Mathematical Modeling and Inference of Epidermal Growth Factor-Induced Mitogen-Activated Protein Kinase Cell Signaling Pathways.

The mitogen-activated protein kinase (MAPK) pathway is an important intracellular signaling cascade that plays a key role in various cellular processes. Understanding the regulatory mechanisms of this pathway is essential for developing effective interventions and targeted therapies for related diseases. Recent advances in single-cell proteomic technologies have provided unprecedented opportunities to investigate the heterogeneity and noise within complex, multi-signaling networks across diverse cells and cell types. Mathematical modeling has become a powerful interdisciplinary tool that bridges mathematics and experimental biology, providing valuable insights into these intricate cellular processes. In addition, statistical methods have been developed to infer pathway topologies and estimate unknown parameters within dynamic models. This review presents a comprehensive analysis of how mathematical modeling of the MAPK pathway deepens our understanding of its regulatory mechanisms, enhances the prediction of system behavior, and informs experimental research, with a particular focus on recent advances in modeling and inference using single-cell proteomic data.

Hypermigration of macrophages through the concerted action of GRA effectors on NF-κB/p38 signaling and host chromatin accessibility potentiates Toxoplasma dissemination.

Mononuclear phagocytes facilitate the dissemination of the obligate intracellular parasite Toxoplasma gondii. Here, we report how a set of secreted parasite effector proteins from dense granule organelles (GRA) orchestrates dendritic cell-like chemotactic and pro-inflammatory activation of parasitized macrophages. These effects enabled efficient dissemination of the type II T. gondii lineage, a highly prevalent genotype in humans. We identify novel functions for effectors GRA15 and GRA24 in promoting CCR7-mediated macrophage chemotaxis by acting on NF-κB and p38 mitogen-activated protein kinase signaling pathways, respectively, with contributions by GRA16/18 and counter-regulation by effector TEEGR. Furthermore, GRA28 boosted chromatin accessibility and GRA15/24/NF-κB-dependent transcription at the Ccr7 gene locus in primary macrophages. In vivo, adoptively transferred macrophages infected with wild-type T. gondii outcompeted macrophages infected with a GRA15/24 double mutant in migrating to secondary organs in mice. The data show that T. gondii, rather than being passively shuttled, actively promotes its dissemination by inducing a finely regulated pro-migratory state in parasitized human and murine phagocytes via co-operating polymorphic GRA effectors. IMPORTANCE: Intracellular pathogens can hijack the cellular functions of infected host cells to their advantage, for example, for intracellular survival and dissemination. However, how microbes orchestrate the hijacking of complex cellular processes, such as host cell migration, remains poorly understood. As such, the common parasite Toxoplasma gondii actively invades the immune cells of humans and other vertebrates and modifies their migratory properties. Here, we show that the concerted action of a number of secreted effector proteins from the parasite, principally GRA15 and GRA24, acts on host cell signaling pathways to activate chemotaxis. Furthermore, the protein effector GRA28 selectively acted on chromatin accessibility in the host cell nucleus to selectively boost host gene expression. The joint activities of GRA effectors culminated in pro-migratory signaling within the infected phagocyte. We provide a molecular framework delineating how T. gondii can orchestrate a complex biological phenotype, such as the migratory activation of phagocytes to boost dissemination.

Comprehensive Review on Bimolecular Fluorescence Complementation and Its Application in Deciphering Protein-Protein Interactions in Cell Signaling Pathways.

Signaling pathways are responsible for transmitting information between cells and regulating cell growth, differentiation, and death. Proteins in cells form complexes by interacting with each other through specific structural domains, playing a crucial role in various biological functions and cell signaling pathways. Protein-protein interactions (PPIs) within cell signaling pathways are essential for signal transmission and regulation. The spatiotemporal features of PPIs in signaling pathways are crucial for comprehending the regulatory mechanisms of signal transduction. Bimolecular fluorescence complementation (BiFC) is one kind of imaging tool for the direct visualization of PPIs in living cells and has been widely utilized to uncover novel PPIs in various organisms. BiFC demonstrates significant potential for application in various areas of biological research, drug development, disease diagnosis and treatment, and other related fields. This review systematically summarizes and analyzes the technical advancement of BiFC and its utilization in elucidating PPIs within established cell signaling pathways, including TOR, PI3K/Akt, Wnt/ß-catenin, NF-κB, and MAPK. Additionally, it explores the application of this technology in revealing PPIs within the plant hormone signaling pathways of ethylene, auxin, Gibberellin, and abscisic acid. Using BiFC in conjunction with CRISPR-Cas9, live-cell imaging, and ultra-high-resolution microscopy will enhance our comprehension of PPIs in cell signaling pathways.

