Intercellular competitive growth dynamics with microenvironmental feedback.

Normal life activities between cells rely crucially on the homeostasis of the cellular microenvironment, but aging and cancer will upset this balance. In this paper we introduce the microenvironmental feedback mechanism to the growth dynamics of multicellular organisms, which changes the cellular competitive ability and thereby regulates the growth of multicellular organisms. We show that the presence of microenvironmental feedback can effectively delay aging, but cancer cells may grow uncontrollably due to the emergence of the tumor microenvironment (TME). We study the effect of the fraction of cancer cells relative to that of senescent cells on the feedback rate of the microenvironment on the lifespan of multicellular organisms and find that the average lifespan shortened is close to the data for non-Hodgkin's lymphoma in Canada from 1980 to 2015. We also investigate how the competitive ability of cancer cells affects the lifespan of multicellular organisms and reveal that there is an optimal value of the competitive ability of cancer cells allowing the organism to survive longest. Interestingly, the proposed microenvironmental feedback mechanism can give rise to the phenomenon of Parrondo's paradox: When the competitive ability of cancer cells switches between a too-high and a too-low value, multicellular organisms are able to live longer than in each case individually. Our results may provide helpful clues for targeted therapies aimed at the TME.

Comprehensive analysis of prognostic value and immunotherapy prospect of brain cytoplasmic RNA1 in hepatocellular carcinoma.

BACKGROUND: The expression of brain cytoplasmic RNA1 (BCYRN1) is linked to the clinicopathology and prognosis of several types of cancers, among which hepatocellular carcinoma (HCC) is one of the most frequent types of cancer worldwide. AIM: To explore the prognostic value and immunotherapeutic potential of BCYRN1 in HCC by bioinformatics and meta-analysis. METHODS: Information was obtained from the Cancer Genome Atlas database. First, the correlation between BCYRN1 expression and prognosis and clinicopathologic characteristics of HCC patients was explored. Univariate and multivariate regression analyses were employed to examine the relationship between BCYRN1 and HCC prognosis. Secondly, potential functions and pathways were explored by means of enrichment analysis of differentially-expressed genes. The relationships between BCYRN1 expression and tumor microenvironment, immune cell infiltration, immune checkpoint, drug sensitivity and immunotherapy effect were also investigated. Finally, three major databases were searched and used to conduct a meta-analysis on the relationship between BCYRN1 expression and patient prognosis. RESULTS: BCYRN1 expression was significantly higher in HCC compared to normal tissues and was linked to a poor prognosis and clinicopathological characteristics. Enrichment analysis showed that BCYRN1 regulates the extracellular matrix and transmission of signaling molecules, participates in the metabolism of nutrients, such as proteins, and participates in tumor-related pathways. BCYRN1 expression was linked to the tumor microenvironment, immune cell infiltration, drug sensitivity and the efficacy of immunotherapy. Furthermore, the meta-analysis in this study showed that BCYRN1 overexpression was related to a worse outcome in HCC patients. CONCLUSION: Overexpression of BCYRN1 relates to poor prognosis and may be a potential prognostic factor and immunotherapeutic target in HCC.

Comparison between laparoscopic uncut Roux-en-Y and Billroth II with Braun anastomosis after distal gastrectomy: A meta-analysis.

