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HOXA transcript at the distal tip (HOTTIP), a newly identified long noncoding RNA, has been shown to exhibit anti-inflammatory effects and inhibit oxygen-glucose deprivation-induced neuronal apoptosis. However, its role in Parkinson's disease (PD) remains unclear. 1-Methyl-4-phenylpyridium (MPP+) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were used to establish PD models in SH-SY5Y and BV2 cells and in C57BL/6 male mice, respectively. In vitro, after HOTTIP knockdown by sh-HOTTIP transfection, HOTTIP and FOXO1 overexpression promoted SH-SY5Y apoptosis, BV2 microglial activation, proinflammatory cytokine expression, and nuclear factor kappa-B and NACHT, LRR and PYD domains-containing protein 3 inflammasome activation. Overexpression of miR-615-3p inhibited MPP+-induced neuronal apoptosis and microglial inflammation and ameliorated HOTTIP- and FOXO1-mediated nerve injury and inflammation. In vivo, HOTTIP knockdown alleviated motor dysfunction in PD mice and reduced neuronal apoptosis and microglial activation in the substantia nigra. These findings suggest that inhibition of HOTTIP mitigates neuronal apoptosis and microglial activation in PD models by modulating miR-615-3p/FOXO1. This study was approved by the Ethics Review Committee of the Affiliated Hospital of Qingdao University, China (approval No. UDX-2018-042) in June 2018.

Skin epidermis constitutes the exterior barrier that protects the body from dehydration and environmental assaults. Barrier defects underlie common inflammatory skin diseases, but the molecular mechanisms that maintain barrier integrity and regulate epidermal–immune cell cross-talk in inflamed skin are not fully understood. In this study, we show that skin epithelia-specific deletion of Ovol1, which encodes a skin disease–linked transcriptional repressor, impairs the epidermal barrier and aggravates psoriasis-like skin inflammation in mice in part by enhancing neutrophil accumulation and abscess formation. Through molecular studies, we identify IL-33, a cytokine with known pro-inflammatory and anti-inflammatory activities, and Cxcl1, a neutrophil-attracting chemokine, as potential weak and strong direct targets of Ovol1, respectively. Further-more, we provide functional evidence that elevated Il33 expression reduces disease severity in imiquimod-treated Ovol1-deficient mice, whereas persistent accumulation and epidermal migration of neutrophils exacerbate it. Collectively, our study uncovers the importance of an epidermally expressed transcription factor that regulates both the integrity of the epidermal barrier and the behavior of neutrophils in psoriasis-like inflammation.

Aims The progression of myocardial infarction (MI) involves multiple metabolic disorders. Bile acid metabolites have been increasingly recognized as pleiotropic signaling molecules that regulate multiple cardiovascular functions. G protein-coupled bile acid receptor (TGR5) is one of the receptors sensing bile acids to mediate their biological functions. In this study, we aimed to elucidate the effects of bile acids-TGR5 signaling pathways in myocardial infarction (MI). Methods and results Blood samples of AMI patients or control subjects were collected and plasma was used for bile acid metabolism analysis. We discovered that bile acid levels were altered and deoxycholic acid (DCA) was substantially reduced in the plasma of AMI patients. Mice underwent either the LAD ligation model of MI or sham operation. Both MI and sham mice were gavaged with 10 mg/kg/d DCA or vehicle control since 3-day before the operation. Cardiac function was assessed by ultrasound echocardiography, infarct area was evaluated by TTC staining and Masson trichrome staining. Administration of DCA improved cardiac function and reduced ischemic injury at the 7th-day post-MI. The effects of DCA were dependent on binding to its receptor TGR5. Tgr5−/− mice underwent the same MI model. Cardiac function deteriorated and infarct size was increased at the 7th-day post-MI, which were not savaged by DCA administration. Moreover, DCA inhibited interleukin (IL)-1β expression in the infarcted hearts, and ameliorated IL-1β activation at 1-day post-MI. DCA inhibited NF-κB signaling and further IL-1β expression in cultured neonatal mouse cardiomyocytes under hypoxia as well as cardio-fibroblasts with the treatment of LPS. Conclusions DCA-TGR5 signaling pathway activation decreases inflammation and ameliorates heart function post-infarction. Strategies that control bile acid metabolism and TGR5 signaling to ameliorate the inflammatory responses may provide beneficial effects in patients with myocardial infarction.

Acute lung injury (ALI) is a life-threatening lung disease and characterized by pulmonary edema and atelectasis. Inula japonica Thunb. is a commonly used traditional Chinese medicine for the treatment of lung diseases. However, the potential effect and mechanism of total terpenoids of I. japonica (TTIJ) on ALI remain obscure.This study focused on the protective effect of TTIJ on lipopolysaccharide (LPS)-induced ALI in mice and its potential mechanism.A mouse model of ALI was established by intratracheal instillation of LPS to investigate the protective effect of TTIJ. RNA-seq and bioinformatics were then performed to reveal the underlying mechanism. Finally, western blot and real-time qPCR were used to verify the effects of TTIJ on the inflammation and oxidative stress.TTIJ notably attenuated LPS-induced histopathological changes of lung. The RNA-seq result suggested that the protective effect of TTIJ on LPS-induced ALI were associated with the Toll-like receptor 4 (TLR4) and nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling pathways. Pretreatment with TTIJ significantly reduced the inflammation and oxidative stress via regulating levels of pro-inflammatory and anti-oxidative cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), superoxide dismutase (SOD), and glutathione (GSH), in LPS-induced ALI mice. TTIJ treatment could suppress the cyclooxygenase-2 (COX-2) expression level and the phosphorylation of p65, p38, ERK, and JNK through the inactivation of the MAPK/NF-κB signaling pathway in a TLR4-independent manner. Meanwhile, TTIJ treatment upregulated expression levels of proteins involved in the Nrf2 signaling pathway, such as heme oxygenase-1 (HO-1), NAD(P)H: quinoneoxidoreductase-1 (NQO-1), glutamate-cysteine ligase catalytic subunit (GCLC), and glutamate-cysteine ligase modifier subunit (GCLM), via activating the Nrf2 receptor, which was confirmed by the luciferase assay.TTIJ could activate the Nrf2 receptor to alleviate the inflammatory response and oxidative stress in LPS-induced ALI mice, which suggested that TTIJ could serve as the potential agent in the treatment of ALI.