Unveiling the Promising Role of Substance P/Neurokinin 1 Receptor in Cancer Cell Proliferation and Cell Cycle Regulation in Human Malignancies.

Neurokinin receptors are a family of G protein-coupled receptors that were first identified in the central and peripheral nervous systems. However these receptors were later found in other types of cells, therefore, new perspectives concerning their novel roles were described. Mammalian has three neurokinin receptors, among which neurokinin-1 receptors [NK1R] have been indicated to be involved in most, if not all, intracellular functions, primarily the regulation of cell proliferation. By interacting with its potent agonist, substance P [SP], NK1R can engage a variety of signaling pathways and serve as a platform for cells to proliferate by regulating the expression of the cell cycle-related genes. Furthermore, the activity of SP/NK1R is stimulated by various oncogenes, indicating the involvement of this pathway in human cancers. As a result, numerous NK1R antagonists have been investigated in oncology trials, and the promising anti-- cancer effect of these receptors has opened up new possibilities for incorporating these antagonists into cancer treatment. Considering these factors, gaining a deeper understanding of the SP/NK1R pathway could offer significant advantages for cancer patients. The more knowledge we acquire about this pathway, the greater the potential for exploiting it in the development of effective treatment strategies. Here, we present a comprehensive review of the current knowledge pertaining to the biological function of the SP/NK1R, with a specific emphasis on its recently discovered role in the regulation of cell proliferation. Moreover, we provide insights into the impact of this pathway in human cancers, along with an overview of the most significant NK1R antagonists currently utilized in cancer research studies.

Can Plant Extracts Help Prevent Hair Loss or Promote Hair Growth? A Review Comparing Their Therapeutic Efficacies, Phytochemical Components, and Modulatory Targets.

This narrative review aims to examine the therapeutic potential and mechanism of action of plant extracts in preventing and treating alopecia (baldness). We searched and selected research papers on plant extracts related to hair loss, hair growth, or hair regrowth, and comprehensively compared the therapeutic efficacies, phytochemical components, and modulatory targets of plant extracts. These studies showed that various plant extracts increased the survival and proliferation of dermal papilla cells in vitro, enhanced cell proliferation and hair growth in hair follicles ex vivo, and promoted hair growth or regrowth in animal models in vivo. The hair growth-promoting efficacy of several plant extracts was verified in clinical trials. Some phenolic compounds, terpenes and terpenoids, sulfur-containing compounds, and fatty acids were identified as active compounds contained in plant extracts. The pharmacological effects of plant extracts and their active compounds were associated with the promotion of cell survival, cell proliferation, or cell cycle progression, and the upregulation of several growth factors, such as IGF-1, VEGF, HGF, and KGF (FGF-7), leading to the induction and extension of the anagen phase in the hair cycle. Those effects were also associated with the alleviation of oxidative stress, inflammatory response, cellular senescence, or apoptosis, and the downregulation of male hormones and their receptors, preventing the entry into the telogen phase in the hair cycle. Several active plant extracts and phytochemicals stimulated the signaling pathways mediated by protein kinase B (PKB, also called AKT), extracellular signal-regulated kinases (ERK), Wingless and Int-1 (WNT), or sonic hedgehog (SHH), while suppressing other cell signaling pathways mediated by transforming growth factor (TGF)-ß or bone morphogenetic protein (BMP). Thus, well-selected plant extracts and their active compounds can have beneficial effects on hair health. It is proposed that the discovery of phytochemicals targeting the aforementioned cellular events and cell signaling pathways will facilitate the development of new targeted therapies for alopecia.

Important molecular mechanisms in ferroptosis.

