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Population aging is a prominent global problem in today's society. However, there are currently no good methods to treat or prevent aging, so anti-aging research has crucial implications. In this research, we screened bacteria from centenarians, and finally selected four probiotics (Lactobacillus fermentum SX-0718, L. casei SX-1107, Bifidobacterium longum SX-1326 , and B. animalis SX-0582) to form a probiotic combination. By using the senescence accelerated mouse prone 8 (SAMP8) model, the anti-aging effects of the probiotic combination were evaluated by using behavioural testing, neuroinflammation, intestinal inflammation, and intestinal microbiota. The results showed that probiotic combination improved the impaired spatial memory, motor dysfunction, and decreased exploratory behavior in aging mice. The probiotic combination inhibited Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NFκB)-induced neuroinflammation and up-regulated the expression of Sirt 1 to protect hippocampal neurons. At the same time, the probiotic combination regulated the intestinal microbiota, reduced the relative abundance of Alistipes and Prevotella in SAMP8 mice, inhibited TLR4/NFκB-induced intestinal inflammation, and increased the expression of intestinal permeability related proteins zonula occludens-1 (ZO-1) and Occuldin. The anti-aging effects of the probiotic combination may be through the regulating intestinal microbiota and inhibiting TLR4/NFκB-induced inflammation. This research provides the basis and technical support for the future production and application of the probiotic combination. [ABSTRACT FROM AUTHOR]

Population aging is a prominent global problem in today’s society. However, there are currently no good methods to treat or prevent aging, so anti-aging research has crucial implications. In this research, we screened bacteria from centenarians, and finally selected four probiotics (Lactobacillus fermentum SX-0718, L. casei SX-1107, Bifidobacterium longum SX-1326, and B. animalis SX-0582) to form a probiotic combination. By using the senescence accelerated mouse prone 8 (SAMP8) model, the anti-aging effects of the probiotic combination were evaluated by using behavioural testing, neuroinflammation, intestinal inflammation, and intestinal microbiota. The results showed that probiotic combination improved the impaired spatial memory, motor dysfunction, and decreased exploratory behavior in aging mice. The probiotic combination inhibited Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NFκB)-induced neuroinflammation and up-regulated the expression of Sirt 1 to protect hippocampal neurons. At the same time, the probiotic combination regulated the intestinal microbiota, reduced the relative abundance of Alistipes and Prevotella in SAMP8 mice, inhibited TLR4/NFκB-induced intestinal inflammation, and increased the expression of intestinal permeability related proteins zonula occludens-1 (ZO-1) and Occuldin. The anti-aging effects of the probiotic combination may be through the regulating intestinal microbiota and inhibiting TLR4/NFκB-induced inflammation. This research provides the basis and technical support for the future production and application of the probiotic combination.

Inflammasome activation is mediated by NOD-like receptors (NLRs) that play important role in cellular proliferation. NLRP3 senses the widest array of stimuli. But its role in the liver regeneration after partial hepatectomy (PHx) is still unknown. Dexmedetomidine (Dex) has been documented to protect the liver against ischemia-reperfusion injury via the suppression of the TLR4/NF-κB pathway, which is important for NLRP3 inflammasome activation and liver regeneration. We tested whether Dex contributes to liver regeneration, and investigated its consequent effect on inflammasome activation. In vitro, L02 human liver cells were treated with Dex at different concentrations. The 70% PHx was performed in C57 BL/6 mice as PHx group, and sham-operated animals as Sham group, Dex-treated animals were assigned into two groups: Dex + PHx, which received single intraperitoneal injections of Dex (25 μg/kg) before PHx 30 mins; Dex + PHx + Dex, which received additional Dex (25 μg/kg) after PHx for 3 days. Dex significantly inhibited the proliferation of Lo2 cells in vitro and decreased the expression of TLR4/NFκB. In vivo, Dex + PHx exhibited promoted effect on liver regeneration and liver function recovery via inhibiting NLRP3 inflammasome activation. Dex + PH + Dex inhibited the liver regeneration, which may be associated with suppressed expression levels of TLR4/NFκB pathway. Though Dex pretreatment contributed to liver regeneration and function recovery via inflammation suppression, excessive inflammation suppression accompanied with TLR4 suppression could be related to the diminished liver regeneration, suggesting that TLR4/NFκB played important role in liver regeneration and Dex + PHx might be a useful therapeutic strategy to promote liver regeneration in clinical. [ABSTRACT FROM AUTHOR]