BACKGROUND: Conventional Billroth II (BII) anastomosis after laparoscopic distal gastrectomy (LDG) for gastric cancer (GC) is associated with bile reflux gastritis, and Roux-en-Y anastomosis is associated with Roux-Y stasis syndrome (RSS). The uncut Roux-en-Y (URY) gastrojejunostomy reduces these complications by blocking the entry of bile and pancreatic juice into the residual stomach and preserving the impulse originating from the duodenum, while BII with Braun (BB) anastomosis reduces the postoperative biliary reflux without RSS. Therefore, the purpose of this study was to compare the efficacy and safety of laparoscopic URY with BB anastomosis in patients with GC who underwent radical distal gastrectomy. AIM: To evaluate the value of URY in patients with GC. METHODS: PubMed, Embase, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang, Chinese Biomedical Database, and VIP Database for Chinese Technical Periodicals (VIP) were used to search relevant studies published from January 1994 to August 18, 2021. The following databases were also used in our search: Clinicaltrials.gov, Data Archiving and Networked Services, the World Health Organization International Clinical Trials Registry Platform Search Portal (https://www.who.int/clinical-trials-registry-platform/the-ictrp-search-portal), the reference lists of articles and relevant conference proceedings in August 2021. In addition, we conducted a relevant search by Reference Citation Analysis (RCA) (https://www.referencecitationanalysis.com). We cited high-quality references using its results analysis functionality. The methodological quality of the eligible randomized clinical trials (RCTs) was evaluated using the Cochrane Risk of Bias Tool, and the non-RCTs were evaluated using the Newcastle-Ottawa scale. Statistical analyses were performed using Review Manager (Version 5.4). RESULTS: Eight studies involving 704 patients were included in this meta-analysis. The incidence of reflux gastritis [odds ratio = 0.07, 95% confidence interval (CI): 0.03-0.19, P < 0.00001] was significantly lower in the URY group than in the BB group. The pH of the postoperative gastric fluid was lower in the URY group than in the BB group at 1 d [mean difference (MD) = -2.03, 95%CI: (-2.73)-(-1.32), P < 0.00001] and 3 d [MD = -2.03, 95%CI: (-2.57)-(-2.03), P < 0.00001] after the operation. However, no significant difference in all the intraoperative outcomes was found between the two groups. CONCLUSION: This work suggests that URY is superior to BB in gastrointestinal reconstruction after LDG when considering postoperative outcomes.

GM-CSF-miRNA-Jak2/Stat3 Signaling Mediates Chemotherapy-Induced Cancer Cell Stemness in Gastric Cancer.

Chemotherapy serves as the first choice in clinic to treat advanced gastric cancer. However, emerging evidence indicated the induction of drug resistance and cancer stem cells occasionally by chemotherapy, which seriously limit the therapeutic effects, but the regulatory mechanism remains unclear. Here we treated two human gastric cancer cell lines SGC7901 and BGC823 with 5-Fluorouracil (5-Fu) or Cisplatin (DDP) in vitro. The survived cells showed significant increase of drug resistance, cell stemness and cytokine GM-CSF expression and secretion. As such, GM-CSF was applied to stimulate gastric cancer cells, followed by the subpopulation of CD133 + CSC analysis, sphere formation assay and stemness genes expression analysis. As a result, CSCs showed induction by GM-CSF treatment. A gastric cancer animal model further indicated that the gastric cancer cells significantly promoted tumor growth after GM-CSF treatment in vivo. High-throughput miRNA and mRNA sequencing analyses identified a subset of miRNAs and mRNAs under regulation of both 5-Fu and GM-CSF in gastric cancer cells, including upregulation of miR-877-3p and downregulation of SOCS2. Targeted overexpression or knockdown of miR-877-3p in gastric cancer cells revealed the oncogenic function of miR-877-3p in regulating gastric cancer by suppressing target gene SOCS2. Jak2/Stat3 signaling pathway, as a downstream target of SOCS2, showed activation in vitro and in vivo after treatment with miR-877-3p or GM-CSF. Our findings not only revealed a novel mechanism through which chemotherapy induced CSCs in gastric cancer via GM-CSF-miRNA-Jak2/Stat3 signaling, but also provided an experimental evidence for appropriate dose reduction of adjuvant chemotherapy in treatment of cancer patients.

Aloe-emodin induces hepatotoxicity by the inhibition of multidrug resistance protein 2.

