Animal models and experimental medicine最新文献

Stem cells possess the unique ability to develop into different cell types within the body. Researchers are exploring the use of different types of stem cells to potentially repair damaged blood vessels, reduce inflammation, and improve overall vascular function, all of which are crucial factors in pulmonary hypertension (PH). While it is important to acknowledge that further clinical studies and trials are necessary to fully understand the efficacy and safety of stem cell therapy for PH, ongoing research and initial findings present promising avenues for potentially developing new treatments or therapeutic strategies for PH.

Background: Intestinal organoids are promising tools in the context of animal experiment reduction but a thorough characterization of the impact of the origin of intestinal stem cells (ISC) on organoid phenotype is needed to routinely use this cellular model. Our objective was to evaluate the effect of ISC donor age on the growth, morphology and cellular composition of intestinal organoids derived from pig.

Methods: Organoids were derived from jejunal and colonic ISC obtained from 1-, 7-, 28-, 36- and 180-day-old pigs and passaged three times.

Results: We first confirmed by qPCR that the expression of 18% of the >80 studied genes related to various intestinal functions differed between jejunal and colonic organoids after two passages (p < 0.05). Growth and morphology of organoids depended on intestinal location (greater number and larger organoids derived from colonic than jejunal ISC, p < 0.05) but also pig age. Indeed, when ISC were derived from young piglets, the ratio of organoids to spheroids was greater (p < 0.05), spheroids were larger during the primary culture but smaller after two passages (p < 0.05) and organoids were smaller after one passage (p > 0.05) compared to ISC from older pigs. Finally, no difference in cellular composition, evaluated by immunostaining of markers of the major intestinal cell types (absorptive, enteroendocrine and goblet cells) was observed between organoids originating from 7- or 180-day-old pigs, but differences between intestinal site origins were noticed.

Conclusion: In conclusion, while the age of the tissue donor affected organoid growth and morphology, it did not influence the phenotype.

Background: Osteoarthritis (OA) is a common joint disease, and existing drugs cannot cure OA, so there is an urgent need to identify new targets. Mitophagy plays an important role in OA; however, the role of mitophagy in the OA immune system is not yet clear.

Methods: In this study, differential analysis and enrichment analysis were used to identify mitophagy-related genes (MRGs) with differential expression in OA and the functional pathways involved in OA. Subsequently, two machine learning methods, RF and LASSO, were used to screen MRGs with diagnostic value and construct nomograms. At the same time, the relationship between mitophagy and OA immune response was explored by immunoinfiltration analysis.

Results: Forty-three differentially MRGs were identified in OA, of which six MRGs (GABARAPL2, PARL, GABARAPL1, JUN, RRAS, and SNX7) were associated with the diagnosis of OA. The ROC analysis results show that these 6 MRGs have high predictive accuracy in the diagnosis of OA. In immune infiltration analysis, we found that the abundance of significantly different immune cells in OA was mostly upregulated. In addition, the expression of diagnostic-related MRGs is correlated with changes in the abundance of immune cells in OA.

Conclusion: This study demonstrates that six MRGs can be used as diagnostic biomarkers. The expression of diagnostic-related MRGs is correlated with changes in the abundance of immune cells in OA. At the same time, mitophagy may affect the immune microenvironment of OA by regulating immune cells, ultimately leading to the progression of OA.

Background: Breast cancer (BC) continues to be a significant global health issue, with a rising number of cases requiring ongoing research and innovation in treatment strategies. Curcumin (CUR), a natural compound derived from Curcuma longa, and similar compounds have shown potential in targeting the STAT3 signaling pathway, which plays a crucial role in BC progression.

Aims: The aim of this study was to investigate the effects of curcumin and its analogues on BC based on cellular and molecular mechanisms.

Materials & methods: The literature search conducted for this study involved utilizing the Scopus, ScienceDirect, PubMed, and Google Scholar databases in order to identify pertinent articles.