Astrocytes have critical roles in immune defense, homeostasis, metabolism, and synaptic remodeling and function in the central nervous system (CNS); however, excessive activation of astrocytes with increased intermediate filaments following neuronal trauma, infection, ischemia, stroke, and neurodegenerative diseases results in a pro-inflammatory environment and promotes neuronal death. As an important neurotrophic factor, the secretion of endogenous basic fibroblast growth factor (bFGF) contributes to the protective effect of neuronal cells, but the mechanism of bFGF in reactive astrogliosis is still unclear. In this study, we demonstrated that exogenous bFGF attenuated astrocyte activation by reducing the expression of glial fibrillary acidic protein (GFAP) and other markers, including neurocan and vimentin, but not nestin and decreased the levels of pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), via the regulation of the upstream toll-like receptor 4/nuclear factor κB (TLR4/NFκB) signaling pathway. Our study suggests that the function of bFGF is not only related to the neuroprotective and neurotrophic effect but also involved in the inhibition of excessive astrogliosis and glial scarring after neuronal injury. [ABSTRACT FROM AUTHOR]

ACTG-toxin H (AH) originates from Alternaria sp. In this study, we explored the molecular mechanism underlying the anti-inflammatory properties of AH. Treatment with AH inhibited lipopolysaccharide (LPS)-induced interleukin-6, IL-1β, inducible nitric oxide synthase, and cyclooxygenase-2 expression and nitric oxide production. Furthermore, AH inhibited LPS-induced P38 MAPK and Akt activation in RAW264.7 cells. Electrophoretic mobility shift assays (EMSAs) showed that AH inhibited LPS-induced nuclear factor-κB (NFκB) DNA-binding activity. Using transfection assay and measurement of an NFκB-sensitive promoter region, we found that transfection of toll-like receptor 4 (TLR4) increased LPS-induced NFκB transcription activity in 293T cells. AH significantly blocked LPS-induced NFκB activation in TLR4-transfected cells. Taken together, our data indicated that anti-inflammatory properties of AH resulted from the inhibition of proinflammatory cytokines and enzyme production via the TLR4/NFκB signaling pathway. [ABSTRACT FROM AUTHOR]

Mycotoxins are toxic metabolites produced by fungal species that occur frequently in cereals and animal forages throughout the world, posing a serious threat to humans and animals. Although some studies showed the immunotoxicity of mycotoxins, little research focused on the two-way effects of mycotoxins on immune response in vitro and vivo. Here, we explored the effects of deoxynivalenol (DON), one of the most widely distributed mycotoxins, on immune function of piglets and porcine alveolar macrophages (PAMs), and found it exhibited bidirectional immune effects due to different exposure doses. Our results revealed that low doses of DON increased the expressions of TNF-α and IL-6 in piglets and PAMs, promoted the chemotaxis and phagocytosis of PAMs and transformed macrophages to M1 phenotype (P < 0.05). Conversely, high doses of DON increased the expressions of TGF-β and IL-10 in piglets and PAMs, inhibited the chemotaxis and phagocytosis of PAMs and induced macrophages M2-type polarization (P < 0.05). Mechanistically, DON exposure significantly activated the TLR4/NFκB pathway at low doses and induced mitophagy-mediated mitochondrial dysfunction at high doses in vitro and vivo. TLR4 interference and mitophagy activator, CCCP, were used to further confirm their roles. Therefore, we concluded that DON exposure at low doses caused immunostimulation via activating TLR4/NFκB, whereas it was immunoinhibitory at high doses through blocking mitophagy. Our study suggested that both high and low doses mycotoxins contamination might be harmful, and further back up the necessity to take a vigilant attitude to minimize humans and animals intake of mycotoxins in the environment. Image 10453 • Both high and low doses mycotoxin contamination could be harmful to animals. • DON displayed two-way immune effects on piglets and PAMs. • DON was immunostimulatory at low doses, but immunoinhibitory at high doses. • DON induced immunosimulation by activating TLR4/NFκB signaling pathway. • DON induced immunosuppression by inhibiting mitophagy. [ABSTRACT FROM AUTHOR]

