Aloin Regulates Matrix Metabolism and Apoptosis in Human Nucleus Pulposus Cells via the TAK1/NF-κB/NLRP3 Signaling Pathway

Intervertebral disc degeneration (IDD) is a degenerative disease that is characterized by decreased matrix synthesis and extra degradation, nucleus pulposus cells (NPCs) apoptosis, and infiltration of inflammatory factors. Aloin, a colored compound from aloe plants, has been shown to be effective against skeletal degenerative diseases, but it is unclear whether it is protective against IDD. Herein, we investigated the role of aloin in NPCs. In our study, the upregulation of proinflammatory factors, apoptosis, and unbalanced matrix metabolism were observed in degenerative NP tissues. We found that aloin had a curative effect on extracellular matrix metabolism and apoptosis in TNF-alpha- (TNF-α-) treated NPCs by inhibiting oxidative stress and the proinflammatory factor expression. Further investigation revealed that aloin treatment suppressed the TAK1/NF-κB pathway. Moreover, the expression level of the NLPR3 inflammasome was downregulated after aloin treatment in TNF-α-treated NPCs. In summary, our results demonstrated that aloin treatment can reverse TNF-α-induced unbalanced matrix metabolism and apoptosis of NPCs via the TAK1/NF-κB/NLRP3 axis. This study supports that aloin can be a promising therapeutic agent for IDD.

Prevotellaceae produces butyrate to alleviate PD-1/PD-L1 inhibitor-related cardiotoxicity via PPARα-CYP4X1 axis in colonic macrophages

Background Immune checkpoint inhibitor-related cardiotoxicity is one of the most lethal adverse effects, and thus, the identification of underlying mechanisms for developing strategies to overcome it has clinical importance. This study aimed to investigate whether microbiota-host interactions contribute to PD-1/PD-L1 inhibitor-related cardiotoxicity. Methods A mouse model of immune checkpoint inhibitor-related cardiotoxicity was constructed by PD-1/PD-L1 inhibitor BMS-1 (5 and 10 mg/kg), and cardiomyocyte apoptosis and cardiotoxicity were determined by hematoxylin and eosin, Masson’s trichome and TUNEL assays. 16S rRNA sequencing was used to define the gut microbiota composition. Gut microbiota metabolites short-chain fatty acids (SCFAs) were determined by HPLC. The serum levels of myocardial enzymes (creatine kinase, aspartate transaminase, creatine kinase-MB and lactate dehydrogenase) and the production of M1 factors (TNF-α and IL-1β) were measured by ELISA. The colonic macrophage phenotype was measured by mmunofluorescence and qPCR. The expression of Claudin-1, Occludin, ZO-1 and p-p65 was measured by western blot. The gene expression of peroxisome proliferator-activated receptor α (PPARα) and cytochrome P450 (CYP) 4X1 was determined using qPCR. Statistical analyses were performed using Student’s t-test for two-group comparisons, and one-way ANOVA followed by Student–Newman–Keul test for multiple-group comparisons. Results We observed intestinal barrier injury and gut microbiota dysbiosis characterized by Prevotellaceae and Rikenellaceae genus depletion and Escherichia-Shigella and Ruminococcaceae genus enrichment, accompanied by low butyrate production and M1-like polarization of colonic macrophages in BMS-1 (5 and 10 mg/kg)-induced cardiotoxicity. Fecal microbiota transplantation mirrored the effect of BMS-1 on cardiomyocyte apoptosis and cardiotoxicity, while macrophage depletion and neutralization of TNF-α and IL-1β greatly attenuated BMS-1-induced cardiotoxicity. Importantly, Prevotella loescheii recolonization and butyrate supplementation alleviated PD-1/PD-L1 inhibitor-related cardiotoxicity. Mechanistically, gut microbiota dysbiosis promoted M1-like polarization of colonic macrophages and the production of proinflammatory factors TNF-α and IL-1β through downregulation of PPARα-CYP4X1 axis. Conclusions Intestinal barrier dysfunction amplifies PD-1/PD-L1 inhibitor-related cardiotoxicity by upregulating proinflammatory factors TNF-α and IL-1β in colonic macrophages via downregulation of butyrate-PPARα-CYP4X1 axis. Thus, targeting gut microbiota to polarize colonic macrophages away from the M1-like phenotype could provide a potential therapeutic strategy for PD-1/PD-L1 inhibitor-related cardiotoxicity. Graphical abstract

The Effect and Mechanism of Exercise Training on Rats with Poststroke Depression Based on the Intestinal Flora

Depression of poststroke depression (PSD) is the most common neuropsychiatric complication after stroke. Patients with PSD had higher mortality, more cognitive disorder, lower quality of life, and higher suicidal tendency. The pathogenesis of PSD mainly involves neurotransmitter inflammatory factors, HPA and BDNF. Enteral dysfunction and intestinal flora disorders caused by stroke can participate in the pathogenesis of PSD through various ways, such as immune, endocrine, and nervous system. In this experiment, we used exercise training as an intervention means to explore the curative effect and possible mechanism by observing the changes of behavior, inflammatory factors, and intestinal flora in rats. The results show that the mechanism of exercise training to improve the depressive behavior of rats may be related to inhibiting the expression of proinflammatory factors and increasing the number of lactic acid bacteria in the intestine.

