Combination Therapy of Acarbose and Cyclosporine a Ameliorates Imiquimod-Induced Psoriasis-Like Dermatitis in Mice.

Moderate to severe psoriasis, an immune-mediated inflammatory disease, adversely affects patients' lives. Cyclosporin A (CsA), an effective immunomodulator, is used to treat psoriasis. CsA is ineffective at low doses and toxic at high doses. Acarbose (Acar), a common antidiabetic drug with anti-inflammatory and immunomodulatory effects, reduces imiquimod (IMQ)-induced psoriasis severity. Combinations of systemic drugs are generally more efficacious and safer than higher doses of single drugs. We observed that mice treated with a combination of Acar (250 mg/kg) and low-dose CsA (10 or 20 mg/kg) exhibited significantly milder IMQ-induced psoriasis-like dermatitis and smoother back skin than those treated with Acar (250 mg/kg), low-dose CsA (10 or 20 mg/kg), or IMQ alone. The combination therapy significantly reduced serum and skin levels of Th17-related cytokines (interleukin (IL)-17A, IL-22, and IL-23) and the Th1-related cytokine tumor necrosis factor-α (TNF-α) compared with Acar, low-dose CsA, and IMQ alone. Additionally, the combination therapy significantly reduced the percentages of IL-17- and IL-22-producing CD4+ T-cells (Th17 and Th22 cells, respectively) and increased that of Treg cells. Our data suggested that Acar and low-dose CsA in combination alleviates psoriatic skin lesions by inhibiting inflammation. The findings provide new insights into the effects of immunomodulatory drugs in psoriasis treatment.

Chlorella sorokiniana Extract Prevents Cisplatin-Induced Myelotoxicity In Vitro and In Vivo.

Cisplatin chemotherapy causes myelosuppression and often limits treatment duration and dose escalation in patients. Novel approaches to circumvent or lessen myelotoxicity may improve clinical outcome and quality of life in these patients. Chlorella sorokiniana (CS) is a freshwater unicellular green alga and exhibits encouraging efficacy in immunomodulation and anticancer in preclinical studies. However, the efficacy of CS on chemoprotection remains unclear. We report here, for the first time, that CS extract (CSE) could protect normal myeloid cells and PBMCs from cisplatin toxicity. Also, cisplatin-induced apoptosis in HL-60 cells was rescued through reservation of mitochondrial function, inhibition of cytochrome c release to cytosol, and suppression of caspase and PARP activation. Intriguingly, cotreatment of CSE attenuated cisplatin-evoked hypocellularity of bone marrow in mice. Furthermore, we observed the enhancement of CSF-GM activity in bone marrow and spleen in mice administered CSE and cisplatin, along with increased CD11b levels in spleen. In conclusion, we uncovered a novel mechanism of CSE on myeloprotection, whereby potentially supports the use of CSE as a chemoprotector against cisplatin-induced bone marrow toxicity. Further clinical investigation of CSE in combination with cisplatin is warranted.

Gold lotion from citrus peel extract ameliorates imiquimod-induced psoriasis-like dermatitis in murine.

BACKGROUND: Gold lotion (GL), a natural mixed product made from the peels of six citrus fruits, has recently been identified as possessing anti-oxidative, anti-inflammatory, and immunomodulatory effects. GL has been used to protect skin against UV-induced damage, but its activity against psoriasis, a chronic autoimmune skin disease caused by dysregulation between immune cells and keratinocytes, is not known. We therefore evaluated the effect of GL on imiquimod (IMQ)-induced psoriasis-like inflammation in mice. RESULTS: GL treatment significantly attenuated IMQ-induced psoriasis-like symptoms in mice. The inflammatory cytokines upregulated by IMQ in skin lesions were also inhibited by feeding GL. In addition, GL treatment reduced the infiltration of CD4+ T cells/neutrophils in skin lesions and the percentage of IL-17-/IL-22-producing T cells in lymph nodes. Furthermore, GL impaired IMQ-induced type I interferon production by plasmacytoid dendritic cells (pDCs) in vitro. CONCLUSION: Our results indicate GL can act to suppress the initiation of psoriasis and strongly suggest that GL may have potential to be applied to the treatment of psoriasis. © 2018 Society of Chemical Industry.

Chlorella sorokiniana induces mitochondrial-mediated apoptosis in human non-small cell lung cancer cells and inhibits xenograft tumor growth in vivo.

