The role of the natural killer (NK) cell modulation in breast cancer incidence and progress.

The importance of the immune system on tumor surveillance has been investigated for many years, and its impact on controlling tumor progression has been verified. An important subgroup of the innate immune system is natural killer (NK) cells, whose essential function in modulating tumor behavior and suppressing metastasis and tumor growth has been demonstrated. The first idea of NK cells' crucial biological processes was demonstrated through their potent ability to conduct direct cellular cytotoxicity, even without former sensitization. These properties of NK cells allow them to recognize transformed cells that have attenuated self-ligand and express stress-induced ligands. Furthermore, secretion of various cytokines and chemokines after their activation leads to tumor elimination via either direct cytotoxic effect on malignant cells or activation of the adaptive immune system. In addition, novel immunotherapeutic approaches tend to take advantage of NK cells' ability, leading to antibody-based approaches, the formation of engineered CAR-NK cells, and adoptive cell transfer. However, the restricted functionality of NK cells and the inability to infiltrate tumors are its blind spots in breast cancer patients. In this review, we gathered newly acquired data on the biology and functions of NK cells in breast cancer and proposed ways to employ this knowledge for novel therapeutic approaches in cancers, particularly breast cancer.

Allergic rhinitis in BALB/c mice is associated with behavioral and hippocampus changes and neuroinflammation via the TLR4/ NF-κB signaling pathway.

BACKGROUND: Allergic rhinitis is a systemic disease with high prevalence, which some of its neuropsychological problems have been reported. The primary pathophysiology and mechanism of the neuropsychological dysfunction of AR patients have not been described yet, so here we subjected an animal model of AR to identify any behavioral or seizure threshold changes and to assess the pathophysiology of the disease. METHODS: Eighty male BALB/C mice were randomly divided into the allergic rhinitis group and controls. Allergic rhinitis was induced in the first group by administering OVA and aluminum hydroxide intraperitoneally and then nasal injection of OVA for 14 consecutive days. Both groups were subjected to different tests for assessing depressive-like behavior, anxiety, spatial and contextual memory, and learning and seizure threshold. Hippocampus and plasma samples of mice were subjected for analyzing cytokines and immune modulators and for pathology and immunohistochemistry evaluation. RESULTS: The depressive and anxiety-like behavior were increased in AR, and the spatial learning and memory were disturbed in the AR group. Also, AR mice had lower seizure thresholds compared to controls. Lab data suggested that TLR4, NF-κB, IL-1ß, and TNFα expressions were increased in the AR hippocampus as well as their plasma proinflammatory cytokines. Likewise, demyelination, cell death, and M1 macrophage aggregation were increased in the AR hippocampus. CONCLUSION: Behavioral and cognitive problems should be taken seriously in patients with AR or other atopic diseases, and more investigating is required to clear the pathophysiology behind it and its treatment.

Role of hypothalamic-pituitary adrenal-axis, toll-like receptors, and macrophage polarization in pre-atherosclerotic changes induced by social isolation stress in mice.

It has been well documented that chronic stress can induce atherosclerotic changes, however, the underlying mechanisms is yet to be established. In this regard, this study aimed to elucidate the relation between hypothalamic-pituitary adrenal-axis (HPA-axis), toll-like receptors (TLRs), as well as M1/M2 macrophage ratio and pre-atherosclerotic changes in social isolation stress (SIS) in mice. We used small interfering RNA against the glucocorticoid receptor (GR) to evaluate the relation between HPA-axis and TLRs. C57BL/6J mice were subjected to SIS and RT-PCR, ELISA, flow cytometry, and immunohistochemistry were used to assess the relations between pre-atherosclerotic changes and TLRs, macrophage polarization, pro-inflammatory cytokines, and cell adhesion molecules in aortic tissue. We used TAK-242 (0.3 mg/kg, intraperitoneally), a selective antagonist of TLR4, as a possible prophylactic treatment for atherosclerotic changes induced by SIS. We observed that isolated animals had higher serum concentration of corticosterone and higher body weight in comparison to normal animals. In isolated animals, results of in vitro study showed that knocking-down of the GR in bone marrow-derived monocytes significantly decreased the expression of TLR4. In vivo study suggested higher expression of TLR4 on circulating monocytes and higher M1/M2 ratio in aortic samples. Pathological study showed a mild pre-atherosclerotic change in isolated animals. Finally, we observed that treating animals with TAK-242 could significantly inhibit the pre-atherosclerotic changes. SIS can possibly increase the risk of atherosclerosis through inducing abnormal HPA-axis activity and subsequently lead to TLR4 up-regulation, vascular inflammation, high M1/M2 ratio in intima. Thus, TLR4 inhibitors might be a novel treatment to decrease the risk of atherosclerosis induced by chronic stress.