Ferroptosis is a type of cell death that is caused by the oxidation of lipids and is dependent on the presence of iron. It was first characterized by Brent R. Stockwell in 2012, and since then, research in the field of ferroptosis has rapidly expanded. The process of ferroptosis-induced cell death is genetically, biochemically, and morphologically distinct from other forms of cellular death, such as apoptosis, necroptosis, and non-programmed cell death. Extensive research has been devoted to comprehending the intricate process of ferroptosis and the various factors that contribute to it. While the majority of these studies have focused on examining the effects of lipid metabolism and mitochondria on ferroptosis, recent findings have highlighted the significant involvement of signaling pathways and associated proteins, including Nrf2, P53, and YAP/TAZ, in this process. This review provides a concise summary of the crucial signaling pathways associated with ferroptosis based on relevant studies. It also elaborates on the drugs that have been employed in recent years to treat ferroptosis-related diseases by targeting the relevant signaling pathways. The established and potential therapeutic targets for ferroptosis-related diseases, such as cancer and ischemic heart disease, are systematically addressed.

Efficacy of Sorafenib-Based Therapies for Non-Small Cell Lung Cancer.

Lung cancer remains the leading cause of cancer-related deaths, with a poor prognosis. Of the two types, non-small cell lung cancer (NSCLC) is the major and most prevalent type and associated with low response rates to the current treatment options. Sorafenib, a multitargeted tyrosine kinase inhibitor used for various malignancies, gained attention for its potential efficacy in NSCLC. This review paper focuses on the findings of recent in vitro, in vivo, and clinical studies regarding the efficacy of sorafenib. Overall, sorafenib has shown definitive therapeutic potential in NSCLC cell lines, xenografts, and human subjects. Novel approaches to sorafenib delivery may improve its efficacy and should be the focus of further studies.

Estrogenic Prenylated Flavonoids in Sophora flavescens.

Sophora flavescens is a medicinal herb distributed widely in Japan and it has been used to treat various diseases and symptoms. To explore its pharmacological use, we examined the estrogenic activity of four prenylated flavonoids, namely kurarinone, kushenols A and I, and sophoraflavanone G, which are characterized by the lavandulyl group at position 8 of ring A, but have variations in the hydroxyl group at positions 3 (ring C), 5 (ring A) and 4' (ring B). These prenylated flavonoids were examined via cell proliferation assays using sulforhodamine B, Western blotting, and RT-PCR, corresponding to cell, protein, and transcription assays, respectively, based on estrogen action mechanisms. All the assays employed here found weak but clear estrogenic activities for the prenylated flavonoids examined. Furthermore, the activities were inhibited by an estrogen receptor antagonist, suggesting that the activities were likely being mediated by the estrogen receptors. However, there were differences in the activity, attributable to the hydroxyl group at position 4', which is absent in kushenol A. While the estrogenic activity of kurarinone and sophoraflavanone G has been reported before, to the best of our knowledge, there are no such reports on kushenols A and I. Therefore, this study represents the first report of their estrogenic activity.

Hypermigration of macrophages through the concerted action of GRA effectors on NF-κB/p38 signaling and host chromatin accessibility potentiates Toxoplasma dissemination.

Mononuclear phagocytes facilitate the dissemination of the obligate intracellular parasite Toxoplasma gondii. Here, we report how a set of secreted parasite effector proteins from dense granule organelles (GRA) orchestrates dendritic cell-like chemotactic and pro-inflammatory activation of parasitized macrophages. These effects enabled efficient dissemination of the type II T. gondii lineage, a highly prevalent genotype in humans. We identify novel functions for effectors GRA15 and GRA24 in promoting CCR7-mediated macrophage chemotaxis by acting on NF-κB and p38 MAPK signaling pathways, respectively, with contributions of GRA16/18 and counter-regulation by effector TEEGR. Further, GRA28 boosted chromatin accessibility and GRA15/24/NF-κB-dependent transcription at the Ccr7 gene locus in primary macrophages. In vivo, adoptively transferred macrophages infected with wild-type T. gondii outcompeted macrophages infected with a GRA15/24 double mutant in migrating to secondary organs in mice. The data show that T. gondii, rather than being passively shuttled, actively promotes its dissemination by inducing a finely regulated pro-migratory state in parasitized human and murine phagocytes via co-operating polymorphic GRA effectors.

Effect and mechanism of recombinant human fibroblast growth factor 18 on osteoporosis in OVX mice.

