Interaction of the Gut Microbiome and Immunity in Multiple Sclerosis: Impact of Diet and Immune Therapy.

The bidirectional communication between the gut and central nervous system (CNS) through microbiota is known as the microbiota-gut-brain axis. The brain, through the enteric neural innervation and the vagus nerve, influences the gut physiological activities (motility, mucin, and peptide secretion), as well as the development of the mucosal immune system. Conversely, the gut can influence the CNS via intestinal microbiota, its metabolites, and gut-homing immune cells. Growing evidence suggests that gut immunity is critically involved in gut-brain communication during health and diseases, including multiple sclerosis (MS). The gut microbiota can influence the development and function of gut immunity, and conversely, the innate and adaptive mucosal immunity can influence microbiota composition. Gut and systemic immunity, along with gut microbiota, are perturbed in MS. Diet and disease-modifying therapies (DMTs) can affect the composition of the gut microbial community, leading to changes in gut and peripheral immunity, which ultimately affects MS. A high-fat diet is highly associated with gut dysbiosis-mediated inflammation and intestinal permeability, while a high-fiber diet/short-chain fatty acids (SCFAs) can promote the development of Foxp3 Tregs and improvement in intestinal barrier function, which subsequently suppress CNS autoimmunity in the animal model of MS (experimental autoimmune encephalomyelitis or EAE). This review will address the role of gut immunity and its modulation by diet and DMTs via gut microbiota during MS pathophysiology.

Insight into the mechanism of action of dimethyl fumarate in multiple sclerosis.

Dimethyl fumarate (DMF) is an oral, disease-modifying agent for the treatment of relapsing-remitting multiple sclerosis (RRMS). However, details regarding its mode of action are still emerging. It is believed that the mode of action of DMF involves both nuclear factor erythroid-derived 2-related factor (Nrf2)-dependent and independent pathways, which lead to an anti-inflammatory immune response due to type II myeloid cell and Th2 cell differentiation and neuroprotection. In this review, we will focus on the molecular and signaling effects of DMF that lead to changes in peripheral immune cell composition and function, alteration in CNS cell-specific functions, and effect on the blood-brain barrier.

Significance of MRI in the diagnosis and differentiation of clear cell sarcoma of tendon and aponeurosis (CCSTA): A case report.

RATIONALE: Clear cell sarcoma of tendon and aponeurosis (CCSTA) or soft parts is a rare malignant melanin producing tumor entity that is derived from the neural crest cells originating from soft tissues displaying melanocytic differentiation. Diagnosis of CCSTA is difficult as it is dependent on age, size, location, necrosis, calcifications, cystic degeneration, and local to distant metastatic deposits. These tumors have very poor prognosis with a survival rate of 5-10 years because of local recurrence, early to late metastasis to lymph nodes, lungs, bones, and liver. PATIENT CONCERNS: A 30-year-old Asian male has presented with a painful mass in the posterior aspect of the right ankle. He recalled of noticing an increase in the size of the lump after a traumatic insult 3 months ago. Physical examination revealed a mass of size 9x4 cm in the posterior ankle with no cutaneous ulcerative lesions. There is no history of any longstanding illness or malignancy. DIAGNOSES: Clear cell Sarcoma of Tendon and Aponeurosis (CCSTA) or CCS of Soft parts. INTERVENTIONS: Conventional radiography demonstrated merely a soft tissue mass in the posterior compartment of the right ankle and significant calcaneal bone erosion with the sparse trabecular pattern. Plain conventional tomography showed a well-defined soft tissue heterogeneous mass with a hypoattenuating osteo-destructive focal lesion in the calcaneus. Magnetic resonance imaging (MRI) - T1 weighted imaging (T1WI) revealed an iso-intense signal relative to adjacent muscle; heterogeneous high-signal intensity on fat saturated T2 weighted imaging (T2WI). On contrast examination, lesion on T1WI, showed a heterogeneous high signal intensity, central low signal intensity with peripheral and septal enhancement. The immune-histochemistry analysis was positive for HMB-45, S-100, myoD1 and Ki67 (30%). Correlating with imaging and immune-histochemistry, a confirmatory diagnosis of CCSTA was made. OUTCOMES: CCSTA is typically a slowly growing painless mass in the deep soft tissues of ear, pancreas, kidney, penis, abdomen, especially in the lower extremities- Achilles tendon and aponeurosis of the ankle or in foot of young adults. As, these tumors are highly malignant, difficult to diagnose, early recognition by imaging and surgical excision are the mainstay of management. LESSONS: Our case emphasizes the importance of recognizing radiological characteristics of CCSTA, and its differentiation from other soft tissue tumors, when presenting atypically. MRI plays a significant role in the diagnosis supported by histopathology and immune-histochemistry. So, radiologists should be familiar about this presentation that could guide other personnel for early detection of soft tissue tumors while including CCSTA into differential diagnosis for evaluation.