Losartan ointment attenuates imiquimod-induced psoriasis-like inflammation.

BACKGROUND: Psoriasis is a chronic skin condition associated with interleukin-23/interleukin-17 (IL-23/IL-17) pathway. Recent evidence declares that angiotensin II (Ang II) induces a potent IL-17-related inflammation. Meanwhile, Losartan, an angiotensin one receptor (AT1R) antagonist, attenuates the TH17-related responses. Therefore, we investigated the possible beneficial effects of topically applied Losartan1% ointment on imiquimod (IMQ)-induced psoriasis in mice. METHOD: Psoriasis was induced in mice consecutively for five days by topical IMQ on the shaved back. The IMQ-induced psoriasis was treated via topical administration of Losartan1% twice a day. The severity of skin inflammation was evaluated employing Psoriasis Area and Severity Index (PASI) scores. Subsequently, the skin samples were assessed using Baker's scoring system, stereological studies, and biochemical assessment with real-time PCR and immunohistochemistry. RESULTS: IMQ administration induced plaque-type psoriasis and skin inflammation. We characterized psoriatic lesions by hyperkeratosis, Munro abscess, rete ridges, and marked T-cell infiltrates. IMQ significantly increased epidermal volume, mRNA expression of IL-17a, IL-23, Ang II, AT1R, and TNF-α levels compared with the Placebo group. Topical administration of Losartan1% on IMQ-induced psoriasis significantly reduced the PASI scores and alleviated the erythema and scaling. The treatment significantly decreased the psoriatic thickness and dermal T-cell infiltration. Regarding biochemical assessment, Losartan1% considerably reduced the IMQ-induced increase of IL-17a, Ang II, and AT1R expression in the skin. CONCLUSION: Topical Losartan1% significantly alleviates psoriasis by reducing AT1R and IL-17a expression. Our results introduce AT1Rs as a promising therapeutic target in psoriasis and represent a link between angiotensin and TH17-related inflammation. However, the effects of AngII-AT1R systems on IL-17 signaling need to be confirmed by further investigations.

Ivermectin-functionalized multiwall carbon nanotube enhanced the locomotor activity and neuropathic pain by modulating M1/M2 macrophage and decrease oxidative stress in rat model of spinal cord injury.

Since the inflammation and oxidative stress is the main pathophysiological pathway of neural damage in spinal cord injury (SCI), we tried to evaluate the role of ivermectin (IVM) combined with multi-walled carbon nanotube (MWCNT) in the treatment settings of SCI and its underlying mechanism. Wistar rats with T9 vertebra laminectomy in five groups of: sham-operated, vehicle, IVM (0.1 mg/kg), IVM-MWCNT (0.1 mg/kg), and minocycline (90 mg/kg) were used. We evaluated the locomotor scaling and other behavioral tests for neuropathic pain. Also, tissue samples were obtained to evaluate the expression of M1 and M2 macrophage marker, concentration of TNF-α, IL-1ß, and IL-1, and oxidative stress level to assess neuroinflammatory changes. Both IVM and IVM-MWCNT after induction of SCI significantly enhanced the experimental tasks' outcomes, including locomotion and neuropathic tests. Also, decreasing in pro-inflammatory cytokines including TNF-α, IL-1ß, and IL-1 in the spinal cord and dorsal root ganglion tissues was also notable in both IVM and IVM-MWCNT-treated groups 28 days after induction of SCI in compared to the vehicle-treated SCI group. Both IVM and IVM-MWCNT significantly decreased oxidative stress, induced by SCI, based on the results of ROS and NADPH activity. IVM-MWCNT-treated animals indicated better outcome in every previous experiment in comparison to IVM-treated animals. The effectiveness of IVM-MWCNT was similar to minocycline treatment in all experimental task (as positive control group). IVM-MWCNT might be a novel treatment in spinal cord injury, which could act through decreasing the oxidative stress and increase the polarization of M1 in comparison to M2 macrophages.

Celiac disease in patients with systemic lupus erythematosus.