OBJECTIVES: This study aimed to investigate the effect and the mechanism of recombinant human fibroblast growth factor 18 (rhFGF18) on postmenopausal osteoporosis. METHODS: The effect of rhFGF18 on the proliferation and apoptosis of osteoblasts and the mechanism underlying such an effect was evaluated using an oxidative stress model of the MC3T3-E1 cell line. Furthermore, ovariectomy was performed on ICR mice to imitate estrogen-deficiency postmenopausal osteoporosis. Bone metabolism and bone morphological parameters in the ovariectomized (OVX) mice were evaluated. RESULTS: The results obtained from the cell model showed that FGF18 promoted MC3T3-E1 cell proliferation by activating the extracellular signal-regulated kinase (ERK) and p38 instead of c-Jun N-terminal kinase (JNK). FGF18 also prevented cells from damage inflicted by oxidative stress via inhibition of apoptosis. After FGF18 administration, the expression level of anti-apoptotic protein Bcl-2 in the mice was upregulated, whereas those of the pro-apoptotic proteins Bax and caspase-3 were downregulated. Administering FGF18 also improved bone metabolism and bone morphological parameters in OVX mice. CONCLUSIONS: FGF18 could effectively prevent bone loss in OVX mice by enhancing osteoblastogenesis and protecting osteoblasts from oxidative stress-induced apoptosis.

Using Human Fetal Neural Stem Cells to Elucidate the Role of the JAK-STAT Cell Signaling Pathway in Oligodendrocyte Differentiation In Vitro.

Oligodendrocytes (OL) are the myelinating cells of the central nervous system that mediate nerve conduction. Loss of oligodendrocytes results in demyelination, triggering neurological deficits. Developing a better understanding of the cell signaling pathways influencing OL development may aid in the development of therapeutic strategies. The primary focus of this study was to investigate and elucidate the cell signaling pathways implicated in the developmental maturation of oligodendrocytes using human fetal neural stem cells (hFNSCs)-derived primary OL and MO3.13 cell line. Successful differentiation into OL was established by examining morphological changes, increased expression of mature OL markers MBP, MOG and decreased expression of pre-OL markers CSPG4 and O4. Analyzing transcriptional datasets (using RNA sequencing) in pre-OL and mature OL derived from hFNSCs revealed the novel and critical involvement of the JAK-STAT cell signaling pathway in terminal OL maturation. The finding was validated in MO3.13 cell line whose differentiation was accompanied by upregulation of IL-6 and the transcription factor STAT3. Increased phosphorylated STAT3 (pY705) levels were demonstrated by western blotting in hFNSCs-derived primary OL as well as terminal maturation in MO3.13 cells, thus validating the involvement of the JAK-STAT pathway in OL maturation. Pharmacological suppression of STAT3 phosphorylation (confirmed by western blotting) was able to prevent the increase of MBP-positive cells as demonstrated by flow cytometry. These novel findings highlight the involvement of the JAK-STAT pathway in OL maturation and raise the possibility of using this as a therapeutic strategy in demyelinating diseases.

An Updated Review on KRAS Mutation in Lung Cancer (NSCLC) and Its Effects on Human Health.

The largest cause of cancer-related fatalities worldwide is lung cancer. In its early stages, lung cancer often exhibits no signs or symptoms. Its signs and symptoms often appear when the condition is advanced. The Kirsten rat sarcoma virus oncogene homolog is one of the most frequently mutated oncogenes found in non-small cell lung cancer. Patients who have these mutations may do worse than those who do not, in terms of survival. To understand the nuances in order to choose the best treatment options for each patient, including combination therapy and potential resistance mechanisms, given the quick development of pharmaceuticals, it is necessary to know the factors that might contribute to this disease. It has been observed that single nucleotide polymorphisms altering let-7 micro-RNA might impact cancer propensity. On the other hand, gefitinib fails to stop the oncogenic protein from directly interacting with phosphoinositide3-kinase, which may explain its resistance towards cancer cells. Additionally, Atorvastatin may be able to overpower gefitinib resistance in these cancer cells that have this mutation regardless of the presence of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha. De novo lipogenesis is also regulated by this virus. To overcome these effects, several targeted therapies have been proposed. One such therapy is to use inhibitors of focal adhesion kinases. When this is inhibited, viral oncogene mutant cancers are effectively stopped because it functions downstream of the virus. Mutant oncoproteins like epidermal growth factor receptor may depend on Heat Shock protein90 chaperones more frequently than they do on natural counterparts that make it more attractive therapeutic target for this virus. Inhibition of the phosphoinositide 3-kinase pathway is frequent in lung cancer, and fabrication of inhibitors against this pathway can also be an effective therapeutic strategy. Blocking programmed cell death ligand1 is another therapy that may help T cells to recognize and eliminate cancerous cells. This homolog is a challenging therapeutic target due to its complex structural makeup and myriad biological characteristics. Thanks to the unrelenting efforts of medical research, with the use of some inhibitors, immunotherapy, and other combination methods, this problem is currently expected to be overcome.