Molecular mechanism of the anti-inflammatory activity of a natural diarylnonanoid, malabaricone C.

The spice-derived phenolic, malabaricone C (mal C), has recently been shown to accelerate healing of the indomethacin-induced gastric ulceration in mice. In this study, we explored its anti-inflammatory activity and investigated the underlying mechanism of the action. Mal C suppressed the microvascular permeability and the levels of tumor necrosis factor-α, interleukin-1ß, and nitric oxide in the lipopolysaccharide (LPS)-administered mice. At a dose of 10 mg/kg, it showed anti-inflammatory activity comparable to that of omeprazole (5 mg/kg) and dexamethasone (50 mg/kg). It also reduced the expression and activities of inducible nitric oxide synthase, cyclooxygenase-2, as well as the pro- vs anti-inflammatory cytokine ratio in the LPS-treated RAW macrophages. Mal C was found to inhibit LPS-induced NF-kB activation in RAW 264.7 cells by blocking the MyD88-dependent pathway. Mal C suppressed NF-κB activation and iNOS promoter activity, which correlated with its inhibitory effect on IκB phosphorylation and degradation, and NF-κB nuclear translocation, in the LPS-stimulated macrophages. It also inhibited LPS-induced phosphorylation of p38 and JNK, which are also upstream activators of NF-κB, without affecting Akt phosphorylation. Mal C also effectively blocked the PKR-mediated activation of NF-κB. These findings indicate that mal C exerts an anti-inflammatory effect through NF-κB-responsive inflammatory gene expressions by inhibiting the p38 and JNK-dependent canonical NF-κB pathway as well as the PKR pathway, and is a potential therapeutic agent against acute inflammation.

Black tea and theaflavins assist healing of indomethacin-induced gastric ulceration in mice by antioxidative action.

The healing activities of black tea (BT) and the theaflavins (TF) against the indomethacin-induced stomach ulceration were studied in a mouse model. Indomethacin (18 mg/kg, p.o.) administration induced maximum ulceration in the glandular portion of the gastric mucosa on the 3rd day, accompanied by increased lipid peroxidation and protein oxidation, depletion of thiol-defense and mucin, as well as reduced expressions of cyclooxygenases (COX) and prostaglandin (PG) E synthesis in the gastric tissues, and plasma total antioxidant status of mice. Treatment with BT (40 mg/kg), TF (1 mg/kg), and omeprazole (3 mg/kg) produced similar (74%-76%) ulcer healing, as revealed from the histopathological studies. Treatment with all the above samples reversed the adverse oxidative effects of indomethacin significantly. BT and TF also enhanced the PGE synthesis by augmenting the expressions of COX 1 and 2, but did not modulate acid secretion.

Effect of extract of Benincasa hispida on oxidative stress in rats with indomethacin induced gastric ulcers.

This study was undertaken to determine the healing of ulcers induced by indomethacin due to antioxidant role of fruit extract of Benincasa hispida (Ashgourd) on ulcers in rats. Malondialdehyde (MDA) in RBC and antral homogenate was determined to measure tissue oxidation. Superoxide dismutase (SOD) in RBC and antral homogenate, plasma and homogenate vitamin C were estimated as measures of antioxidant defense. On induction of gastric ulcer, there was significant increase in SOD in RBC and homogenate levels and vitamin C in plasma. There was an apparent decrease in ulcer index in animals treated with fruit extract. There was significant decrease in MDA with concomitant decrease in SOD and vitamin C levels in the treated rats when compared to those not treated with fruit extract. Benincasa hispida has been shown to contain certain active principles like terpenes, flavanoid C--glycosides and sterols which have antioxidant effects. These probably inhibit gastric mucosal injury by scavenging the free radicals and repress production of SOD and vitamin C in these rats.