The effects of microgravity on stem cells and the new insights it brings to tissue engineering and regenerative medicine.

Conventional two-dimensional (2D) cell culture techniques may undergo modifications in the future, as life scientists have widely acknowledged the ability of three-dimensional (3D) in vitro culture systems to accurately simulate in vivo biology. In recent years, researchers have discovered that microgravity devices can address many challenges associated with 3D cell culture. Stem cells, being pluripotent cells, are regarded as a promising resource for regenerative medicine. Recent studies have demonstrated that 3D culture in microgravity devices can effectively guide stem cells towards differentiation and facilitate the formation of functional tissue, thereby exhibiting advantages within the field of tissue engineering and regenerative medicine. Furthermore, We delineate the impact of microgravity on the biological behavior of various types of stem cells, while elucidating the underlying mechanisms governing these alterations. These findings offer exciting prospects for diverse applications.

Simulated microgravity altered the gene expression profiles and inhibited the proliferation of Kupffer cells in the early phase by downregulating LMO2 and EZH2.

Microgravity is a primary challenge that need to overcome, when human travel to space. Our study provided evidence that Kupffer cells (KCs) are sensitive to simulated microgravity (SMG), and no similar research report has been found in the literature. Using transcriptome sequencing technology, it was showed that 631 genes were upregulated and 801 genes were downregulated in KCs after treatment under SMG for 3 days. The GO analysis indicated that the proliferation of KCs was affected when exposed to SMG for 3 days. CCK-8 assay confirmed that the proliferation of KCs was inhibited in the third day under the environment of SMG. Furthermore, we identified 8 key genes that affect the proliferation of KCs and predicted 2 transcription factors (TFs) that regulate the 8 key genes. Significantly, we found that microgravity could affect the expression of LMO2 and EZH2 to reduce the transcription of Racgap1, Ccna2, Nek2, Aurka, Plk1, Haus4, Cdc20, Bub1b, which resulting in the reduction in KCs proliferation. These finding suggested that the inhibition of KCs proliferation under microgravity may influence the homeostasis of liver, and LMO2 and EZH2 can be the targets in management of KCs' disturbance in the future practice of space medicine.

Determination of optimal mining width for coal mining under the slope by of using numerical simulation.

The stability of slope is critical important topic in rock mass engineering. In Panzhihua #7 Coal Mine, the coal mining is occurred under the slope, to obtain the optimal mining width, 125 numerical simulations were conducted, and the corresponding FOS was calculated. From the analysis of the numerical simulation results, it can be found that FOS decrease and then increase with increasing of filling length, meanwhile, the FOS is minimum value when the filling length is within the ranges of 10 m and 20 m, which is under the toe of slope. Furthermore, the minimum FOS decrease with increasing of mining width. Considered the stability of the slope and mining economy, the mining width is set to 6m, and the numerical simulation results is applied to the engineering practice. To guarantee the safety of the slope, some monitoring points were distributed on the slope, the displacement from numerical simulation and engineering practice is quite close, indicating the numerical simulation results is reliable, and the mining width is reasonable.

Simulated microgravity altered the proliferation, apoptosis, and extracellular matrix formation of L929 fibroblasts and the transforming growth factor-ß1/Smad3 signaling pathway.

Exposure to microgravity can adversely affect the fitness of astronauts. The integrity of the skin plays a crucial role in protecting against mechanical forces and infections, fluid imbalance, and thermal dysregulation. In brief, the skin wound may cause unknown challenges to the implementation of space missions. Wound healing is a physiological process that relies on the synergistic action of inflammatory cells, extracellular matrix (ECM), and various growth factors to maintain the integrity of skin after trauma. Fibroblasts are present almost throughout the entire process of wound repair, especially in the scar formation at the endpoint of wound healing. However, there is limited knowledge about the extent to which fibroblasts are affected by the lack of gravity during wound healing. In this study, we utilized the rotary cell culture system, a ground-based facility that mimics the weightless condition, to study the alterations of L929 fibroblast cells under simulated microgravity (SMG). Our results demonstrated that the SM condition exerted negative influences on the proliferation and ECM formation of the L929 fibroblast. Whereas, the apoptosis of fibroblast was significantly upregulated upon exposure to SMG conditions. Moreover, the transforming growth factor-ß1/Smad3 (TGF-ß1/smad3) signaling pathway of L929 fibroblast related to wound repair was also altered significantly under a weightless environment. Overall, our study provided evidence that fibroblasts are strongly sensitive to SMG and elucidated the potential value of the TGF-ß1/Smad3 signaling pathway modulating wound healing in the future practice of space medicine.