3D biofabrication and space: A 'far-fetched dream' or a 'forthcoming reality'?

The long duration space missions across the Low Earth Orbit (LEO) often expose the voyagers to an abrupt zero gravity influence. The severe extraterrestrial cosmic radiation directly causes a plethora of moderate to chronic healthcare crises. The only feasible solution to manage critical injuries on board is surgical interventions or immediate return to Earth. This led the group of space medicine practitioners to adopt principles from tissue engineering and develop human tissue equivalents as an immediate regenerative therapy on board. The current review explicitly demonstrates the constructive application of different tissue-engineered equivalents matured under the available ground-based microgravity simulation facilities. Further, it elucidates how augmenting the superiority of biomaterial-based 3D bioprinting technology can enhance their clinical applicability. Additionally, the regulatory role of weightlessness condition on the underlying cellular signaling pathways governing tissue morphogenesis has been critically discussed. This information will provide future directions on how 3D biofabrication can be used as a plausible tool for healing on-flight chronic health emergencies. Thus, in our review, we aimed to precisely debate whether 3D biofabrication is deployed to cater to on-flight healthcare anomalies or space-like conditions are being utilized for generating 3D bioprinted human tissue constructs for efficient drug screening and regenerative therapy.

Stenotrophomonas maltophilia promotes lung adenocarcinoma progression by upregulating histone deacetylase 5.

Introduction: Lung cancer is the leading cause of cancer death worldwide, and lung adenocarcinoma (LADC) is the most common lung cancer. Lung cancer has a distinct microbiome composition correlated with patients' smoking status. However, the causal evidence of microbial impacts on LADC is largely unknown. Methods: We investigated microbial communities' differences in Formalin-Fixed Paraffin-Embedded tissues of ever-smoke (n = 22) and never-smoke (n = 31) patients with LADC through bacterial 16S rRNA gene high-throughput sequencing. Then nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung cancer mouse model and A549 cells were used to study the effect of Stenotrophomonas maltophilia (S. maltophilia) in LADC. Results and Discussion: We found a significant increase of genus Stenotrophomonas in LADC tissues of patients with primary tumor size greater than 3 cm and never-smoker patients. We further found that intratracheal infection with S. maltophilia promoted tumor progression in the NNK-induced lung cancer mouse model. We performed RNA-seq analysis on lung tissues and found that S. maltophilia treatment drove inflammation and upregulated tumor associated cell signaling, including Apelin signaling pathway. Mechanistically, histone deacetylase 5 (HDAC5) gene expression was significantly upregulated in S. maltophilia treated groups, and was required for S. maltophilia induced cell proliferation and migration in LADC cell line A549. Therefore, we provide in vivo and in vitro evidence to demonstrate that S. maltophilia promotes LADC progression, in part, through HDAC5.

Chitosan oligosaccharide as a plant immune inducer on the Passiflora spp. (passion fruit) CMV disease.