BACKGROUND: Aloe-emodin (AE) is among the primary bioactive anthraquinones present in traditional Chinese medicinal plants such as Rheum palmatum L. Multidrug resistance protein 2 (ABCC2/ MRP2) is an important efflux transporter of substances associated with cellular oxidative stress. However, the effects of traditional Chinese medicine on this protein remain unclear. PURPOSE: The aim of this research is to study the role of ABCC2 in AE-induced hepatotoxicity. METHODS: The expression of ABCC2 protein and mRNA levels were analyzed by Western-Blotting and qRT-PCR, respectively. The intracellular oxidative stress caused by AE was evaluated by quantifying the levels of intracellular reactive oxygen species, malondialdehyde, glutathione reduced and oxidized glutathione. The levels of adenosine triphosphate, mitochondrial membrane potential and mitochondrial DNA were explored to evaluate the effects of AE on mitochondrial function. The effects of AE on cell apoptosis and cell cycle were detected by flow cytometry. To further clarify the key role of ABCC2 in AE induced cytotoxicity, we used pCI-neo-ABCC2 plasmid to over express ABCC2 protein, and small interfering RNA was used to knockdown ABCC2 in HepG2 cells. Additionally, we investigated the impact of AE on ABCC2 degradation pathway and the hepatotoxic effects of AE in mice. RESULTS: AE was found to inhibit ABCC2 transport activity, downregulate ABCC2 expression and altered intracellular redox balance. Induction of oxidative stress resulted in depletion of intracellular glutathione reduced, mitochondria dysfunction and activation of apoptosis. ABCC2 overexpression significantly reduced AE-induced intracellular oxidative stress and cell death, which was enhanced by ABCC2 knockdown. Furthermore, AE was observed to promote ABCC2 degradation through induction of autophagy and hepatotoxicity was induced in mice by promoting ABCC2 degradation. CONCLUSIONS: The inhibition of ABCC2 is a novel effect of AE that triggers oxidative stress and apoptosis. These findings are helpful in understanding the toxicological effects of AE-containing medicinal plants.

A new abietane diterpenoid from Ajuga ovalifolia var. calantha induces human lung epithelial A549 cell apoptosis by inhibiting SHP2.

The Src-homology 2 domain-containing phosphatase 2 (SHP2), encoded by PTPN11, has been reported oncogenic tyrosine phosphatase associated with various tumors and played critical roles in many cell signaling events. Targeting SHP2 by small molecules may be a promising way for cancer therapy. Herein, a new abietane diterpenoid, named 3-acetoxylteuvincenone G (3-AG), was isolated from the whole plants of Ajuga ovalifolia var. calantha. The structure of the new compound was elucidated by means of extensive spectroscopic analyses. Using recombinant enzyme activity assay and cellular thermal shift assay, we found that 3-AG was a selective inhibitor of SHP2. Molecular docking suggested 3-AG displayed an orientation favorable to nucleophilic attack in the catalytic domain of SHP2. 3-AG suppressed A549 cell proliferation (IC50 = 10.79 ± 0.14 µM), invasion and induced cell apoptosis through SHP2/ERK1/2 and SHP2/AKT pathways. In summary, 3-AG, a potent, selective, and efficacious SHP2 inhibitor, may be a promising small molecule to treat human lung epithelial cancer.

Substance P combined with epidermal stem cells promotes wound healing and nerve regeneration in diabetes mellitus.

Exogenous substance P accelerates wound healing in diabetes, but the mechanism remains poorly understood. Here, we established a rat model by intraperitoneally injecting streptozotocin. Four wounds (1.8 cm diameter) were drilled using a self-made punch onto the back, bilateral to the vertebral column, and then treated using amniotic membrane with epidermal stem cells and/or substance P around and in the middle of the wounds. With the combined treatment the wound-healing rate was 100% at 14 days. With prolonged time, type I collagen content gradually increased, yet type III collagen content gradually diminished. Abundant protein gene product 9.5- and substance P-immunoreactive nerve fibers regenerated. Partial nerve fiber endings extended to the epidermis. The therapeutic effects of combined substance P and epidermal stem cells were better than with amniotic membrane and either factor alone. Our results suggest that the combination of substance P and epidermal stem cells effectively contributes to nerve regeneration and wound healing in diabetic rats.

Microencapsulation improves inhibitory effects of transplanted olfactory ensheathing cells on pain after sciatic nerve injury.