Purpose Osteoarthritis (OA) is one of the most common degenerative joint diseases in the world, characterized primarily by the progressive degradation of articular cartilage. Accumulating evidence has shown that Morusin, a flavonoid derived from the root bark of Morus alba (mulberry) plants, exerts unique protective properties in several diseases. However, its effects on OA, specifically, have not yet been characterized. Methods In this study, we evaluated the anti-inflammatory effect of Morusin on mouse chondrocytes and its underlying mechanism in vitro. In addition, the protective effect of Morusin on destabilization of the medial meniscus (DMM) model was also explored in vivo. Results In vitro, IL-1β-induced activation of inflammatory factors (TNF-α, IL-6, INOS and COX2) was dramatically suppressed by Morusin. Further, Morusin treatment inhibited the expression of ADAMTS5 and metalloproteinase (MMPs), both of which regulate extracellular matrix degradation. Morusin also decreased IL-1β-induced p65 phosphorylation and IκBα degradation. In vivo, degradation of the articular cartilage following surgical DMM, which mimicked OA pathology, was abrogated following treatment with Morusin, thus demonstrating a protective effect in the DMM model. Conclusion Herein, we demonstrate that Morusin reduces the OA inflammatory response in vitro and protects against articular cartilage degradation in vivo potentially via regulation of the NF-κB pathway. Hence, Morusin may prove to be an effective candidate for novel OA therapeutic strategies.

SUMMARY Our knowledge of transcriptional heterogeneities in epithelial stem and progenitor cell compartments is limited. Epidermal basal cells sustain cutaneous tissue maintenance and drive wound healing. Previous studies have probed basal cell heterogeneity in stem and progenitor potential, but a comprehensive dissection of basal cell dynamics during differentiation is lacking. Using single-cell RNA sequencing coupled with RNAScope and fluorescence lifetime imaging, we identify three non-proliferative and one proliferative basal cell state in homeostatic skin that differ in metabolic preference and become spatially partitioned during wound re-epithelialization. Pseudotemporal trajectory and RNA velocity analyses predict a quasi-linear differentiation hierarchy where basal cells progress from Col17a1Hi/Trp63Hi state to early-response state, proliferate at the juncture of these two states, or become growth arrested before differentiating into spinous cells. Wound healing induces plasticity manifested by dynamic basal-spinous interconversions at multiple basal transcriptional states. Our study provides a systematic view of epidermal cellular dynamics, supporting a revised “hierarchical-lineage” model of homeostasis., Graphical Abstract, In Brief Haensel et al. performed a comprehensive dissection of the cellular makeup of skin during homeostasis and wound healing and the molecular heterogeneity and cellular dynamics within its stem-cell-containing epidermal basal layer. Their work provides insights and stimulates further investigation into the mechanism of skin maintenance and repair.

Objective: To explore the postoperative changes in inflammatory markers in children who underwent device closure of an atrial septal defect (ASD) via a transthoracic or transcatheter approach. Methods: The experimental and clinical data were retrospectively collected and analyzed for a total of 53 pediatric patients between September 2018 and December 2018. According to the different treatments, 19 patients who underwent transthoracic device closure were assigned to group A, and the remaining 34 patients who underwent a transcatheter approach were assigned to group B. Results: All patients were successfully occluded without any device-related severe complication. Compared with the preoperative levels, the postoperative levels of most inflammatory cytokines in both groups were significantly increased and reached a peak on the first day after the procedure. The level of postoperative inflammatory cytokines was significantly lower in group B than in group A. In addition, there was no significant difference in procalcitonin before and after the transcatheter approach. Conclusion: Systemic inflammatory reactions occurred after transthoracic or transcatheter device closure of ASDs in pediatric patients. However, these inflammatory reactions were more significant in patients who underwent a transthoracic approach than in patients who underwent a transcatheter approach.

Inflammation in the epididymis and testis contributes significantly to male infertility. Alternative therapeutic avenues treating epididymitis and orchitis are expected since current therapies using antibiotics have limitations associated to side effects and are commonly ineffective for inflammation due to nonbacterial causes. Here, we demonstrated that type 1 parathyroid hormone receptor (PTH1R) and its endogenous agonists, parathyroid hormone (PTH) and PTH-related protein (PTHrP), were mainly expressed in the Leydig cells of testis as well as epididymal epithelial cells. Screening the secretin family G protein–coupled receptor identified that PTH1R in the epididymis and testis was down-regulated in mumps virus (MuV)- or lipopolysaccharide (LPS)-induced inflammation. Remarkably, activation of PTH1R by abaloparatide (ABL), a Food and Drug Administration–approved treatment for postmenopausal osteoporosis, alleviated MuV- or LPS-induced inflammatory responses in both testis and epididymis and significantly improved sperm functions in both mouse model and human samples. The anti-inflammatory effects of ABL were shown to be regulated mainly through the Gq and β-arrestin-1 pathway downstream of PTH1R as supported by the application of ABL in Gnaq(±) and Arrb1(−/−) mouse models. Taken together, our results identified an important immunoregulatory role for PTH1R signaling in the epididymis and testis. Targeting to PTH1R might have a therapeutic effect for the treatment of epididymitis and orchitis or other inflammatory disease in the male reproductive system.

Purpose Chronic low-grade systemic inflammation affects muscle protein metabolism. The dietary inflammatory index (DII®) is a tool designed to assess the inflammatory potential of the diet. The available data on the association between DII and sarcopenia are limited. We aimed to investigate the association of the DII with components of sarcopenia in individuals over 50 years of age. Methods This cross-sectional study used the National Health and Nutrition Examination Survey (NHANES) 1999–2002 dataset. Body composition was measured, and isokinetic strength of the knee extensors (peak force) was evaluated. Low muscle mass and strength were defined using sex-specific thresholds. Energy-adjusted DII (E-DII™) scores were calculated using 24-h dietary recall data. Regression models were fit to evaluate the association between E-DII scores and low muscle mass and low muscle strength, alone and combined. Results Mean age of study participants was 62.1 ± 9.5 years, and 138 participants (7.4%) belonged to the combination group of low muscle mass and low muscle strength. In multivariable-adjusted regression models, higher E-DII score was associated with lower appendicular skeletal muscle index (ASMI) (β = − 0.03, P P trend P = 0.04, P trend = 0.01) and higher likelihood for these components combined (OR = 1.12, 95% CI 1.01–1.25, P = 0.03). Conclusion Higher E-DII score is associated with lower muscle mass and muscle strength, and increased likelihood for the combination of low muscle mass and low muscle strength in older adults. This has important implications for healthy aging.

Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by dementia. Inhibition of soluble epoxide hydrolase (sEH) regulates inflammation involving in central nervous system (CNS) diseases. However, the exactly mechanism of sEH in AD is still unclear. In this study, we evaluated the vital role of sEH in amyloid beta (Aβ)-induced AD mice, and revealed a possible molecular mechanism for inhibition of sEH in the treatment of AD. The results showed that the sEH expression and activity were remarkably increased in the hippocampus of Aβ-induced AD mice. Chemical inhibition of sEH by TPPU, a selective sEH inhibitor, alleviated spatial learning and memory deficits, and elevated levels of neurotransmitters in Aβ-induced AD mice. Furthermore, inhibition of sEH could ameliorate neuroinflammation, neuronal death, and oxidative stress via stabilizing the in vivo level of epoxyeicosatrienoic acids (EETs), especially 8,9-EET and 14,15-EET, further resulting in the anti-AD effect through the regulation of GSK3β-mediated NF-κB, p53, and Nrf2 signaling pathways. These findings revealed the underlying mechanism of sEH as a potential therapeutic target in treatment of AD.

Psoriasis is a common inflammatory skin disease characterized by aberrant inflammation and epidermal hyperplasia. Molecular mechanisms that regulate psoriasis-like skin inflammation remain to be fully understood. Here, we show that the expression of Ovol1 (encoding ovo-like 1 transcription factor) is upregulated in psoriatic skin, and its deletion results in aggravated psoriasis-like skin symptoms following stimulation with imiquimod. Using bulk and single-cell RNA sequencing, we identify molecular changes in the epidermal, fibroblast, and immune cells of Ovol1-deficient skin that reflect an altered course of epidermal differentiation and enhanced inflammatory responses. Furthermore, we provide evidence for excessive full-length IL-1α signaling in the microenvironment of imiquimod-treated Ovol1-deficient skin that functionally contributes to immune cell infiltration and epidermal hyperplasia. Collectively, our study uncovers a protective role for OVOL1 in curtailing psoriasis-like inflammation and the associated skin pathology.

Jumonji domain-containing 3 (JMJD3/KDM6B) is a histone demethylase that plays an important role in regulating development, differentiation, immunity, and tumorigenesis. However, the mechanisms responsible for the epigenetic regulation of inflammation during mastitis remain incompletely understood. Here, we aimed to investigate the role of JMJD3 in the lipopolysaccharide (LPS)-induced mastitis model. GSK-J1, a small molecule inhibitor of JMJD3, was applied to treat LPS-induced mastitis in mice and in mouse mammary epithelial cells in vivo and in vitro. Breast tissues were then collected for histopathology and protein/gene expression examination, and mouse mammary epithelial cells were used to investigate the mechanism of regulation of the inflammatory response. We found that the JMJD3 gene and protein expression were upregulated in injured mammary glands during mastitis. Unexpectedly, we also found JMJD3 inhibition by GSK-J1 significantly alleviated the severity of inflammation in LPS-induced mastitis. These results are in agreement with the finding that GSK-J1 treatment led to the recruitment of histone 3 lysine 27 trimethylation (H3K27me3), an inhibitory chromatin mark, in vitro. Furthermore, mechanistic investigation suggested that GSK-J1 treatment directly interfered with the transcription of inflammatory-related genes by H3K27me3 modification of their promoters. Meanwhile, we also demonstrated that JMJD3 depletion or inhibition by GSK-J1 decreased the expression of toll-like receptor 4 and negated downstream NF-κB proinflammatory signaling and subsequently reduced LPS-stimulated upregulation of Tnfa, Il1b, and Il6. Together, we propose that targeting JMJD3 has therapeutic potential for the treatment of inflammatory diseases.

β cell dedifferentiation is a key mechanism for β cell dysfunction in type 2 diabetes mellitus (T2DM). Although it has been indicated in previous studies that β cell dedifferentiation could be induced by inflammation, the cytohistologic analyses of inflammation-induced β cell dedifferentiation in human islets is lacking. The present study aims to cytohistologically characterize the β cell dedifferentiation of human islets treated by proinflammatory cytokines Interleukin-1β/Tuman necrosis factor-α/Interferon-γ (IL-1β/TNF-α/IFN-γ), which is a frequently-used method to mimic the islet inflammation in previous studies. The loss of cytosolic FOXO1 expression, the loss of nucleic NKX6.1 expression, and the gain of ALDH1A3 expression in β cells are proclaimed as marking events for β cell dedifferentiation. Taking advantages of islets from organ donors and the immunofluorescence staining methods, the present study visualized the β cell dedifferentiation events marked by different markers, and quantified the frequency of each event as well. We successfully captured and described the characteristics of the differentiating/differentiated β cells. We found that dedifferentiated β cells were increased in the cytokines treated islets, evidenced by the increase of β cells with FOXO1 translocated to the nucleus (INS+FOXOnuc), β cells with NKX6.1 exported from the nucleus (INS+NKX6.1cyt), and β cells loss of NKX6.1 expression (INS+NKX6.1-), and β cells with dual expression of insulin and progenitor marker ALDH1A3. Consistently, we found that proinflammatory cytokines IL-1β/TNF-α/IFN-γ treatment reduced the mRNA expression of key β cell markers, but elevated the expression of progenitor marker genes. This study gives the most direct evidence for inflammation-induced β cell dedifferentiation in human islets, and supports the concept that anti-inflammation treatments may facilitate alleviating the β cell dedifferentiation in human T2DM islets.

Neuroimaging plays an important role in assessing axonal pathology after traumatic spinal cord injury. However, coexisting inflammation confounds imaging assessment of the severity of axonal injury. Herein, we applied diffusion basis spectrum imaging (DBSI) to quantitatively differentiate and quantify underlying pathologies in traumatic spinal cord injury at 3 days post-injury. Results reveal that DBSI was capable of detecting and differentiating axonal injury, demyelination, and inflammation-associated edema and cell infiltration in contusion-injured spinal cords. DBSI was able to detect and quantify axonal loss in the presence of white matter tract swelling. The DBSI-defined apparent axonal volume correlated with the corresponding histological markers. DBSI-derived pathological metrics could serve as neuroimaging biomarkers to differentiate and quantify coexisting white matter pathologies in spinal cord injury, providing potential surrogate outcome measures to assess spinal cord injury progression and response to therapies.