Cucumber mosaic virus (CMV), one of the main viruses, is responsible for Passiflora spp. (passion fruit) virus diseases, which negatively affect its planting, cultivation, and commercial quality. In this study, a laboratory anti-CMV activity screening model for Passiflora spp. CMV disease was first established. Then, the effects of different antiviral agents of chitosan oligosaccharide (COS), dufulin (DFL), and ningnanmycin (Ning) on CMV virulence rate in Passiflora spp. were determined. The virulence rate and anti-CMV activity in Passiflora spp. treated with COS were 50% and 45.48%, respectively, which were even better than those of DFL (66.67% and 27.30%, respectively) and Ning (83.30% and 9.17%, respectively). Field trials test results showed COS revealed better average control efficiency (47.35%) against Passiflora spp. CMV disease than those of DFL (40.93%) and Ning (33.82%), indicating that COS is effective in the control of the Passiflora spp. CMV disease. Meanwhile, the nutritional quality test results showed that COS could increase the contents of soluble solids, titratable acids, vitamin C, and soluble proteins in Passiflora spp. fruits as well as enhance the polyphenol oxidase (PPO), superoxide dismutase (SOD), and peroxidase (POD) activity in the leaves of Passiflora spp. seedlings. In addition, the combined transcriptome and proteome analysis results showed that COS mainly acted on the Brassinosteroids (BRs) cell signaling pathway, one of plant hormone signal transduction pathway, in Passiflora spp., thus activating the up-regulated expression of TCH4 and CYCD3 genes to improve the resistance to CMV disease. Therefore, our study results demonstrated that COS could be used as a potential plant immune inducer to control the Passiflora spp. CMV disease in the future.

Melatonin-Assisted Cisplatin Suppresses Urinary Bladder Cancer Cell Proliferation and Growth through Inhibiting PrPC-Regulated Cell Stress and Cell Proliferation Signaling.

This study investigated whether melatonin (Mel) would promote cisplatin to suppress the proliferation and growth of bladder cancer (BC) cells by inhibiting cellular prion protein (PrPC)-mediated cell stress and cell proliferation signaling. An immunohistochemical staining of tissue arrays from BC patients demonstrated that the PrPC expression was significantly upregulated from stage I to III BC (p < 0.0001). The BC cellline of T24 was categorized into G1 (T24), G2 (T24 + Mel/100 µM), G3 (T24+cisplatin/6 µM), G4 (PrPC overexpression in T24 (i.e., PrPC-OE-T24)), G5 (PrPC-OE-T24+Mel), and G6 (PrPC-OE-T24+cisplatin). When compared with a human uroepithelial cell line (SV-HUC-1), the cellular viability/wound healing ability/migration rate were significantly increased in T24 cells (G1) and further significantly increased in PrPC-OE-T24 cells (G4); and they were suppressed in Mel (G2/G5) or cisplatin (G3/G6) treatment (all p < 0.0001). Additionally, the protein expressions of cell proliferation (PI3K/p-Akt/p-m-TOR/MMP-9/PrPC), cell cycle/mitochondrial functional integrity (cyclin-D1/clyclin-E1/ckd2/ckd4/mitochondrial-cytochrome-C/PINK1), and cell stress (RAS/c-RAF/p-MEK1/2, p-ERK1/2) markers showed a similar pattern of cell viability among the groups (all p < 0.001). After the BC cell line of UMUC3 was implanted into nude mouse backs, by day 28 mthe BC weight/volume and the cellular levels of PrPC/MMP-2/MMP-9 were significantly, gradually reduced from groups one to four (all p < 0.0001). The protein expressions of cell proliferation (PI3K/p-Akt/p-m-TOR/MMP-9/PrPC), cell cycle/mitophagy (cyclin-D1/clyclin-E1/ckd2/ckd4/PINK1), and cell stress (RAS/c-RAF/p-MEK1,2/p-ERK1,2) signaling were significantly, progressively reduced from groups one to four, whereas the protein expressions of apoptotic (Mit-Bax/cleaved-caspase-3/cleaved-PARP) and oxidative stress/mitochondrial damaged (NOX-1/NOX-2/cytosolic-cytochrome-C/p-DRP1) markers expressed an opposite pattern of cell proliferation signaling among the groups (all p < 0.0001). Mel-cisplatin suppressed BC cell growth/proliferation via inhibiting the PrPC in upregulating the cell proliferation/cell stress/cell cycle signaling.

Research progress on Astragalus active ingredient in treatment of hepatic fibrosis based on cell signaling pathway / 中国药理学通报

Hepatic fibrosis is present in most chronic liver disease processes, and there are no ideal anti-fibrotic drugs available. Astragalus has a long history of medicinal use, and its anti-fibrotic effects have been confirmed by modern studies. In this study we have searched the literature to identify the signaling pathways and mechanisms of action of Astragalus and its active ingredients on hepatic fibrosis in recent years, so as to provide the basis and ideas for the development of anti-fibrotic drugs and mechanisms of Astragalus. It is showed that the active ingredients of Astragalus act through regulating p38MAPK, TGF-pl/Smads,NF-

Pendimethalin exposure induces bovine mammary epithelial cell death through excessive ROS production and alterations in the PI3K and MAPK signaling pathways.