The addition of repeated lipopolysaccharide (LPS) to chronic mild stress was recently proposed in our lab as an alternative model of depression, highlighting the possible interaction between stress and immune-inflammatory pathways in predisposing depression. Given that CMS-induced depressive behavior was previously related to impaired hippocampal energy metabolism and mitochondrial dysfunction, our current study aimed to investigate the interplay between toll-like receptor 4 (TLR4) signaling and peroxisome proliferator-activated receptor gamma coactivators-1-alpha (PGC1-α) as a physiological regulator of energy metabolism and mitochondrial biogenesis in the combined LPS/CMS model. Male Wistar rats were exposed to either LPS (50 μg/kg i.p.) over 2 weeks, CMS protocol for 4 weeks or LPS over 2 weeks followed by 4 weeks of CMS (LPS/CMS). Three additional groups of rats were exposed to LPS/CMS protocol and treated with either pentoxifylline (PTX), fluoxetine (FLX) or a combination of both. Rats were examined for behavioral, neurochemical, gene expression and mitochondrial ultra-structural changes. LPS/CMS increased the expression of TLR4 and its downstream players; MyD88, NFκB and TNF-α along with an escalation in hippocampal-energy metabolism and p-AMPK. Simultaneously LPS/CMS attenuated the expression of PGC1-α/NRF1/Tfam and mt-DNA. The antidepressant (AD) 'FLX', the TNF-α inhibitor 'PTX' and their combination ameliorated the LPS/CMS-induced changes. Interestingly, all the aforementioned changes induced by the LPS/CMS combined model were significantly less than those induced by CMS alone. Blocking the TLR4/NFκB signaling enhanced the activation of the PGC1-α/NRF1/Tfam and mt-DNA content independent on the activation of the energy-sensing kinase AMPK. Signaling pathways implicating the crosstalk between TLR4 signaling and mitochondrial biogenesis: Effects of fluoxetine and pentoxifylline. (1) Stimulation of TLR4 by repeated administration of low doses of LPS may lead to the recruitment of the TLR4 signaling adaptor protein TIRAP which in turn activate MYD88 adaptor protein which culminates in the activation of NFκB. Once activated the NFκB translocate to the nucleus leading to an enhancement in the expression of pro-inflammatory cytokine such as TNF-α. (2) CMS-exposure will engender further stimulation of TLR4; either through the enhanced translocation of LPS from the gut (leaky gut theory) or the stress-induced production of DAMP. This subsequent stimulation of TLR4 may further activate the MyD88 and NFκB pathway. CMS may cause a further increase in the mediators such as TNF-α; which in turn may also lead to the activation to the NFκB. (3) The CMS may also induce a significant enhancement in the release of glucocorticoids that may induce mitochondrial damage directly or indirectly via translocation into the nucleus. The resultant mitochondrial dysfunction may lead to a decrease in the energy production and a consequent elevation in the AMP/ATP ratio; an established activator of the mitochondrial biogenesis via activation of PGC-1α. (4) A shared component in such pathway is the enhanced activation of the core co-activators and/or transcription factors controlling mitochondrial biogenesis "PGC-1α, NRF1 and TFAM". PGC-1α activates the expression of the nuclear respiratory factor NRF1 that in turn regulate the transcription of the mitochondrial transcription factor TFAM which contribute to the regulation of mitochondrial biogenesis. However, the enhanced NFκB activation may attenuate the activation of the PGC-1α and its downstream players thus hindering mitochondrial biogenesis. CMS: Chronic mild stress; DAMP: Damage associated molecular pattern; FLX: Fluoxetine; mt-DNA: Mitochondrial DNA; MyD88: Myeloid differentiation protein 88 ; NFκB: Nuclear factor kappa-B; NRF1: Nuclear respiratory factor 1; PGC-1α: Peroxisome proliferator-activated receptor gamma co-activators1-alpha; PTX: Pentoxifylline; TFAM: Mitochondrial transcription factor A; TLR4 : Toll like receptor 4; TNF-α Tumor necrosis factor α; TIRAP: Toll-interleukin 1 receptor (TIR) domain containing adaptor protein, ** The LPS challenge, majority of the stressors application, drug administrations and behavioral testing were done in the dark cycle. Image 1 [ABSTRACT FROM AUTHOR]

Astrocytes have critical roles in immune defense, homeostasis, metabolism, and synaptic remodeling and function in the central nervous system (CNS); however, excessive activation of astrocytes with increased intermediate filaments following neuronal trauma, infection, ischemia, stroke, and neurodegenerative diseases results in a pro-inflammatory environment and promotes neuronal death. As an important neurotrophic factor, the secretion of endogenous basic fibroblast growth factor (bFGF) contributes to the protective effect of neuronal cells, but the mechanism of bFGF in reactive astrogliosis is still unclear. In this study, we demonstrated that exogenous bFGF attenuated astrocyte activation by reducing the expression of glial fibrillary acidic protein (GFAP) and other markers, including neurocan and vimentin, but not nestin and decreased the levels of pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), via the regulation of the upstream toll-like receptor 4/nuclear factor κB (TLR4/NFκB) signaling pathway. Our study suggests that the function of bFGF is not only related to the neuroprotective and neurotrophic effect but also involved in the inhibition of excessive astrogliosis and glial scarring after neuronal injury.