Osteoarthritis (OA), which is characterized as a common degenerative joint disease, is presently the most prevalent chronic degenerative joint disease. Accumulating evidence has shown a biological function for Garcinol in a variety of diseases; however, whether it could be used to treat OA remains unclear. In this study, we explored the protective effects of garcinol on the progression of OA and explored the underlying mechanism. In vitro, garcinol reduced the expression of pro-inflammatory cytokines, such as IL-6 and tumor necrosis factor alpha (TNF-α). It also decreased the expression of inducible nitric oxide synthase (iNOS), as well as cyclooxygenase-2 (COX-2). Furthermore, garcinol inhibited the expression of thrombospondin motifs 5(ADAMTS5) and metalloproteinase (MMPs), both of which regulate extracellular matrix degradation. These changes could be attributed to garcinol-related suppression of the IL-1β-induced NF-κB signaling pathway. Moreover, we investigated the protective effects of garcinol on the surgical destabilization of the medial meniscus (DMM) of the mouse, an in vivo model of OA. Taken together, our data suggest garcinol as a potential future agent for the treatment of OA.

Introduction. Type 2 diabetes is a worldwide disease which is associated with chronic, low-grade inflammation. The PD-1/PD-L1 pathway has been reported to be a negative regulatory element in immune homeostasis and to be involved in many diseases. Materials and Methods. Peripheral blood mononuclear cells (PBMCs) were obtained from type 2 diabetes patients (n=23) and healthy donors (n=20). The PD-L1 and PD-1 expressions on corresponding immune cells were evaluated by flow cytometry. Results. The PD-L1 expression on corresponding immune cells has no significant difference between these two groups. We showed the downregulated PD-1 expression in type 2 diabetes patients. The correlation analysis indicated that the PD-1 on NK cells has a positive correlation with insulin and diabetes duration. And an inverse correlation has been shown between the PD-1 expression on monocytes and BMI (body mass index). Conclusions. The results in this article suggest that PD-1, unlike PD-L1, might participate in the progression of type 2 diabetes. This investigation will provide evidence for the potential immune therapy for T2D.

Background The immune protective mechanisms during severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection remain to be deciphered for the development of an effective intervention approach. Methods We examined early responses of interleukin 37 (IL-37), a powerful anti-inflammatory cytokine, in 254 SARS-CoV-2–infected patients before any clinical intervention and determined its correlation with clinical prognosis. Results Our results demonstrated that SARS-CoV-2 infection causes elevation of plasma IL-37. Higher early IL-37 responses were correlated with earlier viral RNA negative conversion, chest computed tomographic improvement, and cough relief, consequently resulted in earlier hospital discharge. Further assays showed that higher IL-37 was associated with lower interleukin 6 and interleukin 8 (IL-8) and higher interferon α responses and facilitated biochemical homeostasis. Low IL-37 responses predicted severe clinical prognosis in combination with IL-8 and C-reactive protein. In addition, we observed that IL-37 administration was able to attenuate lung inflammation and alleviate respiratory tissue damage in human angiotensin-converting enzyme 2–transgenic mice infected with SARS-CoV-2. Conclusions Overall, we found that IL-37 plays a protective role by antagonizing inflammatory responses while retaining type I interferon, thereby maintaining the functionalities of vital organs. IL-37, IL-8, and C-reactive protein might be formulated as a precise prediction model for screening severe clinical cases and have good value in clinical practice.

The original version of this article contained mistakes, and the authors would like to correct them.

We investigated the effects of rapamycin (RAPA) and chloroquine (CQ) in supporting growth performance and the intestinal mucosal barrier in response to deoxynivalenol (DON) in piglets. A total of 32 healthy weaned piglets (bodyweight 7.10±0.58 kg) were divided into four groups and treated daily with RAPA (1 mg/kg BW), CQ (10 mg/kg BW), or a control volume of normal saline (two groups) until the end of the experiment. After feeding a basal diet for seven days, three groups were then switched to mildewed feed containing 1 mg kg/DON for a further seven days. In contrast to the control group, DON-treated piglets showed decreased average daily gain (ADG) and daily feed intake (ADFI), as well as negatively affected intestinal morphology as indicated by villus height, crypt depth, and tight junction protein expression. A group treated with RAPA and DON showed increased intestinal autophagy, aggravated inflammatory responses, and damage to the intestinal mucosa and permeability, leading to reduced growth performance. Meanwhile, a group treated with CQ and DON showed indices comparable to the non-DON control group, with alleviated inflammatory cytokines and healthy intestinal morphology and structure. They also showed better growth performance compared to DON treatment alone. These findings have important implications for mediating autophagy against DON in vivo, as well as the potential for CQ in improving growth performance and maintaining intestinal barrier integrity in weanling piglets.

Background Retinal degeneration is often accompanied by microglia-mediated neuroinflammation. Ferulic acid (FA), an active ingredient of traditional Chinese medicines (TCMs), has been reported to have anti-inflammatory effects. This study explores the impact of FA on microglia-mediated neuroinflammation and associated retinal degeneration in rd10 mice. Methods Rd10 mice received different concentrations of FA every day from postnatal day (P)4 to P24. On P25, the visual function of the mice was evaluated by electroretinogram, and retinae were collected for further investigation. Microglial activation and the expression of relevant cytokines in the retina were evaluated by qPCR, western blotting and immunofluorescence staining. Retinal structure was assessed by haematoxylin and eosin (HE) staining. Results Supplementation with 50 mg/kg FA provided optimal protection against retinal degeneration, with treated mice exhibiting more photoreceptor nuclei as well as greater wave amplitude amplification on electroretinogram than untreated mice. FA suppressed microglial activation both in vivo and in vitro, and inhibited the expression of pro-inflammatory factors Tnfα, IL1β, and Ccl2 in the retinae of rd10 mice. Furthermore, FA suppressed the activation of STAT1 and subsequently inhibited IRF8 expression, potentially highlighting a role for these pathways in FA-mediated immunomodulatory activity. Conclusions Attenuation of neuroinflammation by FA may be beneficial for retarding retinal degeneration.