Results: This narrative review explores the potential of CUR and similar compounds in inhibiting STAT3 activation, thereby suppressing the proliferation of cancer cells, inducing apoptosis, and inhibiting metastasis. The review demonstrates that CUR directly inhibits the phosphorylation of STAT3, preventing its movement into the nucleus and its ability to bind to DNA, thereby hindering the survival and proliferation of cancer cells. CUR also enhances the effectiveness of other therapeutic agents and modulates the tumor microenvironment by affecting tumor-associated macrophages (TAMs). CUR analogues, such as hydrazinocurcumin (HC), FLLL11, FLLL12, and GO-Y030, show improved bioavailability and potency in inhibiting STAT3, resulting in reduced cell proliferation and increased apoptosis.

Conclusion: CUR and its analogues hold promise as effective adjuvant treatments for BC by targeting the STAT3 signaling pathway. These compounds provide new insights into the mechanisms of action of CUR and its potential to enhance the effectiveness of BC therapies.

Animal models have been a crucial tool in neuroscience research for decades, providing insights into the biomedical and evolutionary mechanisms of the nervous system, disease, and behavior. However, their use has raised concerns on several ethical, clinical, and scientific considerations. The welfare of animals and the 3R principles (replacement, reduction, refinement) are the focus of the ethical concerns, targeting the importance of reducing the stress and suffering of these models. Several laws and guidelines are applied and developed to protect animal rights during experimenting. Concurrently, in the clinic and biomedical fields, discussions on the relevance of animal model findings on human organisms have increased. Latest data suggest that in a considerable amount of time the animal model results are not translatable in humans, costing time and money. Alternative methods, such as in vitro (cell culture, microscopy, organoids, and micro physiological systems) techniques and in silico (computational) modeling, have emerged as potential replacements for animal models, providing more accurate data in a minimized cost. By adopting alternative methods and promoting ethical considerations in research practices, we can achieve the 3R goals while upholding our responsibility to both humans and other animals. Our goal is to present a thorough review of animal models used in neuroscience from the biomedical, evolutionary, and ethical perspectives. The novelty of this research lies in integrating diverse points of views to provide an understanding of the advantages and disadvantages of animal models in neuroscience and in discussing potential alternative methods.

Background: Autism and schizophrenia are environmental risk factors associated with prenatal viral infection during pregnancy. It is still unclear whether behavior phenotypes change at different developmental stages in offspring following the activation of the maternal immune system.

Methods: Sprague-Dawley rats received a single caudal vein injection of 10 mg/kg polyinosinic:polycytidylic acid (poly I:C) on gestational day 9 and the offspring were comprehensively tested for behaviors in adolescence and adulthood.

Results: Maternal serum levels of interleukin (IL)-6, IL-1β and tumor necrosis factor-α were elevated in poly I:C-treated dams. The offspring of maternal poly I:C-induced rats showed increased anxiety, impaired social approach, and progressive impaired cognitive and sensorimotor gating function.

Conclusion: Maternal immune activation led to developmental specificity behavioral impairment in offspring.

Streptozocin (STZ) aggravates diabetic atherosclerosis in aged ApoE^-/- mice. (A). Study design: ApoE^-/- mice were given STZ (50 mg/kg/day) or vehicle by intraperitoneal injection for five days consecutively to induce diabetes. (B). Body weight and blood glucose levels were measured in mice on the baseline, 16th, and 32nd weeks. (C). Representative oil red O staining of en face aorta and quantifications of the lesional area of the whole aortic tree (D). Representative micrographs stained by H&E and Oil red O (left), and quantifications of microscopic atherosclerotic area. All data are expressed as mean ± SEM; All data were tested for normality and equal variance. For analysis of body weight and blood glucose, two-way ANOVA analysis was used (B). For normally or approximately normally distributed data, a Student's t-test was performed (C, D). n = 6 mice/group. *p<0.05 and **p<0.01 vs vehicle group.

Background: A stable and standardized source of mesenchymal stem cells is a prerequisite for bone repair tissue engineering research and application. We aimed to establish a stable cell line of bone marrow mesenchymal stem cells from New Zealand rabbits and explore their osteogenic differentiation capacity.

