current experiment intends to inspect the anticancer and antiangiogenic mechanism of bosentan targeting epidermal growth factor receptor (EGFR) /extra-cellular Signal Regulated Kinase (ERK) /c-Jun/vascular endothelial growth factor (VEGF) carcinogenic pathway. BALB/c mice were randomized into four groups, the first received the vehicle, the second received 100 mg/kg oral bosentan alone, the third has non-small cell lung cancer (NSCLC) induced by two doses of 1.5g/kg urethane i.p. and finally the fourth has NSCLC received bosentan. To determine the anti-proliferative impact of bosentan, cytokeratin 19 fragments (CYFRA 21-1) level was assessed, and Ki-67 positive cells were counted by immunohistochemical (IHC). Molecular expression of EGFR via IHC, relative expression of p-ERK1/2 and p-c-Jun via western blotting and caspase 3, Bcl-2 Associated X-protein (BAX)/B-cell lymphoma 2 (Bcl-2) ratio and VEGF via ELISA were quantified. Bosentan showed pronounced improvement in lung index and histopathological examinations. Bosentan exerted a noticeable arrest of lung cancer growth indicated by the attenuation of CYFRA 21-1 and Ki-67 positive cell counts besides the boost of BAX/Bcl-2 ratio and caspase 3. Bosentan induced a remarkable decline of EGFR, T-ERK1/2/p-ERK1/2, T-c-Jun/p-c-Jun, and VEGF. Bosentan induced cytotoxic and anti-angiogenic impact through regulation of EGFR/ERK/c-Jun/VEGF axis suggesting its potential therapeutic impact against lung cancer.

Antitumor Effects of Tryptanthrin on Colorectal Cancer by Regulating the Mitogen-Activated Protein Kinase Signaling Pathway and Targeting Topo I and IDO1.

Tryptanthrin (TRYP) is an indole quinazoline alkaloid with a range of pharmaceutical activities, but the specific mechanism of TRYP against colorectal cancer (CRC) remains obscure. The purpose of this study was to evaluate the antitumor effects of TRYP on CRC models both in vitro and in vivo and further analyze its concrete mechanisms. The results of the in vitro experiment show that TRYP effectively inhibited the proliferation and migration of SW620 cells, arrested the cell cycle at the S phase, and induced cell apoptosis. Deeply, TRYP dramatically increased the expression of Bax and cleaved caspase 3 while decreasing the expression of Bcl-2. The results of transcriptome sequencing implied that the inhibitory effects of TRYP were closely related to the mitogen-activated protein kinase (MAPK) signaling pathway, and the results of western blotting verified that TRYP could decrease the expression of p-Erk and increase the expression of p-p38 and p-Jnk. Besides, our results identified that topoisomerase I (Topo I) and indole amine 2,3-dioxygenase 1 (IDO1) were the targets of TRYP. In vivo, the results showed that different TRYP doses significantly inhibited tumor growth in mice, induced different degrees of necrosis in tumor tissues, decreased the expression level of Ki67 protein, and increased the apoptotic signal in tumor tissues. The findings demonstrated the inhibitory effects of TRYP on CRC, and the mechanisms were tightly connected to inhibiting the activity of Topo I and IDO1 and regulating the expression of the MAPK signaling pathway. Especially, it was first identified that TRYP could directly inhibit Topo I to arrest SW620 at the S phase. Therefore, this work established a scientific basis for the development of TRYP.

Endoplasmic reticulum stress in the salivary glands of patients with primary and associated Sjögren’s disease, and non-Sjögren’s sicca syndrome: a comparative analysis and the influence of chloroquine

BackgroundEndoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) are adaptive mechanisms for conditions of high protein demand, marked by an accumulation of misfolded proteins in the endoplasmic reticulum (ER). Rheumatic autoimmune diseases (RAD) are known to be associated with chronic inflammation and an ERS state. However, the activation of UPR signaling pathways is not completely understood in Sjögren’s disease (SD). This study evaluated the expression of ERS-related genes in glandular tissue of patients with primary SD (pSD), associated SD (aSD) with other autoimmune diseases, and non-Sjögren sicca syndrome (NSS).MethodsIn a cross-sectional study, minor salivary gland biopsies were obtained from 44 patients with suspected SD and 13 healthy controls (HC). Patients were classified as pSD, aSD, or NSS based on clinical, serological, and histological assessment. Histopathological analysis and mRNA expression analysis of genes associated with ERS and UPR (PERK, XBP1, ATF-6, ATF-4, CANX, CALR, CHOP, and BIP) were performed on the samples. Differences between groups (pSD, aSD, NSS, and HC) were assessed. The influence of chloroquine (CQ) on the ER was also investigated.ResultsTwenty-eight SD patients showed increased expression of PERK (p = 0.0117) and XBP1 (p = 0.0346), and reduced expression of ATF-6 (p = 0.0003) and CHOP (p = 0.0003), compared to the HC group. Increased expression of BIP (p < 0.0001), PERK (p = 0.0003), CALR (p < 0.0001), and CANX (p = 0.0111) was also observed in the SD group compared to the NSS group (n = 16). Patients receiving CQ (n = 16) showed a significant increase in ATF-6 (p = 0.0317) compared to patients not taking the medication (n = 29).ConclusionsAltogether, the results suggest a greater activation of the ERS and UPR genes in patients with SD, especially in the pSD group. Antimalarial drugs, like CQ, used to treat RAD, may affect the ER function in exocrine glands.