Metabolomic Study of Zuojin Pill in Relieving 1-Methyl-3-nitro-1-nitrosoguanidine-Induced Chronic Atrophic Gastritis

The classic prescription Zuojin Pill (ZJP) shows a good therapeutic effect on chronic atrophic gastritis (CAG); it is of great significance to clarify its specific mechanism. Therefore, we explore the mechanism of ZJP on MNNG-induced CAG by integrating approaches. First of all, through the pathological changes of gastric tissue and the expression level of PGI and PGI/II in serum, the expression of inflammation-related factors was determined by RT-PCR to determine the efficacy. Then, UPLC-Q-TOF/MS was used for plasma and urine metabolomic analysis to screen the specific potential biomarkers and metabolic pathway of ZJP in ameliorating CAG and to explore its possible mechanism. ZJP significantly ameliorate the pathological injury of gastric tissue, increase levels of PGI and PGI/II, and reduce the expression level of proinflammatory factors. Through metabolomic analysis, 9 potential metabolic differences were identified and 6 related metabolic pathways were enriched. These findings indicate for the first time the potential mechanism of ZJP in improving CAG induced by MNNG and are of great significance to the clinical development and application of ZJP-related drugs.

Puerarin mitigates acute liver injury in septic rats by regulating proinflammatory factors and oxidative stress levels

Purpose: To determine the protective effect of puerarin against acute liver injury in septic rats, and the mechanism involved.Methods: Eighty-seven Sprague-Dawley (SD) rats were assigned to control, sepsis and puerarin groups (each having 29 rats). Serum levels of NF-kB, TNF-α, IL-1 β, IL-6, ALT and AST were assayed. Liver lesions and levels of NO, SOD, iNOS and malondialdehyde (MDA) were measured using standard procedures.Results: Compared with the control group, the levels of NF-kB, TNF-α, IL-1β, IL-6, AST, ALT, NO, MDA and iNOS significantly increased in the sepsis group, while SOD level decreased significantly. In contrast, there were marked decreases in NF-kB, TNF-α, IL-1β, AST, ALT, NO, MDA and iNOS in puerarin group, relative to the sepsis group, while SOD expression level was significantly increased (p <0.05). The level of p-p38 in liver of septic rats was up-regulated, relative to control rats, while Nrf2 significantly decreased (p < 0.05). The expression level of p-p38 in the puerarin group was significantly decreased, relative to the sepsis group, while the expression level of Nrf2 significantly increased (p < 0.05).Conclusion: Puerarin mitigates acute liver injury in septic rats by inhibiting NF-kB and p38 signaling pathway, down-regulating proinflammatory factors, and suppressing oxidative stress. Thus, puerarin may be developed for use in the treatment liver injury.

Acupuncture for Primary Dysmenorrhea: A Potential Mechanism from an Anti-Inflammatory Perspective

The low adverse effects of acupuncture for primary dysmenorrhea (PD), known as one of the most commonly reported gynecological debilitating conditions affecting women’s overall health, have been thus far confirmed. Moreover, it has been increasingly recognized that inflammation is involved in such menstrual cramps, and recent studies have further shown that the anti-inflammatory effects of acupuncture are helpful in its control. This review portrays the role of inflammation in PD pathophysiology, provides evidence from clinical and animal studies on acupuncture for inflammation-induced visceral pain, and reflects on acupuncture-related therapies for dysmenorrhea with regard to their anti-inflammatory characteristics. Further research accordingly needs to be carried out to clarify the effects of acupuncture on proinflammatory factors in PD, particularly chemokines and leukocytes. Future studies on this condition from an anti-inflammatory perspective should be also performed in line with the notion of emphasizing stimulation modes to optimize the clinical modalities of acupuncture. Additionally, the effects and mechanism of more convenient self-healing approaches such as TENS/TEAS for PD should be investigated.

Follistatin-like I promotes endometriosis by increasing proinflammatory factors and promoting angiogenesis

Endometriosis (EMS) is a chronic benign inflammatory disease characterized by the growth of endometrial-like tissue in aberrant locations outside of the uterine cavity. Angiogenesis and abnormal immune responses are the fundamental requirements of endometriotic lesion survival in the peritoneal cavity. Follistatin-like I (FSTL1) is a secreted glycoprotein that exhibits varied expression levels in cardiovascular disease, cancer and arthritis. However, the role of FSTL1 in the development of EMS remains to be fully elucidated. Results of the present study demonstrated that the expression of FSTL1 was significantly increased in ectopic endometrial stromal cells (ESCs) and peritoneal fluid from patients with EMS, compared the control group. Both conditions of hypoxia and estrogen treatment induced human ESCs to produce increased levels of FSTL1 and disco-interacting protein 2 homolog A (DIP2A). Furthermore, the expression levels of DIP2A, IL-8 and IL-1β were increased in FSTL1 overexpressed HESCs. Additionally, FSTL1 treatment increased the proliferation of HUVECs in a dose-dependent manner in vitro, and markedly increased the tube formation of HUVECs. Moreover, treatment with FSTL1 facilitated M1 polarization of macrophages, increased the secretion of proinflammatory factors and inhibited the expression of scavenger receptor CD36. Results of the present study suggested that the elevated expression of FSTL1 may play a key role in accelerating the development of EMS via enhancing the secretion of proinflammatory factors and promoting angiogenesis.