The aim of this study was to determine the feasibility of diffusion basis spectrum imaging in multiple sclerosis at 7 T and to investigate the pathological substrates of tissue damage in lesions and normal-appearing white matter. To this end, 43 patients with multiple sclerosis (24 relapsing-remitting, 19 progressive), and 21 healthy control subjects were enrolled. White matter lesions were classified in T1-isointense, T1-hypointense and black holes. Mean values of diffusion basis spectrum imaging metrics (fibres, restricted and non-restricted fractions, axial and radial diffusivities and fractional anisotropy) were measured from whole brain white matter lesions and from both lesions and normal appearing white matter of the corpus callosum. Significant differences were found between T1-isointense and black holes (P ranging from 0.005 to

Rutin is a flavonol glycoside widely existing in plants, used as food antioxidant and nutritional enhancer. Rutin has vitamin P-like effect and anti-inflammatory effect. This study aims to investigate the effects and potential mechanisms of rutin against hepatic fibrosis in vivo and in vitro. The present study found that rutin significantly decreased fibrosis markers, and TLR4, IRAK4, P2X7r/NLRP3 signaling pathway in activated HSCs, as well as functioning as TLR4 inhibitor. In primary hepatocytes, rutin also inhibited TLR4-IRAK-P2X7r signaling pathway underlying TGF-β stimulation. In TAA-induced mice, rutin could attenuate the histopathological changes, fibrosis markers, and inflammatory factor. Rutin also suppressed TLRs, IL-1 receptor associated kinase, P2X7r, and NLRP3 expressions. Activation of TLRs/P2X7r signaling is required for HSCs activation, contributing to hepatic fibrosis in mice. Rutin exhibited a protective effect against hepatic fibrosis at least partly through suppressing TLR4 and P2X7r signaling.

Type 2 diabetes mellitus (T2DM) is recognized as a chronic low-grade inflammatory disease characterized by insulin resistance and pancreatic β-cell dysfunction; however, the underlying molecular mechanism remains unclear. Here, we report a new β-cell–macrophage crosstalk pathway mediated by the “miRNA-29-TNF receptor-associated factor 3 (TRAF3)” axis. β-cell specific transgenic miR-29a/b-1 mice are predisposed to develop glucose intolerance and insulin resistance when fed a high-fat diet (HFD). The metabolic effect of β-cell miR-29 is largely mediated through macrophages, as either depletion of macrophages or reconstitution with miR-29-signaling defective bone marrow improved metabolic parameters in the transgenic mice. Mechanistically, our data showed that miR-29 promoted the recruitment and activation of circulating monocytes/macrophages, and hence inflammation, via miR-29 exosomes in a TRAF3-dependent manner. Our results demonstrate the ability of β cells to modulate the systemic inflammatory tone and glucose homeostasis via miR-29 in response to nutrient overload.

Vibrio parahaemolyticus (V. parahaemolyticus) caused huge diseases and economic losses in shrimp aquaculture. Understanding the infection mechanism might help develop new strategies for controlling pathogen outbreak. Redistribution of trace element homeostasis, accompanied by impairment of antioxidant status and immune response, was observed during various infections. Accordingly, we hypothesized that V. parahaemolyticus infection might influence trace element homeostasis, impair antioxidant function, and induce inflammation response in shrimp. In the present study, the aim of this study was to investigate the influence of V. parahaemolyticus infection on trace element homeostasis, antioxidant status, and inflammation response in Litopenaeus vannamei (L. vannamei). The results showed that compared with the control group, V. parahaemolyticus infection significantly increased (P

S100A8/A9, a heterodimer of the two calcium-binding proteins S100A8 and S100A9, has emerged as an important proinflammatory mediator in acute and chronic inflammation. However, whether S100A8/A9 is implicated in microglial‑induced neuroinflammatory response remains unclear. Here, we found that S100A8/A9 significantly increased the secretion of proinflammatory cytokines inclu-ding tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in cultured BV-2 microglial cells. Inhibition of the Toll-like receptor 4 (TLR4) and the receptor for advanced glycation end-products (RAGE) with C225 and a RAGE-blocking antibody, respectively significantly reduced the secretion of TNF-α and IL-6 from S100A8/A9-stimulated BV-2 microglial cells. Furthermore, S100A8/A9 markedly enhanced the nuclear translocation of NF-κB p65 and the DNA-binding activities of NF-κB in BV-2 microglial cells, and suppression of ERK and JNK/MAPK signaling pathways by PD98059 or SP600125 significantly inhibited NF-κB activity and the release of TNF-α and IL-6 in the S100A8/A9-treated BV-2 microglial cells. Our data also showed that inhibition of NF-κB with pyrrolidine dithiocarbamate (PDTC) significantly reduced the secretion of TNF-α and IL-6 from BV-2 microglial cells treated with S100A8/A9. Taken together, our data suggest that S100A8/A9 acts directly on BV-2 microglial cells via binding to TLR4 and RAGE on the membrane and then stimulates the secretion of proinflammatory cytokines through ERK and JNK-mediated NF-κB activity in BV-2 microglial cells. Targeting S100A8/A9 may provide a novel therapeutic strategy in microglial-induced neuroinflammatory diseases.

Background/Aims Xuezhikang (XZK), a red yeast rice extract with lipid-lowering effect, contains a family of naturally statins, such as lovastatin. In recent years, its effect beyond the regulation of lipids has also been received increasing attention. Therefore, the purpose of this study was to explore the protective effects and possible molecular mechanisms of XZK on brain injury after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR), and to investigate whether it has a dose-dependent effect and the difference with lovastatin. Methods Rats were treated with low-dose XZK (XZK-L, 20 mg/kg/d), high-dose XZK (XZK-H, 200 mg/kg/d) and lovastatin by gavage once daily for 2 weeks before CA. The levels of TNF-α, IL-6 and IL-1β were evaluated at 1, 4, and 72 h post-CA/CPR. The survival rate, neurological deficit score (NDS), and expression of TLR4, phosphorylated NF-κB and TNF-α in hippocampal tissues were evaluated at 72 h post-CA/CPR. Results CA/CPR induced a significant increase in serum TNF-α, IL-6 and IL-1β, as well as increased expressions of TLR4, phosphorylated NF-κB and TNF-α in the hippocampus. Both low-dose and high-dose XZK treatment inhibited the expression of these inflammatory cytokines. In addition, it reduced the number of defibrillations and shortened the duration of CPR required for return of spontaneous circulation (ROSC). XZK treatment also improved neurological function and 72-hour survival rate in rats. However, high-dose XZK was superior to lovastatin in the suppression of IL-1β mRNA level and TNF-α protein level in hippocampal tissue after CPR. There were no significant differences observed among high-dose XZK, low-dose XZK and lovastatin groups in other respects. Conclusion These results indicated that XZK had a protective effect against brain injury post-CA/CPR. The mechanisms underlying the protective effects of XZK may be related to the suppressing of CA/CPR-induced inflammatory response through the inhibiting TLR4/NF-κB signaling pathway.