Effects of Bifidobacterium lactis BLa80 on fecal and mucosal flora and stem cell factor/c-kit signaling pathway in simulated microgravity rats.

Simulated microgravity environment can lead to gastrointestinal motility disturbance. The pathogenesis of gastrointestinal motility disorders is closely related to the stem cell factor (SCF)/c-kit signaling pathway associated with intestinal flora and Cajal stromal cells. Moreover, intestinal flora can also affect the regulation of SCF/c-kit signaling pathway, thus affecting the expression of Cajal stromal cells. Cajal cells are the pacemakers of gastrointestinal motility. To investigate the effects of Bifidobacterium lactis (B. lactis) BLa80 on the intestinal flora of rats in simulated microgravity and on the gastrointestinal motility-related SCF/c-kit pathway. The internationally recognized tail suspension animal model was used to simulate the microgravity environment, and 30 rats were randomly divided into control group, tail suspension group and drug administration tail suspension group with 10 rats in each group for a total of 28 days. The tail group was given B. lactis BLa80 by intragastric administration, and the other two groups were given water intragastric administration, the concentration of intragastric administration was 0.1 g/mL, and each rat was 1 mL/day. Hematoxylin & eosin staining was used to observe the histopathological changes in each segment of the intestine of each group, and the expression levels of SCF, c-kit, extracellular signal-regulated kinase (ERK) and p-ERK in the gastric antrum of each group were detected by Western blotting and PCR. The fecal flora and mucosal flora of rats in each group were detected by 16S rRNA. Simulated microgravity resulted in severe exfoliation of villi of duodenum, jejunum and ileum in rats, marked damage, increased space between villi, loose arrangement, shortened columnar epithelium of colon, less folds, narrower mucosal thickness, reduced goblet cell number and crypts, and significant improvement after probiotic intervention. Simulated microgravity reduced the expressions of SCF and c-kit, and increased the expressions of ERK and P-ERK in the gastric antrum of rats. However, after probiotic intervention, the expressions of SCF and c-kit were increased, while the expressions of ERK and P-ERK were decreased, with statistical significance (P < 0.05). In addition, simulated microgravity can reduce the operational taxonomic unit (OTU) of the overall intestinal flora of rats, B. lactis BLa80 can increase the OTU of rats, simulated microgravity can reduce the overall richness and diversity of stool flora of rats, increase the abundance of firmicutes in stool flora of rats, and reduce the abundance of Bacteroides in stool flora of rats, most of which are mainly beneficial bacteria. Simulated microgravity can increase the overall richness and diversity of mucosal flora, increase the abundance of Bacteroides and Desulphurides in the rat mucosal flora, and decrease the abundance of firmicutes, most of which are proteobacteria. After probiotics intervention, the overall Bacteroidetes trend in simulated microgravity rats was increased. B. lactis BLa80 can ameliorate intestinal mucosal injury, regulate intestinal flora, inhibit ERK expression, and activate the SCF/c-kit signaling pathway, which may have a facilitating effect on gastrointestinal motility in simulated microgravity rats.

Elucidating the anticancer potential of dendrobine in renal cell carcinoma treatment.

Renal cell carcinoma (RCC) is the predominant form of kidney cancer. Despite the significant improvements in survival rates for advanced RCC patients due to targeted therapy and immunotherapy, challenges such as drug resistance and severe adverse reactions continue to hinder effective management. Therefore, there is an urgent need to identify new therapeutic agents for RCC. Natural products, derived from plants, animals, and microorganisms, are increasingly recognized for their potential in treating complex diseases such as cancer. Dendrobine, a natural product extracted from Dendrobium, holds significant anticancer potential. However, its role in anti-RCC therapy remains poorly understood. This study applied network pharmacology to explore the role of Dendrobine in RCC treatment, identifying STAT3 as a key target. Furthermore, a series of in vitro experiments confirmed that Dendrobine inhibits RCC cell growth. CCK-8 assays demonstrated that Dendrobine inhibits RCC cell viability in a concentration-dependent manner, with an IC50 of 142.5μM for 786-O cells and 146.5μM for A498 cells. Clonogenic formation assays and EdU staining confirmed that Dendrobine suppresses RCC cell proliferation. Wound healing and invasion assays showed that Dendrobine inhibits RCC cell migration and invasion. Hoechst 33342/PI co-staining demonstrated that Dendrobine induces apoptosis in RCC cells. Mechanistically, Western blot analysis revealed that Dendrobine targets the PI3K/Akt signaling pathway by inhibiting the expression of p-PI3K, p-Akt, and p-Erk. Overall, this study seeks to elucidate the underlying pharmacological mechanisms and provide new insights for potential therapeutic strategies in RCC.