Modulation of CXCL10 activity as a therapeutic target of ocular toxoplasmosis in diabetic mice.

Ocular toxoplasmosis is likely the most common cause of infectious posterior uveitis worldwide. CXCL10 chemokine has an important role in the maintenance of the T-cell response and the control of Toxoplasma gondii in the eye during chronic infection. Drugs that can modulate the chemokine activity could be effective against the parasite. In this work, CXCL10 local retinal expression was investigated in a diabetic mouse model with ocular toxoplasmosis for the first time. In addition, the efficacy of naphthoquinones and quinolones was compared to spiramycin (SP) in treating the infection and modulating the chemokine expression. Our results revealed that chloroquine (CQ) achieved the best results regarding the reduction of cerebral cyst burden (84.36%), improving the retinal histopathological changes, cellular infiltrates, and vasculitis significantly (P < 0.005), and balancing the strong CXCL10 expression caused by the infection. Buparvaquone-treated mice showed a significant percentage of reduction of brain cysts (76.25%), moderate improvement of histopathology, and mild to moderate CXCL10 expression. While SP showed the least efficacy against the parasite in the eye in the form of mild improvement of histopathological changes and downregulation of retinal chemokine expression with the least reduction rate of cerebral parasitic burden (57%). In conclusion, Optimal control of pathogens probably needs a balanced immune response with an optimum expression of chemokines. So, targeting the modulation of retinal CXCL10 may eventually be beneficial in the management of ocular toxoplasmosis plus its potential to act as a marker for predictive local immunological response during the infection.

Ivermectin modulated cerebral γ-aminobutyric acid (GABA) and reduced the number of chronic Toxoplasma gondii cysts significantly in the brains of immunocompromised mice.

Disruption of GABAergic signaling could exaggerate the inflammatory reaction associated with Toxoplasma gondii infection, as well as produce neurophysiological consequences including seizures that occur within the brain tissues. The current study aimed to evaluate the efficacy of ivermectin (IVM) in treating latent cerebral toxoplasmosis and define its role in the neuromodulation of cerebral tissue GABA expression, conducted in an immunocompromised dexamethasone-treated mouse model infected with the ME49 Toxoplasma strain. The control (non-infected non-treated) group showed a mean of 22.1 ± 0.71 for local expression of GABA. Significantly lower expression (3.78 ± 1.38) was recorded in the infected non-treated group (p ≤ 0.05). On the contrary, a significantly higher expression was reported in the group infected and treated with IVM than in the infected non-treated group (19.8 ± 0.8). While the infected spiramycin (SP)-treated group reported a significantly lower level than the control. Non-infected groups that received only IVM or SP recorded 22.3 ± 0.45 and 22 ± 0.89 respectively with no significant difference. IVM is shown in this work, not only to reduce the size and the number of Toxoplasma cystic lesions within the brain significantly with a reduction rate of 68.85% but to also increase the level of GABA local expression significantly in addition to improving cerebral histopathology. Thus, IVM by its ability to modulate GABA expression may improve such clinical situations, if used as a treatment either exclusively or in combination with other medications.

Type-1 diabetes mellitus down-regulated local cerebral glial fibrillary acidic protein expression in experimental toxoplasmosis.

Cerebral toxoplasmosis is an opportunistic infection, occurring mostly in immunosuppressed patients due to the reactivation of latent Toxoplasma cysts. The cerebral comorbidity in diabetic patients tends to intensify the burden of pathogenic infection within the brain. The aim of this work was to study the effect of cerebral toxoplasmosis in experimentally infected hyperglycemic mice, on histopathology and glial fibrillary acidic protein (GFAP) expression, compared to normoglycemic mice at different time intervals. Vasculopathy was exclusively observed in diabetic groups, with features of increased severity during Toxoplasma infection. Gliosis was observed in diabetic groups, while hyperactive astroglial activity was detected in normoglycemic groups, especially at 6 weeks of infection. GFAP expression showed significant up-regulation in normoglycemic mice at 6 weeks of infection (40.03 ± 1.41) afterwards, it decreased to 22.22 ± 3.14 at 12 weeks which was statistically insignificant to the normal level, possibly indicating the successful Toxoplasma stage transformation (to bradyzoite), thereby limiting the infection within the brain. In hyperglycemic infected groups, GFAP was significantly down-regulated, in both acute and chronic phases of infection, most likely indicating failure of stage transformation and infection limitation. This may expose those vulnerable groups to the risk of dissemination, resulting in life-threatening diffuse encephalitis. The current study emphasized the importance of rapid diagnosis of Toxoplasma infection in diabetic subjects, and highlighted the value of using GFAP as a neurological indicator of disease progression in those comorbid cases.