Spinal cord injury (SCI) is an independent risk factor for type 2 diabetes, and may induce insulin resistance that leads to this disease. Studies have shown that greater phosphoinositide 3-kinase (PI3K) activation in the hypothalamus leads to activation of the anti-inflammatory pathway, and the anti-inflammatory reflex may protect against insulin resistance and type 2 diabetes. However, the importance of this phenomenon in type 2 diabetes pathogenesis after SCI remains elusive. In the present study, the expression of c-Fos in the hypothalamus of rats with SCI was elevated, and the hypothalamus injury was observer following SCI. Then we showed that SCI could induce increased levels of blood glucose and glucose tolerance in rats. Also, we found that SCI could damage the liver, adipocyte and pancreas, and led to lipid position in liver. Western blots were used to detect the level of PI3K and p-Akt in the hypothalamus, and the results showed a significant downregulation of PI3K and p-Akt after SCI. Furthermore, to verify the activity of the PI3K signaling pathway, immunofluorescence was used to examine the expression of neurons positive for p-S6 (a marker of PI3K activation) after SCI. The results showed that the expression of p-S6-positive neurons decreased after SCI. In addition, the effect of SCI on peripheral inflammation was also investigated. Following SCI, the serum levels of tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 increased. Collectively, our results suggest abnormality in glucose metabolism after SCI, and demonstrate that SCI may impair activation of the PI3K signaling pathway in the hypothalamus. The reduced activity of the PI3K signaling pathway in the hypothalamus may lead to peripheral inflammation, which might be the mechanism underlying the development of insulin resistance and type 2 diabetes following SCI.

Hepatocyte apoptosis is a hallmark of nonalcoholic steatohepatitis (NASH) and contributes to liver injury, fibrosis, and inflammation. However, the molecular mechanisms underlying excessive hepatocyte apoptosis in NASH remain largely unknown. This study aimed to explore whether and how the v-ets avian erythroblastosis virus E26 oncogene homolog 1 (Ets-1) is involved in diet-induced hepatocyte apoptosis in mice. The study found that the expression level of hepatic Ets-1 was elevated in a NASH mouse model as a result of the activation of transforming growth factor beta1 (TGF-β1) signaling. In the presence of TGF-β1, phosphorylated mothers against decapentaplegic homolog 2/3 (p-Smad2/3) translocated to the binding sites of the Ets-1 promoter to upregulate the expression of Ets-1 in primary hepatocytes. In addition, Ets-1 bound directly to phosphorylated Smad3 (p-Smad3), thereby preventing the ubiquitination and proteasomal degradation of p-Smad3 and enhancing the activity of TGF-β1/Smad3 signaling. Consequently, elevated Ets-1 stimulated TGF-β1-induced hepatocyte apoptosis. However, Ets-1 knockdown alleviated diet-induced hepatocyte apoptosis and NASH with reduced liver injury, inflammation, and fibrosis. Taken together, Ets-1 had an adverse impact on hepatocyte survival under TGF-β1 treatment and accelerated the development of NASH in mice.

Type 2 diabetes mellitus (T2DM) is recognized as a chronic, low-grade inflammatory disease characterized by insulin resistance and pancreatic β cell dysfunction; however, the underlying molecular mechanism remains unclear. Here, we report a key β cell-macrophage crosstalk pathway mediated by the miRNA-29-TNF-receptor-associated factor 3 (TRAF3) axis. β cell-specific transgenic miR-29a/b/c mice are predisposed to develop glucose intolerance and insulin resistance when fed a high-fat diet (HFD). The metabolic effect of β cell miR-29 is largely mediated through macrophages because either depletion of macrophages or reconstitution with miR-29-signaling defective bone marrow improves metabolic parameters in the transgenic mice. Mechanistically, our data show that miR-29 promotes the recruitment and activation of circulating monocytes and macrophages and, hence, inflammation, via miR-29 exosomes in a TRAF3-dependent manner. Our results demonstrate the ability of β cells to modulate the systemic inflammatory tone and glucose homeostasis via miR-29 in response to nutrient overload.

// Peng Sun 1, 2, * , Fei Zhang 1, 2, * , Cui Chen 3, * , Xiwen Bi 1, 2 , Hang Yang 1, 2 , Xin An 1, 2 , Fenghua Wang 1, 2 , Wenqi Jiang 1, 2 1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong Province 510060, P. R. China 2 Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong Province 510060, P. R. China 3 Department of Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province 510080, P. R. China * These authors have contributed equally to this work Correspondence to: Fenghua Wang, email: wangfh@sysucc.org.cn Wenqi Jiang, email: jiangwq@sysucc.org.cn Keywords: esophageal squamous cell carcinoma (ESCC), hemoglobin, red cell distribution width (RDW), prognosis, survival Received: February 14, 2016 Accepted: April 16, 2016 Published: May 20, 2016 ABSTRACT Background: We propose a novel prognostic parameter for esophageal squamous cell carcinoma (ESCC)—hemoglobin/red cell distribution width (HB/RDW) ratio. Its clinical prognostic value and relationship with other clinicopathological characteristics were investigated in ESCC patients. Results: The optimal cut-off value was 0.989 for the HB/RDW ratio. The HB/RDW ratio ( P = 0.035), tumor depth ( P = 0.020) and lymph node status ( P

Vagus nerve stimulation (VNS), a method for activating cholinergic anti-inflammatory pathways, could suppress endothelial activation and minimize tissue injury during inflammation. The aim of this study was to investigate the effects of chronic VNS on endothelial impairments and the inflammatory profile in ovariectomized (OVX) rats. Sprague-Dawley rats (7-8 months old) were randomly assigned to the following four groups: sham-OVX, OVX, OVX+sham-VNS, and OVX+VNS. Throughout the experimental period, the OVX+VNS group received VNS for 3h (20.0 Hz, 1.0 mA, and 10.00 ms pulse width) at the same time every other day. After 12 weeks of VNS, blood samples and thoracic aortas were collected for further analyses. Light microscopy and electron microscopy analyses showed that chronic VNS prevented endothelial swelling, desquamation and even necrosis in the OVX rats. In addition, it obviously improved endothelial function in the OVX rats by restoring the endothelial nitric oxide synthase (e-NOS) and serum endothelin-1 level. Increased expression of cell adhesion molecules (VCAM-1, ICAM-1 and E-selectin) in the thoracic aortas and increases in the levels of circulating cytokines (TNF-α, IL-6, MCP-1, and CINC/KC) were also observed in the OVX rats. Chronic VNS significantly restored these detrimental changes partly by increasing the ACh concentrations in vascular walls and blocking NF-κB pathway activity. The results of this in vivo study have shown that the administration of chronic VNS during, in the early stage of estrogen deficiency, protects OVX rats from endothelial impairments and the inflammatory profile. These findings indicate that activation of the vagus nerve could be a promising supplemental therapy for reducing the risks of suffering from further CVDs in postmenopausal women.

