Hepatocellular Carcinoma Cell-Derived Exosomal miR-21-5p Induces Macrophage M2 Polarization by Targeting RhoB.

M2-like polarized tumor-associated macrophages (TAMs) are the major component of infiltrating immune cells in hepatocellular carcinoma (HCC), which have been proved to exhibit significant immunosuppressive and pro-tumoral effects. However, the underlying mechanism of the tumor microenvironment (TME) educating TAMs to express M2-like phenotypes is still not fully understood. Here, we report that HCC-derived exosomes are involved in intercellular communications and exhibit a greater capacity to mediate TAMs' phenotypic differentiation. In our study, HCC cell-derived exosomes were collected and used to treat THP-1 cells in vitro. Quantitative polymerase chain reaction (qPCR) results showed that the exosomes significantly promoted THP-1 macrophages to differentiate into M2-like macrophages, which have a high production of transforming growth factor-ß (TGF-ß) and interleukin (IL)-10. The analysis of bioinformatics indicated that exosomal miR-21-5p is closely related to TAM differentiation and is associated with unfavorable prognosis in HCC. Overexpressing miR-21-5p in human monocyte-derived leukemia (THP-1) cells induced down-regulation of IL-1ß levels; however, it enhanced production of IL-10 and promoted the malignant growth of HCC cells in vitro. A reporter assay confirmed that miR-21-5p directly targeted Ras homolog family member B (RhoB) 3'-untranslatedregion (UTR) in THP-1 cells. Downregulated RhoB levels in THP-1 cells would weaken mitogen-activated protein kinase (MAPK) axis signaling pathways. Taken together, tumor-derived miR-21-5p promote the malignant advance of HCC, which mediated intercellular crosstalk between tumor cells and macrophages. Targeting M2-like TAMs and intercepting their associated signaling pathways would provide potentially specific and novel therapeutic approaches for HCC treatment.

Probiotics improves abnormal behavior and hippocampal injury in pregnant-stressed offspring rats. / ç›Šç”ŸèŒæ”¹å–„å­•æœŸåº”æ¿€å­ä»£å¤§é¼ å¼‚å¸¸è¡Œä¸ºå’Œæµ·é©¬æŸä¼¤.

OBJECTIVES: During pregnancy, pregnant women are prone to stress reactions due to external stimuli, affecting their own health and fetal development. At present, there is no good treatment for the stress reactions from pregnant women during pregnancy. This study aims to explore the effect of probiotics on abnormal behavior and hippocampal injury in pregnant stressed offspring. METHODS: SD pregnant rats were divided into a control group, a stress group, and a probiotics group, with 6 rats in each group. The control group was untreated; the stress group was given restraint stress on the 15th-20th day of pregnancy; the probiotics group was given both bifidobacterium trisporus capsules and restraint stress on the 15th-20th day of pregnancy, and the offspring continued to be fed with probiotics until 60 days after birth (P60). The offspring rats completed behavioral tests such as the open field test, the elevated plus maze test, the new object recognition test, and the barnes maze test at 60-70 d postnatally. Nissl's staining was used to reflect the injury of hippocampal neurons; immunohistochemical staining was used to detect the expression of microglia marker ionized calcium binding adapter molecule 1 (IBA-1) which can reflect microglia activation; ELISA was used to detect the content of plasma TNF-α and IL-1ß; Western blotting was used to detect the expression of Bax, Bcl-2, and caspase-3. RESULTS: The retention time of offspring rats in the stress group in the central area of the open field was significantly less than that in the control group (P<0.01), and the retention time of offspring rats in the probiotic group in the central area of the open field was significantly more than that in the stress group (P<0.05). The offspring rats in the stress group stayed in the open arm for a shorter time than the control group (P<0.05) and entered the open arm less often than the control group (P<0.01); the offspring rats in the probiotic group stayed in the open arm for a longer time than the stress group and entered the open arm more often than the stress group (both P<0.05). The discrimination ratio for new to old objects in the offspring rats of the stress group was significantly lower than that of the control group (P<0.01), and the discrimination ratio for new to old objects in the offspring rats of the probiotic group was significantly higher than that of the stress group (P<0.05). The offspring rats in the stress group made significantly more mistakes than the control group (P<0.05), and the offspring rats in the probiotic group made significantly fewer mistakes than the stress group (P<0.05). Compared with the control group, the numbers of Nissl bodies in CA1, CA3, and DG area were significantly reduced in the offspring rats of the stress group (all P<0.001), the number of activated microglia in DG area of hippocampus was significantly increased (P<0.01), the contents of TNF-α and IL-1ß in peripheral blood were significantly increased (P<0.05 or P<0.01), the protein expression level of Bcl-2 was significantly down-regulated, and the protein expression levels of Bax and caspase-3 were significantly up-regulated (all P<0.001). Compared with the stress group, the numbers of Nissl bodies in CA1, CA3, and DG area were significantly increased in the probiotic group offspring rats (P<0.001, P<0.01, P<0.05), the number of activated microglia in the DG area of hippocampus was significantly reduced (P<0.05), and the TNF-α and IL-1ß levels in peripheral blood were significantly decreased (both P<0.05), the protein expression level of Bcl-2 was significantly up-regulated, and the protein expression levels of Bax and caspase-3 were significantly down-regulated (all P<0.001). CONCLUSIONS: Probiotic intervention partially ameliorated anxiety and cognitive impairment in rats offspring of pregnancy stress, and the mechanism may be related to increasing the number of neurons, inhibiting the activation of hippocampal microglia, and reducing inflammation and apoptosis.