Autophagy in hepatic macrophages can be regulator and potential therapeutic target of liver diseases: A review.

Hepatic macrophages are a complex population of cells that play an important role in the normal functioning of the liver and in liver diseases. Autophagy, as a maintainer of cellular homeostasis, is closely connected to many liver diseases. And its roles are not always beneficial, but manifesting as a double-edged sword. The polarization of macrophages and the activation of inflammasomes are mediated by intracellular and extracellular signals, respectively, and are important ways for macrophages to take part in a variety of liver diseases. More attention should be paid to autophagy of hepatic macrophages in liver diseases. In this review, we focus on the regulatory role of hepatic macrophages' autophagy in a variety of liver diseases; especially on the upstream regulator of polarization and inflammasomes activation of the hepatic macrophages. We believe that the autophagy of hepatic macrophages can become a potential therapeutic target for management of liver diseases.

Proteomic analysis of the effects of simulated microgravity in human gastric mucosal cells.

Microgravity is an ecological factor that affects the environment of the body. In this study, quantitative isobaric labeling (tandem mass tag) method was used to study the changes in human gastric mucosal cells under simulated microgravity for the first time. Comparative proteomic analysis identified 394 (202 upregulated and 192 downregulated) and 542 (286 upregulated and 256 downregulated) proteins differentially regulated by simulated microgravity after 3 and 7 days, respectively. Then the identified proteins were subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses for further exploration. The results of the analysis showed that the ribosomes of gastric mucosal cells were significantly impacted after exposure to simulated microgravity for 3 days, and the cells appeared to be in a state of stress and inflammation. Exposure to simulated microgravity for 7 days significantly affected the mitochondria of the cells, oxidative stress became more evident, while inflammation and weakened connections were observed in the cells. The results of this study highlighted the temporal response trend of gastric mucosal cells to the stressor of microgravity at the two time points of 3 and 7 days. These findings will provide insights into the development of methods to protect the gastric mucosa during space flight.

Inflammation is involved in response of gastric mucosal epithelial cells under simulated microgravity by integrated transcriptomic analysis.

Astronauts suffer from inflammatory changes induced by microgravity during space flight. Microgravity can significantly affect the inflammatory response of various cell types and multiple systems of the human body, such as cardiovascular system, skeletal muscle system, and digestive system. The aim of this research was to identify the key genes and pathways of gastric mucosa affected by microgravity. Human gastric mucosal epithelial GES-1 cells were cultured in a rotary cell culture system (RCCS) bioreactor to simulate microgravity. The gene expression profiles of GES-1 cells were obtained using Illumina sequencing platform and differentially expressed genes were identified by DESeq2 software, then Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. Subsequently, a protein-protein interaction (PPI) network was constructed. Compared with a normal gravity (NG) group, a total of 943 DEGs, including 192 downregulated genes and 751 upregulated genes, were identified. These DEGs were associated with findings that included response to interleukin-1, positive regulation of inflammatory response, and positive regulation of neuroinflammatory response. Furthermore, these DEGs were mainly enriched in herpes simplex virus 1 infection, cytokine-cytokine receptor interaction, and NOD-like receptor signaling pathway. Thus, 21 hub genes were identified from PPI network, including IL6, IL1B, ITGAM, CXCL8, ITGAX, CCL5, SERPINA1, APOE, CSF1R, VWF, GBP1, APOB, CYBB, HLA-DRB1, CD68, FGG, FGA, OASL, NOD2, OAS2 and FCGR2A. These findings suggested that simulated microgravity upregulated inflammation-related genes and pathways of GES-1 cells, which may play important roles in the response to microgravity and provide useful information for preventing mucosal damage in astronauts. In conclusion, this study revealed the key genes and pathways associated with simulated microgravity and indicated that simulated microgravity induced an inflammatory response in gastric mucosal epithelial cells.