Highlights: (1) Potato extract (PE) exhibits non-toxic effects on mice. (2) Cigarette smoke (CS)–induced COPD rats exhibit significant thickened and disordered lung markings. (3) PE could improve the histopathological symptoms of lung tissue in COPD. (4) PE could increase the expression of IL-10 and reduce the expression of TNF-α and G-CSF in COPD rats. Objective This study aimed to evaluate the therapeutic effects of potato extract (PE) on cigarette smoke (CS)–induced chronic obstructive pulmonary disease (COPD). Methods PE was first prepared by frozen centrifugation, and its amino acid composition was detected. Toxicity of PE was analyzed by changes in morphology, behavior, routine blood indexes, and biochemical criteria of mice. Then, the COPD rat model was established by CS exposure, and PE, doxofylline, and prednisolone acetate were used to treat these rats. After 45 days of treatment, the morphology and behavior of rats were recorded. In addition, the histopathology of lung tissue was evaluated by chest x-ray and hematoxylin and eosin staining. The expression of interleukine-10 (IL-10), tumor necrosis factor-α (TNF-α), and granulocyte colony-stimulating factor (G-CSF) was detected in serum and lung tissue by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, respectively. Results Various amino acids were identified in PE, and no toxicity was exhibited in mice. The CS-induced COPD rat model was successfully established, which exhibited significant thickened and disordered lung markings on 90% of the rats. After administering doxofylline and prednisolone acetate, inflammation symptoms were improved. However, side effects such as emaciation, weakness, and loosening of teeth appeared. In the PE group, obviously improved histopathology was observed in lung tissues. Meanwhile, it was revealed that PE could increase the expression of IL-10 and reduce the expression of TNF-α and G-CSF in COPD rats, and doxofylline and prednisolone acetate also elicited similar results. Conclusion Our study suggests PE might be effective in the treatment of CS-induced COPD by inhibiting inflammation.

Osteoarthritis (OA) is a chronic musculoskeletal degeneration disease, resulting in severe consequences such as chronic pain and functional disability. Owing to the complex pathology, there are currently available preventative clinical therapies for OA. Several studies have reported the potential anti-inflammatory effects of byakangelicin (BYA), a component of the Angelica dahurica root extract; however, the effects of BYA in OA remain unknown. In this study, we investigated the protective effects of BYA in interleukin (IL)-1β-induced mouse chondrocytes in vitro and on surgical destabilization in a medial meniscus (DMM) mouse OA model in vivo. In vitro, BYA treatment inhibited IL-1β-mediated inducible nitric oxide synthase, cyclooxygenase-2, tumor necrosis factor-alpha, and IL-6 expression. Moreover, BYA promoted the expression of type two collagen and aggrecan but inhibited the expression of thrombospondin motifs 5 and matrix metalloproteinases, leading to degradation of the extracellular matrix. In addition, BYA mechanistically suppressed nuclear factor-kappa B signaling in the IL-1β-induced chondrocytes. The protective effects of BYA in OA development were also observed in vivo using the DMM model. In conclusion, our results highlight BYA as a candidate for OA treatment and prevention.

Early weaning stress impairs the development of gastrointestinal barrier function, causing immune system dysfunctions, reduction in feed intake, and growth retardation. Autophagy was hypothesized to be a key underlying cellular process in these dysfunctions. We conjectured that rapamycin (RAPA) and chloroquine (CQ), as two autophagy-modifying agents, regulate the autophagy process and may produce deleterious or beneficial effects on intestinal health and growth. To explore the effect of autophagy on early weaning stress in piglets, 18 early-weaned piglets were assigned to three treatments (each treatment of six piglets) and treated with an equal volume of RAPA, CQ, or saline. The degree of autophagy and serum concentrations of immunoglobulins and cytokines, as well as intestinal morphology and tight junction protein expression, were evaluated. Compared with the control treatment, RAPA-treated piglets exhibited activated autophagy and had decreased final body weight (BW) and average daily gain (ADG) (p &lt, 0.05), impaired intestinal morphology and tight junction function, and higher inflammatory responses. The CQ-treated piglets showed higher final BW, ADG, jejuna and ileal villus height, and lower autophagy and inflammation, compared with control piglets (p &lt, 0.05). Throughout the experiment, CQ treatment was beneficial to alleviate early weaning stress and intestinal and immune system dysfunction.

Background Systemic inflammation and immune dysfunction has been proved to be significantly associated with cancer progression and metastasis in many cancer types, including colorectal cancer. We examined the prognostic significance of the systemic immune-inflammation index (SII) in patients with metastatic colorectal cancer (mCRC) and the relationship between the lymphocytic response to the tumor and this index. Methods This retrospective study evaluated 240 consecutive patients with newly diagnosed stage IV mCRC who underwent surgical resection. The SII values were calculated based on preoperative laboratory data regarding platelet, neutrophil, and lymphocyte counts. Tumor-infiltrating lymphocytes were evaluated using the surgical specimens. The overall survival and their 95% confidence interval (95% CI) were estimated by regression analyses and the Kaplan–Meier method. Results After a mean follow-up of 26.7 (1.1–92.4) months, 146 patients (60.8%) died. In the univariate analysis, a high SII was significantly associated with poor overall survival (P = 0.009). The multivariable analysis also confirmed that a high SII was independently associated with poor overall survival (hazard ratio: 1.462, 95% confidence interval 1.049–2.038, P = 0.025). The SII value was significantly correlated with the TILs value at the tumor’s center (P = 0.04), but not at the invasive margin (P = 0.39). When we evaluated overall survival for groupings of the tumor-infiltrating lymphocytes and SII values, we identified three distinct prognostic groups. The group with low tumor-infiltrating lymphocyte values and high SII values had the worst prognosis. Conclusions A high SII value independently predicts poor clinical outcomes among patients with mCRC. In addition, combining the lymphocytic response to the tumor and SII could further enhance prognostication for mCRC. Electronic supplementary material The online version of this article (10.1186/s12967-018-1638-9) contains supplementary material, which is available to authorized users.