HIV-Proteins-Associated CNS Neurotoxicity, Their Mediators, and Alternative Treatments.

Human immunodeficiency virus (HIV)-infected people's livelihoods are gradually being prolonged with the use of combined antiretroviral therapy (ART). Conversely, despite viral suppression by ART, the symptoms of HIV-associated neurocognitive disorder (HAND) endure. HAND persists because ART cannot really permanently confiscate the virus from the body. HAND encompasses a variety of conditions based on clinical presentation and severity level, comprising asymptomatic neurocognitive impairment, moderate neurocognitive disorder, and HIV-associated dementia. During the early stages of HIV infection, inflammation compromises the blood-brain barrier, allowing toxic virus, infected monocytes, macrophages, T-lymphocytes, and cellular products from the bloodstream to enter the brain and eventually the entire central nervous system. Since there are no resident T-lymphocytes in the brain, the virus will live for decades in macrophages and astrocytes, establishing a reservoir of infection. The HIV proteins then inflame neurons both directly and indirectly. The purpose of this review is to provide a synopsis of the effects of these proteins on the central nervous system and conceptualize avenues to be considered in mitigating HAND. We used bioinformatics repositories extensively to simulate the transcription factors that bind to the promoter of the HIV-1 protein and possibly could be used as a target to circumvent HIV-associated neurocognitive disorders. In the same vein, a protein-protein interaction complex was also deduced from a Search Tool for the Retrieval of Interacting Genes. In conclusion, this provides an alternative strategy that could be used to avert HAND.

Extracellular vesicles derived from mesenchymal stem cells: A platform that can be engineered.

Mesenchymal stem cells play an important role in tissue damage and repair. This role is mainly due to a paracrine mechanism, and extracellular vesicles (EVs) are an important part of the paracrine function. EVs play a vital role in many aspects of cell homeostasis, physiology, and pathology, and EVs can be used as clinical biomarkers, vaccines, or drug delivery vehicles. A large number of studies have shown that EVs derived from mesenchymal stem cells (MSC-EVs) play an important role in the treatment of various diseases. However, the problems of low production, low retention rate, and poor targeting of MSC-EVs are obstacles to current clinical applications. The engineering transformation of MSC-EVs can make up for those shortcomings, thereby improving treatment efficiency. This review summarizes the latest research progress of MSC-EV direct and indirect engineering transformation from the aspects of improving MSC-EV retention rate, yield, targeting, and MSC-EV visualization research, and proposes some feasible MSC-EV engineering methods of transformation.