LncRNA NEAT1 is upregulated in recurrent aphthous stomatitis (RAS) and has predictive values

Background LncRNA NEAT1 promotes inflammatory responses, which contribute to recurrent aphthous stomatitis (RAS). This study focused on the involvement of NEAT1 in RAS. Methods RT-qPCR and ELISA were performed to determine the expression of NEAT1 and proinflammatory factors (IL-2, IL-1β, and TNF-α) in plasma from patients with a history of RAS and showing symptom (n = 80, S-RAS group), people with a history of RAS but showing no symptom (n = 80, NS-RAS group), and controls without a history of RAS (n = 80, Control group). Correlation analysis was performed with Pearson’s correlation coefficient. S-RAS group received treatmen,t and plasma levels of NEAT1 and proinflammatory factors were compared before and after treatment. S-RAS group was followed up for 12 months, and the recurrence was recorded. Results Plasma NEAT1, IL-2, IL-1β, and TNF-α levels were the highest in the S-RAS group, followed in turn by NS-RAS and control groups. NEAT1 was positively and significantly correlated with IL-2, IL-1β, and TNF-α across S-RAS and NS-RAS samples, but not control samples. After treatment, plasma levels of NEAT1, IL-2, IL-1β, and TNF-α decreased significantly. Moreover, a higher recurrence rate was observed during the follow-up in patients with high plasma NEAT1 levels. Conclusion NEAT1 is upregulated in RAS and correlated with multiple proinflammatory factors. Moreover, NEAT1 has predictive values for RAS.

Adiponectin Ameliorates Cognitive Behaviors and in vivo Synaptic Plasticity Impairments in 3xTg-AD Mice

Background: Cognitive deficit is mainly clinical characteristic of Alzheimer’s disease (AD). Recent reports showed adiponectin and its analogues could reverse cognitive impairments, lower amyloid-β protein (Aβ) deposition, and exert anti-inflammatory effects in different APP/PS1 AD model mice mainly exhibiting amyloid plaque pathology. However, the potential in vivo electrophysiological mechanism of adiponectin protecting against cognitive deficits in AD and the neuroprotective effects of adiponectin on 3xTg-AD mice including both plaque and tangle pathology are still unclear. Objective: To observe the effects of adiponectin treatment on cognitive deficits in 3xTg-AD mice, investigate its potential in vivo electrophysiological mechanism, and testify its anti-inflammatory effects. Methods: Barnes maze test, Morris water maze test, and fear conditioning test were used to evaluate the memory-ameliorating effects of adiponectin on 3xTg-AD mice. In vivo hippocampal electrophysiological recording was used to observe the change of basic synaptic transmission, long-term potentiation, and long-term depression. Immunohistochemistry staining and western blot were used to observe the activation of microglia and astroglia, and the expression levels of proinflammatory factors and anti-inflammtory factor IL-10. Results: Adiponectin treatment could alleviate spatial memory and conditioned fear memory deficits observed in 3xTg-AD mice, improve in vivo LTP depression and LTD facilitation, inhibit overactivation of microglia and astroglia, decrease the expression of proinflammatory factors NF- κB and IL-1β, and increase the expression level of IL-10 in the hippocampus of 3xTg-AD mice. Conclusion: Adiponectin could ameliorate cognitive deficits in 3xTg-AD mice through improving in vivo synaptic plasticity impairments and alleviating neuroinflammation in the hippocampus of 3xTg-AD mice.

An Oligomannuronic Acid–Sialic Acid Conjugate Capable of Inhibiting Aβ42 Aggregation and Alleviating the Inflammatory Response of BV-2 Microglia

Oligomannuronic acid (MOS) from seaweed has antioxidant and anti-inflammatory activities. In this study, MOS was activated at the terminal to obtain three different graft complexes modified with sialic acid moiety (MOS-Sia). The results show that MOS-Sia addition can reduce the β-structure formation of Aβ42, and the binding effect of MOS-Sia3 is more obvious. MOS-Sia conjugates also have a better complexing effect with Ca2+ while reducing the formation of Aβ42 oligomers in solutions. MOS-Sia3 (25–50 μg/mL) can effectively inhibit the activation state of BV-2 cells stimulated by Aβ42, whereas a higher dose of MOS-Sia3 (>50 μg/mL) can inhibit the proliferation of BV-2 cells to a certain extent. A lower dose of MOS-Sia3 can also inhibit the expression of IL-1β, IL-6, TNF-α, and other proinflammatory factors in BV-2 cells induced by Aβ42 activation. In the future, the MOS-Sia3 conjugate can be used to treat Alzheimer’s disease.