OBJECTIVES: Celiac disease (CD) is one of the most common chronic diseases. Celiac disease has been associated with several autoimmune disorders, but the association with systemic lupus erythematosus (SLE) as a systemic autoimmune disease is still controversial. In this study, we aimed to determine the prevalence of biopsy-proven CD in patients with SLE, and to determine the clinical symptoms and laboratory data in these patients. MATERIAL AND METHODS: In a cross-sectional study, SLE patients at a referral clinic were evaluated for gastrointestinal symptoms between March and December 2016. Patients were evaluated by a gastroenterologist, and upper gastrointestinal endoscopy with intestinal biopsy was performed if deemed necessary. The clinical symptoms, laboratory data, and endoscopy results were recorded and compared between groups. RESULTS: In total, 130 patients were evaluated in this study. Gastrointestinal symptoms were present in 40% of the patients. Endoscopy was performed in all SLE patients with gastrointestinal symptoms. Four patients (3%) were diagnosed as having CD based on biopsy results and response to a gluten-free diet. Anti-endomysium antibody (AEA) was found to be 100% sensitive and 99.2% specific for the diagnosis of CD in SLE patients, and anti-gliadin antibody (AGA) had a 50% sensitivity and 98% specificity. Patients with comorbid CD and SLE were significantly more likely to have diarrhea, abdominal pain, nausea/vomiting, recurrent oral aphthosis, and anemia. CONCLUSIONS: The results of this study suggest that a significant association is present between CD and SLE. We found a prevalence of 3% for biopsy-proven CD in patients with SLE, which is five times the prevalence of CD in the general population.

Protective effect of minocycline on LPS-induced mitochondrial dysfunction and decreased seizure threshold through nitric oxide pathway.

Lipopolysaccharide (LPS) increases inflammatory cytokines of the brain and deregulates the mitochondrial function, thus could increase the seizure susceptibility. Studies have shown that minocycline has neuroprotective and antioxidant properties. In this study, we aimed to evaluate the anticonvulsant properties of minocycline in LPS-treated animals and the possible involvement of nitric oxide and mitochondrial pathways. In a PTZ model of seizure in mice, minocycline was administrated to LPS-treated mice. Then followed by co-injection of its sub-effective dose and NOS inhibitors including 7-Nitroindazole (7-NI), aminoguanidine (AG) and L-NG-Nitroarginine methyl ester (L-NAME) to evaluate the changes in seizure threshold and the possible involvement of nitrergic system. Molecular assessments were used to evaluate the effects of each treatment on inflammation and mitochondrial function in the brain. LPS-treated animals had lower seizure threshold compared to intact animals; injection of minocycline (80 mg/kg) to LPS-treated mice reversed this effect. Co-injection of sub-effective doses of minocycline (40 mg/kg) and L-NAME to LPS-treated animals significantly increased seizure threshold. We observed that co-treatment of minocycline and AG dissimilar to 7-NI could increase the seizure threshold of LPS-treated animals. L-arginine reversed the anticonvulsant effect of minocycline. Also, molecular evaluations showed that LPS could increase the ATP levels, GSH levels, and reactive oxygen species formation. However, minocycline at both doses significantly reversed the effect of LPS. Minocycline counteracts the proconvulsant effects of LPS through regulating of mitochondrial function and decreasing of neuro-inflammation. Also, co-administration of minocycline and i-NOS inhibitors could intensify anticonvulsant effects of minocycline.

Evaluation of the pharmacological involvement of ATP-sensitive potassium (KATP) channels in the antidepressant-like effects of topiramate on mice.

Acute doses of topiramate (TPM) have been shown to reduce immobility time in the mice forced swimming test (FST) through inhibition of the nitric oxide (NO) pathway. Adenosine triphosphate-sensitive potassium (KATP) channels are known to have an active role in depression. This study investigates the potential participation of KATP channels in the antidepressant-like effect of TPM through the stimulatory effects of NO. FST and tail suspension tests (TST) were applied to adult male mice for assessment of the antidepressant-like activity of TPM. Different doses of glibenclamide and cromakalim were also applied in order to investigate the involvement of KATP channels. Fluoxetine was used as a positive control for evaluation of antidepressant-like effects. In addition, each animal's locomotor activity was evaluated by the open-field test (OFT). TPM (30 mg/kg intraperitoneal (i.p.)) had a significant reductive effect on the immobility behavior similar to fluoxetine (20 mg/kg). Co-administration of sub-effective doses of glibenclamide (1 mg/kg i.p.) and TPM (10 mg/kg i.p.) led to significant synergistic effects in FST and TST. Additionally, the results showed that administration of the sub-effective dose of cromakalim (0.1 and 0.3 mg/kg i.p.) blocked the antidepressant-like effects of TPM (30 mg/kg i.p.) in both tests. These interventions had no impact on the locomotor movement of mice in OFT. This study shows that the antidepressant-like activity of TPM may potentially be mediated by the blocking of the KATP channels.