Autophagy in Gastric Mucosa: The Dual Role and Potential Therapeutic Target.

The incidence of stomach diseases is very high, which has a significant impact on human health. Damaged gastric mucosa is more vulnerable to injury, leading to bleeding and perforation, which eventually aggravates the primary disease. Therefore, the protection of gastric mucosa is crucial. However, existing drugs that protect gastric mucosa can cause nonnegligible side effects, such as hepatic inflammation, nephritis, hypoacidity, impotence, osteoporotic bone fracture, and hypergastrinemia. Autophagy, as a major intracellular lysosome-dependent degradation process, plays a key role in maintaining intracellular homeostasis and resisting environmental pressure, which may be a potential therapeutic target for protecting gastric mucosa. Recent studies have demonstrated that autophagy played a dual role when gastric mucosa exposed to biological and chemical factors. More indepth studies are needed on the protective effect of autophagy in gastric mucosa. In this review, we focus on the mechanisms and the dual role of various biological and chemical factors regulating autophagy, such as Helicobacter pylori, virus, and nonsteroidal anti-inflammatory drugs. And we summarize the pathophysiological properties and pharmacological strategies for the protection of gastric mucosa through autophagy.

Influence of intrinsic motivations on the continuity of scientific knowledge contribution to online knowledge-sharing platforms.

Scientific knowledge contribution to online knowledge-sharing platforms has long been regarded as instrumental behavior based on utilitarian considerations. Employing cognitive evaluation theory, this study examines scientific expert users' behavioral metrics to understand the factors responsible for users continuing to contribute their scientific knowledge for an extended period or a very short span. We found that expert users' intrinsic motivations, which has received little attention in recent studies, constitute an important indicator of sustained online scientific knowledge contribution. Furthermore, although social rewards fail to predict the continuity of scientific knowledge contribution, they prolong the duration of knowledge contribution by enhancing the intrinsic motivations of expert users. In conclusion, a self-reinforcement mechanism underlies the relationship of intrinsic motivation with social rewards, which governs continuous online scientific knowledge contribution behavior.

Effect of simulated microgravity on metabolism of HGC-27 gastric cancer cells.

The understanding into the pathogenesis and treatment of gastric cancer has improved in recent years; however, a number of limitations have delayed the development of effective treatment. Cancer cells can undergo glycolysis and inhibit oxidative phosphorylation in the presence of oxygen (Warburg effect). Previous studies have demonstrated that a rotary cell culture system (RCCS) can induce glycolytic metabolism. In addition, the potential of regulating cancer cells by targeting their metabolites has led to the rapid development of metabolomics. In the present study, human HGC-27 gastric cancer cells were cultured in a RCCS bioreactor, simulating weightlessness. Subsequently, liquid chromatography-mass spectrometry was used to examine the effects of simulated microgravity (SMG) on the metabolism of HGC-27 cells. A total of 67 differentially regulated metabolites were identified, including upregulated and downregulated metabolites. Compared with the normal gravity group, phosphatidyl ethanolamine, phosphatidyl choline, arachidonic acid and sphinganine were significantly upregulated in SMG conditions, whereas sphingomyelin, phosphatidyl serine, phosphatidic acid, L-proline, creatine, pantothenic acid, oxidized glutathione, adenosine diphosphate and adenosine triphosphate were significantly downregulated. The Human Metabolome Database compound analysis revealed that lipids and lipid-like metabolites were primarily affected in an SMG environment in the present study. Overall, the findings of the present study may aid our understanding of gastric cancer by identifying the underlying mechanisms of metabolism of the disease under SMG.

Simulated microgravity significantly altered metabolism in epidermal stem cells.