Herbicides are chemicals that have been established to have adverse impacts. However, they are still widely used in agriculture. Pendimethalin (PDM) is an herbicide that is widely used in many countries to control annual grasses. The possibility of livestock being exposed to PDM is relatively high, considering the half-life of PDM and its residues in water, soil and crops. However, the toxicity of PDM in cattle, especially in the mammary glands, has not been reported. Therefore, we investigated whether PDM has toxic effects in the mammary epithelial cells (MAC-T) of cattle. MAC-T cells were treated with various doses (0, 2.5, 5 and 10 µM) of PDM. We found that PDM affected cell viability and cell proliferation and causes cell cycle arrest. Furthermore, PDM triggered cell apoptosis, induced excessive ROS production and mitochondrial membrane potential (MMP) loss, and disrupted calcium homeostasis. In addition, PDM altered the activation of proteins associated with the endoplasmic reticulum (ER) stress response and modified PI3K and MAPK signaling cascades. In conclusion, our current study unveiled the mechanism of PDM in MAC-T cells and we suggest that PDM might be harmful to the mammary gland system of cattle, possibly affecting milk production.

Molecular Cluster Mining of Adrenocortical Carcinoma via Multi-Omics Data Analysis Aids Precise Clinical Therapy.

Adrenocortical carcinoma (ACC) is a malignancy of the endocrine system. We collected clinical and pathological features, genomic mutations, DNA methylation profiles, and mRNA, lncRNA, microRNA, and somatic mutations in ACC patients from the TCGA, GSE19750, GSE33371, and GSE49278 cohorts. Based on the MOVICS algorithm, the patients were divided into ACC1-3 subtypes by comprehensive multi-omics data analysis. We found that immune-related pathways were more activated, and drug metabolism pathways were enriched in ACC1 subtype patients. Furthermore, ACC1 patients were sensitive to PD-1 immunotherapy and had the lowest sensitivity to chemotherapeutic drugs. Patients with the ACC2 subtype had the worst survival prognosis and the highest tumor-mutation rate. Meanwhile, cell-cycle-related pathways, amino-acid-synthesis pathways, and immunosuppressive cells were enriched in ACC2 patients. Steroid and cholesterol biosynthetic pathways were enriched in patients with the ACC3 subtype. DNA-repair-related pathways were enriched in subtypes ACC2 and ACC3. The sensitivity of the ACC2 subtype to cisplatin, doxorubicin, gemcitabine, and etoposide was better than that of the other two subtypes. For 5-fluorouracil, there was no significant difference in sensitivity to paclitaxel between the three groups. A comprehensive analysis of multi-omics data will provide new clues for the prognosis and treatment of patients with ACC.

Multiple proliferation signaling pathways are modulated by octacalcium phosphate in osteoblasts.

Octacalcium phosphate (OCP), a type of bioactive ceramics, may be associated with dentine, tooth apatite, and especially bone generation, and promotes wound healing after fracture. Recently, commercial bone grafting products containing a large amount of OCP material have been released because OCP can be synthesized in large quantities. It is reported to increase cell proliferation, but the interaction between OCP and cell signaling pathways is still unclear. In this study, first, we demonstrated OCP mediated cell signaling pathways with only purified OCP materials. OCP regulated P38, JNK (c-Jun N-terminal kinase), Src, and AKT (protein kinase B) signaling pathways. OCP crystals appeared in the characteristic ribbon shape but varied by several tens of micrometers in size. The X-ray diffraction pattern was the same as previously reported. We studied two concentrations of OCP (10 mg/ml and 20 mg/ml) to understand whether the effect of OCP on cell signaling pathways is dose dependent. We confirmed that OCP treatment affected cell proliferation and alkaline phosphatase and disrupted Src phosphorylation but did not change the total protein level. P38 phosphorylation was activated with OCP treatment and inhibited by SB203580, but P38 total protein level did not change. OCP inhibited JNK phosphorylation signaling, whereas PD98509 inhibited JNK phosphorylation with or without OCP. Interestingly, the AKT total level decreased after OCP treatment, but AKT phosphorylation increased considerably. Our results demonstrate that OCP materials modulate cell signaling pathways and increase cell proliferation.