Antiparasitic and immunomodulating effects of nitazoxanide, ivermectin and selenium on Cryptosporidium infection in diabetic mice.

The present work aims to investigate the antiparasitic and the immunomodulating effects of nitazoxanide (NTZ) and ivermectin (IVC) alone or combined together or combined with selenium (Se), on Cryptosporidium infection in diabetic mice. The results revealed that the combined NTZ and IVC therapy achieved the highest reduction of fecal oocysts (92%), whereas single NTZ showed the lowest reduction (63%). Also, adding Se to either NTZ or IVC resulted in elevation of oocyst reduction from 63% to 71% and from 82% to 84% respectively. All treatment regimens, with the exception of NTZ monotherapy, showed a significant improvement in the intestinal histopathology, the highest score was in combined NTZ and IVC therapy. The unique results of immunohistochemistry in this study showed reversal of the normal CD4/CD8 T cell ratio in the infected untreated mice, however, following therapy it reverts back to a normal balanced ratio. The combined (NTZ+ IVC) treatment demonstrated the highest level of CD4 T cell expression. Taken together, NTZ and IVC combined therapy showed remarkable anti-parasitic and immunostimulatory effects, specifically towards the CD4 population that seem to be promising in controlling cryptosporidiosis in diabetic individuals. Further research is required to explore other effective treatment strategies for those comorbid patients.

Punica granatum and amygdalin extracts plus cobalamin combined with albendazole reduce larval burden and myositis in experimental trichinosis.

Trichinellosis is a zoonosis results from eating raw or semi-cooked meat of infected animals. Medicinal plants have been used lately as alternatives and/or combined therapies to resolve some drawbacks of the current regimens. This work analyzed the effect of albendazole monotherapy on Trichinella spiralis experimental infection (group A), in comparison to P. granatum and amygdalin extracts +cobalamin (group B), plus its combination with albendazole (group C). The study revealed that the extracts alone or combined with albendazole had an inferior effect to albendazole monotherapy regarding number of adult worms (40.83 ±3.82, 18.67 ±1.86 and 16.83 ±2.32, respectively). However, their effect was more obvious in muscle phase combined with albendazole, achieving the lower number of larvae/mL tissue homogenate (22.33 ±3.27 in comparison to 39.67 ±2.58 achieved by albendazole monotherapy). The extracts exerted a significant immunomodulatory effect by reducing the local CD4+ expression in the intestine as well as in muscle phase (1.15 ±0.25 and 3.80 ±0.65 in comparison to 4.97 ±0.37 and 12.20 ±0.87 with albendazole monotherapy, respectively). So, these extracts improved the therapeutic efficacy of albendazole, specifically in muscle phase and counteracted the inflammatory reaction caused by albendazole monotherapy, thus extensively alleviating the resulting myositis.