Simulated microgravity can significantly affect various cell types and multiple systems of the human body, such as cardiovascular system, skeletal muscle system, and immune system, and is known to cause anemia and loss of electrolyte and fluids. Epidermal stem cells (EpSCs) were cultured in a rotary cell culture system (RCCS) bioreactor to simulate microgravity. The metabolites of EpSCs were identified by liquid chromatography-mass spectrometry (LC-MS). Compared with normal gravity (NG) group, a total of 57 different metabolites of EpSCs were identified (P < 0.05, VIP > 1), including lipids and lipid-like molecules (51 molecules), amino acids (5 molecules), nucleosides, nucleotides, and analogues (1 molecule). According to the partial least squares discriminant analysis (PLS-DA) score plot, a VIP > 1 and P < 0.05 were obtained for the 57 different metabolites, of which 23 molecules were significantly downregulated and 34 were significantly upregulated in simulated microgravity (SMG) group. These results showed that SMG has a significant impact on different pathways, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis indicated that multiple pathways were involved, mainly the amino acid metabolism pathway, lipid metabolism pathway, membrane transport pathway, and cell growth and death pathways. Thus, the metabolic profile of EpSCs was changed under SMG. Exploring the metabolic profile of EpSCs would be helpful to further understand the growth characteristics of EpSCs under SMG, which will provide a new approach to explore the metabolomics mechanism of stress injury and repair trauma under SMG.

The effects of microgravity on the digestive system and the new insights it brings to the life sciences.

BACKGROUND: Weightlessness is a component of the complex space environment. It exerts adverse effects on the human body, and may pose unknown challenges to the implementation of space missions. The regular function of the digestive system is an important checkpoint for astronauts to conduct missions. Simulated microgravity can recreate the changes experienced by the human body in a weightless environment in space to a certain extent, providing technical support for the exploration of its mechanism and a practical method for other scientific research. METHODS AND MATERIALS: In the present study, we reviewed and discussed the latest research on the effects of weightlessness or simulated microgravity on the digestive system, as well as the current challenges and future expectations for progress in medical science and further space exploration. RESULTS: A series of studies have investigated the effects of weightlessness on the human digestive system. On one hand, weightlessness and the changing space environment may exert certain adverse effects on the human body. Studies based on cells or animals have demonstrated the complex effects on the human digestive system in response to weightlessness. On the other hand, a microgravity environment also facilitates the ideation of novel concepts for research in the domain of life science. CONCLUSION: The effects of weightlessness on the digestive system are considerably complicated. The emergence of methods that help simulate a weightless environment provides a more convenient alternative for assessing the impact and the mechanism underlying the effect of weightlessness on the human body. In addition, the simulated microgravity environment facilitates the ideation of novel concepts for application in regenerative medicine and other fields of life science.

Effect of Weightlessness on the 3D Structure Formation and Physiologic Function of Human Cancer Cells.

With the rapid development of modern medical technology and the deterioration of living environments, cancer, the most important disease that threatens human health, has attracted increasing concerns. Although remarkable achievements have been made in tumor research during the past several decades, a series of problems such as tumor metastasis and drug resistance still need to be solved. Recently, relevant physiological changes during space exploration have attracted much attention. Thus, space exploration might provide some inspiration for cancer research. Using on ground different methods in order to simulate microgravity, structure and function of cancer cells undergo many unique changes, such as cell aggregation to form 3D spheroids, cell-cycle inhibition, and changes in migration ability and apoptosis. Although numerous better experiments have been conducted on this subject, the results are not consistent. The reason might be that different methods for simulation have been used, including clinostats, random positioning machine (RPM) and rotating wall vessel (RWV) and so on. Therefore, we review the relevant research and try to explain novel mechanisms underlying tumor cell changes under weightlessness.

miR-375 mediates the CRF signaling pathway to regulate catecholamine biosynthesis by targeting Sp1 in porcine adrenal gland.