BACKGROUND: Lung cancer is one of the leading causes of cancer related deaths worldwide. Marine microalgae are a source of biologically active compounds and are widely consumed as a nutritional supplement in East Asian countries. It has been reported that Chlorella or Chlorella extracts have various beneficial pharmacological compounds that modulate immune responses; however, no studies have investigated the anti-cancer effects of Chlorella sorokiniana (CS) on non-small cell lung cancer (NSCLC). METHODS: In this study, we evaluated the anti-cancer effects of CS in two human NSCLC cell lines (A549 and CL1-5 human lung adenocarcinoma cells), and its effects on tumor growth in a subcutaneous xenograft tumor model. We also investigated the possible molecular mechanisms governing the pharmacological function of CS. RESULTS: Our results showed that exposure of the two cell lines to CS resulted in a concentration-dependent reduction in cell viability. In addition, the percentage of apoptotic cells increased in a dose-dependent manner, suggesting that CS might induce apoptosis in human NSCLC cells. Western blot analysis revealed that exposure to CS resulted in increased protein expression of the cleaved/activated forms of caspase-3, caspase-9, and PARP, except caspase-8. ZDEVD (caspase-3 inhibitor) and Z-LEHD (caspase-9 inhibitor) were sufficient at preventing apoptosis in both A549 and CL1-5 cells, proving that CS induced cell death via the mitochondria-mediated apoptotic pathway. Exposure of A549 and CL1-5 cells to CS for 24 h resulted in decreased expression of Bcl-2 protein and increased expression of Bax protein as well as decreased expression of two IAP family proteins, survivin and XIAP. CONCLUSIONS: We demonstrated that CS induces mitochondrial-mediated apoptosis in NSCLC cells via downregulation of Bcl-2, XIAP and survivin. In addition, we also found that the tumors growth of subcutaneous xenograft in vivo was markedly inhibited after oral intake of CS.

Oral administration of acarbose ameliorates imiquimod-induced psoriasis-like dermatitis in a mouse model.

Psoriasis is a chronic autoimmune disease of undefined etiology that involves dysregulated interplay between immune cells and keratinocytes. Acarbose was found to decrease inflammatory parameters in diabetic patients in addition to its anti-diabetic effects. Here, we report that imiquimod (IMQ)-induced epidermal hyperplasia and psoriasis like-inflammation were significantly inhibited by acarbose treatment. Real-time PCR showed that mRNA levels of the cytokines TNF-α, IL-6, IL-1ß IL-17A, and IL-22 in skin were also decreased significantly by acarbose. In addition, we found that acarbose reduced infiltration of CD3(+) T cells and GR-1(+) neutrophils in lesional skin and also reduced the percentage of IL-17-producing CD4(+) T cells (Th17) and IL-17- and IL-22-producing γδ T cells in the spleen. In contrast, acarbose increased the frequency of IL-10-producing CD4(+) regulator Tr1 T cells in the spleen and small intestine. These results indicate that oral administration of acarbose can attenuate the severity of imiquimod-induced psoriasis with local and systemic anti-inflammatory and immune modulation effects, thus suggesting that acarbose is an effective therapeutic strategy for psoriasis regulation.

Potent Antiarthritic Properties of Phloretin in Murine Collagen-Induced Arthritis.

In the exploration of potential therapeutic agents for rheumatoid arthritis (RA), DBA/1J mice are used as the RA model of collagen-induced arthritis (CIA). Phloretin, a flavonoid compound extracted from Prunus mandshurica, has been found to exhibit anti-inflammatory activity, making it a potential candidate for treatment of RA. The objective of this study was to evaluate the therapeutic effects of phloretin on CIA mice. CIA mice were dosed daily with phloretin at either 50 or 100 mg/kg among two treatment groups. CIA treated mice showed mitigation of clinical symptoms of RA in addition to reduced inflammation of hind-limbs compared to mice who did not receive phloretin. Histological analysis showed that phloretin suppressed the severity of RA and effectively mitigated joint inflammation and cartilage- and bone-destruction via reducing proinflammatory cytokine productions (TNF-α, IL-6, IL-1ß, and IL-17). This was at least partially mediated by causing inadequate splenocyte activation and proliferation. Moreover, phloretin-treated CIA mice showed decreased oxidative stress and diminished levels of malondialdehyde (MDA) and hydrogen peroxide (H2O2) in paw tissues as well as reduced productivity of anti-collagen antibodies in serum. We have concluded that phloretin could be a potent and effective antiarthritis agent, demonstrating anti-inflammatory, antioxidative, and immunomodulatory effects in CIA mice.

Acarbose Decreases the Rheumatoid Arthritis Risk of Diabetic Patients and Attenuates the Incidence and Severity of Collagen-induced Arthritis in Mice.

Acarbose has been found to decrease some inflammatory parameters in diabetic patients. This study aimed to examine the influence of acarbose on rheumatoid arthritis (RA) risk in diabetes mellitus (DM) patients and on the incidence and severity of collagen-induced arthritis (CIA) in mice. In a nationwide, matched case-control study, we identified 723 incident RA cases and selected 7,230 age-, sex- and RA diagnosis date-matched controls from all newly treated DM patients. We found that use of acarbose at > 16,950 mg per year was associated with a lower RA risk (odds ratio 0.60; 95% CI, 0.41-0.89). In the CIA mouse study, acarbose was orally administered from days -7 to 38 relative to type II collagen (CII) immunization. The results revealed that acarbose at the dose of 500 mg/kg/day attenuated the incidence and severity of arthritis and the expression of proinflammatory cytokines, including TNF-α, IL-6 and IL-17 in the paw tissues. Acarbose further decreased the productions of anti-CII-IgG, IL-17 and IFN-γ by collagen-reactive lymph node cells. This work suggests that the use of acarbose decreased RA risk in DM patients and the incidence of CIA in mice. Acarbose also attenuated the severity of CIA via anti-inflammatory and immunomodulatory effects.