Olfactory bulb tissue transplantation inhibits P2X2/3 receptor-mediated neuropathic pain. However, the olfactory bulb has a complex cellular composition, and the mechanism underlying the action of purified transplanted olfactory ensheathing cells (OECs) remains unclear. In the present study, we microencapsulated OECs in alginic acid, and transplanted free and microencapsulated OECs into the region surrounding the injured sciatic nerve in rat models of chronic constriction injury. We assessed mechanical nociception in the rat models 7 and 14 days after surgery by measuring paw withdrawal threshold, and examined P2X2/3 receptor expression in L4-5 dorsal root ganglia using immunohistochemistry. Rats that received free and microencapsulated OEC transplants showed greater withdrawal thresholds than untreated model rats, and weaker P2X2/3 receptor immunoreactivity in dorsal root ganglia. At 14 days, paw withdrawal threshold was much higher in the microencapsulated OEC-treated animals. Our results confirm that microencapsulated OEC transplantation suppresses P2X2/3 receptor expression in L4-5 dorsal root ganglia in rat models of neuropathic pain and reduces allodynia, and also suggest that transplantation of microencapsulated OECs is more effective than transplantation of free OECs for the treatment of neuropathic pain.

[Experimental study on the differentiation of human induced pluripotent stem cells into epidermal-like stem cells].

OBJECTIVE: To investigate the feasibility of differentiation of human induced pluripotent stem cells (iPSCs) into epidermal-like stem cells. METHODS: (1) Human strain of iPSCs were plated on-to trophoblast of inactivated Fb strain of mouse embryos and cultured in complete medium of embryonic stem cells, iPSCs were subcultured by collagenase IV digestion method. The morphology and growth of iPSCs were observed under inverted phase contrast microscope, and the cells were stained with alkaline phosphatase (AKP). iPSCs were cultured in incomplete medium of embryonic stem cells to observe the ability of embryoid body formation. (2) Human iPSCs were inoculated onto 6-well plate covered with human amniotic membrane to culture as induction group. Other iPSCs were cultured on 6-well plate without human amniotic membrane as control group. Morphological changes in iPSCs in two groups were observed. Expressions of integrin beta1 and CK19 of iPSCs in two groups were determined by immunocytochemical staining. RESULTS: Human iPSCs showed a typical stem cell clone-like growth with a clear boundary, and they proliferated vigorously in complete medium of embryonic stem cells. These cells were AKP-positive. iPSCs formed embryoid body in trophoblast-free and suspension culture conditions. After 4 days of co-culture, stem cell clones were formed on the surface of amniotic membrane in induction group, and part of the cells were integrin beta1 and CK19 positive. Most of the cells died, and no integrin beta1 and CK19 positive cells were found in control group. CONCLUSIONS: Human iPSCs can be differentiated into epidermal-like stem cells by amniotic membrane induction, and it lays an experimental basis for providing new source of seed cells of skin tissue engineering.

[Differential expression profile of microRNA between hyperplastic scar and normal skin].

OBJECTIVE: To explore the miRNA differential expression profiles of hyperplastic scar and normal skin so as to further elucidate the pathogenesis of hyperplastic scar and search for new therapeutic targets. METHODS: The total RNA was extracted from 5 human hyperplastic scar and normal skin tissues by Trizol. The specimens were collected from the First Affiliated Hospital of Nanchang University from November 2010 to May 2011, and purified by mirVana(TM) miRNA Isolation Kit and then labeled and hybridized by miRNA Complete Labeling and Hyb Kit. The images of hybridization were analyzed by the Feature Extraction (v10.7) software and the microarray results confirmed by quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: In hyperplastic scar, 92 miRNA genes were up-regulated and 13 down-regulated. The most significantly up-regulated miRNAs were hsa-miR-564 and hsa-miR-936, etc. while hsa-miR-451, hsa-miR-223, hsa-miR-363 and hsa-miR-29b-1* became significantly down-regulated. The findings of RT-PCR on hsa-miR-21 and hsa-miR-451 of regulation were in a high concordance with the microarray results. CONCLUSION: Distinct differences of miRNA expression between human hyperplastic scar and normal skin, it may be closely correlated with the formation, development and evolution of hyperplastic scar.

[Analysis of total alkaloids in Meconopsis quintuplinervia from different localtites of Qinghai].

The contents of total alkaloids in Meconopsis quintuplinervia Regel, grown in the different localtites of Qinghai Province, are detected by the method of spectrophometry. The result showed that total alkaloid in different localities were 0. 0262% to approximately 0.0788% , its mean was 0.0502%. The content of total alkaloids in the herb increased with elevation, not with latitude.