Methods: Primary rabbit bone marrow mesenchymal stem cells (RBMSCs) were isolated and immortalized via retroviral expression of SV40 Large T antigen (LTA). To assess the osteogenic differentiation capacity of the cells in vitro, we studied the alkaline phosphatase (ALP) expression level and calcium deposition in bone morphogenetic protein 9 (BMP9)-induced immortalized cells using ALP staining and quantification, as well as alizarin red staining. Ectopic bone formation by the cells was assessed using micro-computed tomography (μCT) and histological examination.

Results: The immortalized cell line we established using SV40 LTA, which we termed iRBMSCs, was non-tumorigenic and maintained long-term proliferative activity. We further discovered that BMP9 (MOI = 30) effectively induced the osteogenic differentiation capacity of iRBMSCs in vitro, and there was a synergy with GelMA hydrogel in inducing osteogenic differentiation of the iRBMSCs in vivo.

Conclusion: We confirmed that iRBMSCs are promising as a stable cell line source for bone defect repair engineering.

Background: Esophageal strictures following esophageal atresia repair are a source of significant morbidity. To test new therapeutic approaches, we designed a piglet model of esophageal stricture by resecting variable lengths of esophagus with subsequent re-anastomosis. This study describes the model and validates its physiologic impact by blinded analysis of the weight gains of the piglets.

Methods: A total of 24 two-week old Pietrain piglets had esophageal resections performed, ranging from 0 to 5 cm, with the goal of inducing postoperative esophageal strictures. Postoperative body-weights were evaluated by repeated analysis of variance followed by pairwise group-comparisons based on estimated marginal means. In addition, body weight was modeled by linear-mixed model regression. Different resection lengths were compared. The esophagi were evaluated postmortem for stricture.

Results: Of 24 operated piglets, 23 reached the endpoint, and 90% developed an esophageal stricture that was radiologically visible in a contrast study, as well as appreciable macroscopically in the necropsy. We found differences in pre- and postoperative body weights for all piglets (F (1, 18) = 298.54, p < 0.001), but no differences between resection lengths (F (4, 18) = 0.36, p = 0.837).

Conclusion: Our model of postoperative esophageal stricture offers the opportunity to investigate potential treatments for strictures associated with esophageal atresia, since it reliably induces strictures and results in minimal loss of animals. The similar body weight gain in all groups indicates that stricture is mainly the result of esophageal resection and re-anastomosis, regardless of the length of the resected segment.

Hypertriglyceridemia (HTG) often accompanies diabetes and is considered a risk factor for diabetic vascular complications. However, inducing diabetic HTG typically requires high-fat diets in certain animal models. Leveraging our newly developed LDL receptor knockout hamster model, which exhibits features akin to human lipid metabolism, we sought to determine whether these animals would develop HTG without dietary manipulations in diabetes. Diabetes was induced via intraperitoneal injection of STZ in wild type and heterozygous LDL receptor deficient hamsters. Blood glucose, triglyceride, and cholesterol were measured over 60 days. Plasma TG clearance was determined via olive oil gavage. The effect of insulin on diabetic HTG was assessed on Day 60 post-diabetes induction. Blood glucose increased over threefold, while plasma insulin decreased to 30% of controls after STZ injection in both wild type and heterozygous hamsters by Day 7, remaining stable for 60 days. Plasma TG in wild-type hamsters remained unchanged at Day 7 post-STZ injection but increased slightly thereafter. Conversely, heterozygous hamsters exhibited severe HTG by Day 7 until the end of the study. Olive oil gavage revealed much slower plasma triglyceride clearance in heterozygous hamsters compared to WT animals, despite significantly reduced lipoprotein lipase activity in post-heparin plasma in both animals. Hyperglycemia and HTG in heterozygous hamsters were reversed to pre-diabetic levels following intraperitoneal insulin administration. In conclusion, severe HTG in diabetic heterozygous LDL receptor deficient hamsters developed spontaneously and was insulin-dependent. Thus, this hamster model holds promise for effectively studying the complications associated with human diabetic HTG.