Corticotropin-releasing-factor (CRF) is a key regulator of catecholamines (CATs) biosynthesis in the adrenal gland. Furthermore, miR-375 has been confirmed to be localized in the mouse adrenal gland. However, the relationships between miR-375 and CRF in regulating CATs biosynthesis remain to be established. This study was designed to investigate the relationship between CRF and miR-375 in the regulation of CATs biosynthesis in the porcine adrenal gland. Eight adult female pigs (four controls; four injected intracerebroventricularly with 50 µg of CRF) were used for the in vivo experiments in this study. The results showed that miR-375 was exclusively localized in porcine adrenal medullary cells. Functional studies showed that miR-375 negatively regulated CATs synthesis in primary cells by affecting the expression of the CATs synthetases tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH), and phenylethanolamine-N-methyltransferase (PNMT). CRF up-regulated the expression of CATs synthetase in primary adrenal medullary cells under basal conditions and upon endogenous miR-375 inhibition; the enhanced effects vanished when cellular miR-375 was overexpressed by transfecting miR-375-mic. CRF decreased the expression of miR-375 both in vivo and in vitro. Our in vitro results showed that CRF significantly decreased the expression of miR-375, perhaps by binding to CRFR1. miR-375 functions by directly binding to the 3'-UTR region of specificity protein 1 (Sp1), which is involved in regulating Th and Dbh expression. These data collectively indicate that miR-375 plays an important role in regulating CATs synthesis and mediates the CRF signaling pathway in porcine adrenal medullary cells.

Novel treatment strategies for patients with HER2-positive breast cancer who do not benefit from current targeted therapy drugs.

Human epidermal growth factor receptor-2 positive breast cancer (HER2+ BC) is characterized by a high rate of metastasis and drug resistance. The advent of targeted therapy drugs greatly improves the prognosis of HER2+ BC patients. However, drug resistance or severe side effects have limited the application of targeted therapy drugs. To achieve more effective treatment, considerable research has concentrated on strategies to overcome drug resistance. Abemaciclib (CDK4/6 inhibitor), a new antibody-drug conjugate (ADC), src homology 2 (SH2) containing tyrosine phosphatase-1 (SHP-1) and fatty acid synthase (FASN) have been demonstrated to improve drug resistance. In addition, using an effective vector to accurately deliver drugs to tumors has shown good application prospects. Many studies have also found that natural anti-cancer substances produced effective results during in vitro and in vivo anti-HER2+ BC research. This review aimed to summarize the current status of potential clinical drugs that may benefit HER2+ BC patients in the future.

Risk of gastrointestinal complications in breast cancer patients treated with neratinib: a meta-analysis.

BACKGROUNDS: Neratinib is a potent EGFR/HER2 kinase inhibitor. Gastrointestinal complications (i.e. diarrhea, vomiting and nausea) are the most common adverse events. In this study, we aimed to investigate (1) the overall incidence and relative risk (RR) of diarrhea, vomiting and nausea and (2) whether combination neratinib therapy increased the incidence of gastrointestinal complications versus neratinib alone. METHODS: Relevant studies were identified from the PubMed database, from abstracts presented at the American Society of Clinical Oncology annual conference and from the Web of Science database. Incidences, RRs, and 95% confidence intervals (CIs) were calculated. RESULTS: The incidences of all-grade diarrhea, vomiting and nausea in the neratinib groups were 89% (95% CI = 77-95%), 31% (95% CI = 25-37%) and 44% (95% CI = 33-55%), respectively. The neratinib arms significantly increased the risk of diarrhea and vomiting in comparison with the control groups (diarrhea: all-grade, RR = 2.06, 95% CI = 1.38-3.08, P = 0.0004; grade 3/4, RR = 8.77, 95% CI = 2.91-26.40, P = 0.0001; vomiting: all-grade, RR = 2.02, 95% CI = 1.10-3.71, P = 0.02; grade 3/4, RR = 7.10, 95% CI = 3.33-15.15, P < 0.00001). CONCLUSIONS: Our meta-analysis demonstrates that the neratinib arms are associated with a significantly increased risk of diarrhea and vomiting.