Hippocampal CA1 inflammation and dendritic loss are common in epilepsy. Quantitative detection of coexisting brain inflammation and injury could be beneficial in monitoring disease progression and assessing therapeutic efficacy. In this work, we used conventional diffusion tensor imaging (DTI, known to detect axonal injury and demyelination) and a novel diffusion basis spectrum imaging (DBSI, known to detect axonal injury, demyelination, and inflammation) to detect hippocampal CA1 lesions resulting from neuronal dendritic injury/loss and concomitant inflammation in Theiler's murine encephalomyelitis virus (TMEV)-induced seizure mice. Following the cross-sectional ex vivo diffusion magnetic resonance imaging measurements, immunohistochemistry was performed to validate DTI and DBSI findings. Both DTI and DBSI detected immunohistochemistry-confirmed dendritic injury in the hippocampal CA1 region. Additionally, DBSI-derived restricted isotropic diffusion tensor fraction correlated with 4',6-diamidine-2'-phenylindole dihydrochloride (DAPI)-positive nucleus counts, and DBSI-derived fiber fraction correlated with dendrite density assessed by microtubule-associated protein 2 staining. DTI-derived fractional anisotropy (FA) correlated with dendrite density and negatively correlated with DAPI-positive nucleus counts. Although both DTI and DBSI detected hippocampal injury/inflammation, DTI-FA was less specific than DBSI-derived pathological metrics for hippocampal CA1 dendritic injury and inflammation in TMEV-induced seizure mice.

Sterile inflammation is an essential factor causing hepatic ischemia/reperfusion (I/R) injury. As a critical regulator of inflammation, the role of monocyte chemoattractant protein-induced protein 1 (MCPIP1) in hepatic I/R injury remains undetermined. In this study, we discovered that MCPIP1 downregulation was associated with hepatic I/R injury in liver transplant patients and a mouse model. Hepatocyte-specific Mcpip1 gene knockout and transgenic mice demonstrated that MCPIP1 functions to ameliorate liver damage, reduce inflammation, prevent cell death, and promote regeneration. A mechanistic study revealed that MCPIP1 interacted with and maintained hypoxia-inducible factor 1α (HIF-1α) expression by deubiquitinating HIF-1α. Notably, the HIF-1α inhibitor reversed the protective effect of MCPIP1, whereas the HIF-1α activator compensated for the detrimental effect of MCPIP1 deficiency. Thus, we identified the MCPIP1-HIF-1α axis as a critical pathway that may be a good target for intervention in hepatic I/R injury. (Hepatology 2018; 00:000-000).

Background & Aims The hepatic injury caused by ischemia/reperfusion (I/R) insult is predominantly determined by the complex interplay of sterile inflammation and liver cell death. Caspase recruitment domain family member 6 (CARD6) was initially shown to play important roles in NF-κB activation. In our preliminary studies, CARD6 downregulation was closely related to hepatic I/R injury in liver transplantation patients and mouse models. Thus, we hypothesized that CARD6 protects against hepatic I/R injury and investigated the underlying molecular mechanisms. Methods A partial hepatic I/R operation was performed in hepatocyte-specific Card6 knockout mice (HKO), Card6 transgenic mice with CARD6 overexpression specifically in hepatocytes (HTG), and the corresponding control mice. Hepatic histology, serum aminotransferases, inflammatory cytokines/chemokines, cell death, and inflammatory signaling were examined to assess liver damage. The molecular mechanisms of CARD6 function were explored in vivo and in vitro. Results Liver injury was alleviated in Card6-HTG mice compared with control mice as shown by decreased cell death, lower serum aminotransferase levels, and reduced inflammation and infiltration, whereas Card6-HKO mice had the opposite phenotype. Mechanistically, phosphorylation of ASK1 and its downstream effectors JNK and p38 were increased in the livers of Card6-HKO mice but repressed in those of Card6-HTG mice. Furthermore, ASK1 knockdown normalized the effect of CARD6 deficiency on the activation of NF-κB, JNK and p38, while ASK1 overexpression abrogated the suppressive effect of CARD6. CARD6 was also shown to interact with ASK1. Mutant CARD6 that lacked the ability to interact with ASK1 could not inhibit ASK1 and failed to protect against hepatic I/R injury. Conclusions CARD6 is a novel protective factor against hepatic I/R injury that suppresses inflammation and liver cell death by inhibiting the ASK1 signaling pathway. Lay summary The protein CARD6 plays an important role during the process of liver blood flow restriction (ischemia) and restoration (reperfusion). By suppressing the activity of ASK1, CARD6 can protect against hepatocyte injury. Targeting CARD6 is a potential strategy for prevention and treatment of ischemia/reperfusion injury.

Axon injury/loss, demyelination and inflammation are the primary pathologies in multiple sclerosis lesions. Despite the prevailing notion that axon/neuron loss is the substrate of clinical progression of multiple sclerosis, the roles that these individual pathological processes play in multiple sclerosis progression remain to be defined. An imaging modality capable to effectively detect, differentiate and individually quantify axon injury/loss, demyelination and inflammation, would not only facilitate the understanding of the pathophysiology underlying multiple sclerosis progression, but also the assessment of treatments at the clinical trial and individual patient levels. In this report, the newly developed diffusion basis spectrum imaging was used to discriminate and quantify the underlying pathological components in multiple sclerosis white matter. Through the multiple-tensor modelling of diffusion weighted magnetic resonance imaging signals, diffusion basis spectrum imaging resolves inflammation-associated cellularity and vasogenic oedema in addition to accounting for partial volume effects resulting from cerebrospinal fluid contamination, and crossing fibres. Quantitative histological analysis of autopsied multiple sclerosis spinal cord specimens supported that diffusion basis spectrum imaging-determined cellularity, axon and myelin injury metrics closely correlated with those pathologies identified and quantified by conventional histological staining. We demonstrated in healthy control subjects that diffusion basis spectrum imaging rectified inaccurate assessments of diffusion properties of white matter tracts by diffusion tensor imaging in the presence of cerebrospinal fluid contamination and/or crossing fibres. In multiple sclerosis patients, we report that diffusion basis spectrum imaging quantitatively characterized the distinct pathologies underlying gadolinium-enhanced lesions, persistent black holes, non-enhanced lesions and non-black hole lesions, a task yet to be demonstrated by other neuroimaging approaches. Diffusion basis spectrum imaging-derived radial diffusivity (myelin integrity marker) and non-restricted isotropic diffusion fraction (oedema marker) correlated with magnetization transfer ratio, supporting previous reports that magnetization transfer ratio is sensitive not only to myelin integrity, but also to inflammation-associated oedema. Our results suggested that diffusion basis spectrum imaging-derived quantitative biomarkers are highly consistent with histology findings and hold promise to accurately characterize the heterogeneous white matter pathology in multiple sclerosis patients. Thus, diffusion basis spectrum imaging can potentially serve as a non-invasive outcome measure to assess treatment effects on the specific components of underlying pathology targeted by new multiple sclerosis therapies.