Protein Inhibitor of Activated STAT Y (PIASy) Regulates Insulin Secretion by Interacting with LIM Homeodomain Transcription Factor Isl1.

It is known that the LIM homeodomain transcription factor Isl1 is highly expressed in all pancreatic endocrine cells and functions in regulating pancreatic development and insulin secretion. The Isl1 mutation has been found to be associated with type 2 diabetes, but the mechanism responsible for Isl1 regulation of insulin synthesis and secretion still needs to be elucidated. In the present study, the protein inhibitor of activated STAT Y (PIASy) was identified as a novel Isl1-interacting protein with a yeast two-hybrid system, and its interaction with Isl1 was further confirmed by a co-immunoprecipitation experiment. PIASy and Isl1 colocalize in human and mouse pancreas and NIT beta cells. Furthermore, PIASy and Isl1 upregulate insulin gene expression and insulin secretion in a dose-dependent manner by activating the insulin promoter. PIASy and Isl1 mRNA expression levels were also increased in type 2 diabetic db/db mice. In addition, our results demonstrate that PIASy and Isl1 cooperate to activate the insulin promoter through the Isl1 homeodomain and PIASy ring domain. These data suggest that that PIASy regulates insulin synthesis and secretion by interacting with Isl1 and provide new insight into insulin regulation, although the detailed molecular mechanism needs to be clarified in future studies.

Psoriasis with extramammary paget disease in a male: a case report.

Psoriasis is a chronic inflammatory skin disease that is characterized by erythematous, sharply demarcated papules and plaques covered by scales. Extramammary Paget disease (EMPD) is a uncommon neoplastic condition of apocrine gland-bearing skin and its occurrence in combination with psoriasis is very rare. We report an interesting case of a 61-year-old male with extensive psoriasis presented with penoscrotal EMPD, which was confirmed by histopathological stain.

An unusual presentation of Paget's disease of the nipple in a young woman: a case report.

A 27-year-old female patient presented with a slight scaly, crusting, erythematous patch close to the right nipple 10 years ago. When her symptoms failed to respond to topical therapy 3 months later, nipple biopsy was performed and revealed Paget's disease of the breast. The patient underwent unilateral mastectomies with sentinel lymph node biopsy. She has stayed healthy and has had no evidence of breast cancer recurrence since surgery.

Development and evaluation of the quantitative real-time PCR assay in detection and typing of herpes simplex virus in swab specimens from patients with genital herpes.

Genital herpes (GH), which is caused mainly by herpes simplex virus (HSV)-2 and HSV-1, remains a worldwide problem. Laboratory confirmation of GH is important, particularly as there are other conditions which present similarly to GH, while atypical presentations of GH also occur. Currently, virus culture is the classical method for diagnosis of GH, but it is time consuming and with low sensitivity. A major advance for diagnosis of GH is to use Real-time polymerase chain reaction (PCR). In this study, to evaluate the significance of the real-time PCR method in diagnosis and typing of genital HSV, the primers and probes targeted at HSV-1 DNA polymerase gene and HSV-2 glycoprotein D gene fraction were designed and applied to amplify DNA from HSV-1 or HSV-2 by employing the real-time PCR technique. Then the PCR reaction system was optimized and evaluated. HSV in swab specimens from patients with genital herpes was detected by real-time PCR. The real-time PCR assay showed good specificity for detection and typing of HSV, with good linear range (5×10(2)~5×10(8) copies/ml, r=0.997), a sensitivity of 5×10(2) copies/ml, and good reproducibility (intra-assay coefficients of variation 2.29% and inter-assay coefficients of variation 4.76%). 186 swab specimens were tested for HSV by real-time PCR, and the positive rate was 23.7% (44/186). Among the 44 positive specimens, 8 (18.2%) were positive for HSV-1 with a viral load of 8.5546×10(6) copies/ml and 36 (81.2%) were positive for HSV-2 with a viral load of 1.9861×10(6) copies/ml. It is concluded that the real-time PCR is a specific, sensitive and rapid method for the detection and typing of HSV, which can be widely used in clinical diagnosis of GH.