Punica granatum and amygdalin extracts plus cobalamin combined with albendazole reduce larval burden and myositis in experimental trichinosis / Extratos de Punica granatum e amígdalina mais cobalamina combinado com albendazol reduzem a carga larvar e a miosite na triquinose experimental

Abstract Trichinellosis is a zoonosis results from eating raw or semi-cooked meat of infected animals. Medicinal plants have been used lately as alternatives and/or combined therapies to resolve some drawbacks of the current regimens. This work analyzed the effect of albendazole monotherapy on Trichinella spiralis experimental infection (group A), in comparison to P. granatum and amygdalin extracts +cobalamin (group B), plus its combination with albendazole (group C). The study revealed that the extracts alone or combined with albendazole had an inferior effect to albendazole monotherapy regarding number of adult worms (40.83 ±3.82, 18.67 ±1.86 and 16.83 ±2.32, respectively). However, their effect was more obvious in muscle phase combined with albendazole, achieving the lower number of larvae/mL tissue homogenate (22.33 ±3.27 in comparison to 39.67 ±2.58 achieved by albendazole monotherapy). The extracts exerted a significant immunomodulatory effect by reducing the local CD4+ expression in the intestine as well as in muscle phase (1.15 ±0.25 and 3.80 ±0.65 in comparison to 4.97 ±0.37 and 12.20 ±0.87 with albendazole monotherapy, respectively). So, these extracts improved the therapeutic efficacy of albendazole, specifically in muscle phase and counteracted the inflammatory reaction caused by albendazole monotherapy, thus extensively alleviating the resulting myositis.

Resumo Trichinellosis é uma zoonose resultante da ingestão de carne crua ou semicozida de animais infectados. As plantas medicinais têm sido usadas, ultimamente, como alternativas e/ou terapias combinadas, para resolver algumas desvantagens dos regimes atuais. Este trabalho analisou o efeito da monoterapia albendazole na infecção experimental por Trichinella spiralis (grupo A), em comparação com extratos de P. granatum e amígdalina +cobalamina (grupo B), além de sua combinação com albendazol (grupo C). O estudo revelou que os extratos sozinho ou combinado com albendazol teve efeito inferior à monoterapia albendazol em relação ao número de vermes adultos (40,83 ±3,82, 18,67 ±1,86 e 16,83 ±2,32, respectivamente). No entanto, seu efeito foi mais óbvio na fase muscular combinado com o albendazol, alcançando o menor número de larvas/mL homogeneizado de tecido (22,33 ±3,27 em comparação com 39,67 ±2,58 obtidos pela monoterapia albendazol). Os extratos exerceram um efeito imunomodulatório significativo, ao reduzir a expressão local CD4+ no intestino, bem como na fase muscular (1,15 ±0,25 e 3,80 ±0,65 em comparação com 4,97 ±0,37 e 12,20 ±0,87 com monoterapia albendazol, respectivamente). Assim, esses extratos melhoraram a eficácia terapêutica do albendazol, especificamente na fase muscular e neutralizaram a reação inflamatória causada pela monoterapia albendazol, aliviando extensivamente a miosite resultante.

Antiparasitic and immunomodulating effects of nitazoxanide, ivermectin and selenium on Cryptosporidium infection in diabetic mice / Efeitos antiparasitários e imunomodulantes da nitazoxanida, ivermectina e selênio sobre a infecção por Cryptosporidium em camundongos diabéticos

Abstract The present work aims to investigate the antiparasitic and the immunomodulating effects of nitazoxanide (NTZ) and ivermectin (IVC) alone or combined together or combined with selenium (Se), on Cryptosporidium infection in diabetic mice. The results revealed that the combined NTZ and IVC therapy achieved the highest reduction of fecal oocysts (92%), whereas single NTZ showed the lowest reduction (63%). Also, adding Se to either NTZ or IVC resulted in elevation of oocyst reduction from 63% to 71% and from 82% to 84% respectively. All treatment regimens, with the exception of NTZ monotherapy, showed a significant improvement in the intestinal histopathology, the highest score was in combined NTZ and IVC therapy. The unique results of immunohistochemistry in this study showed reversal of the normal CD4/CD8 T cell ratio in the infected untreated mice, however, following therapy it reverts back to a normal balanced ratio. The combined (NTZ+ IVC) treatment demonstrated the highest level of CD4 T cell expression. Taken together, NTZ and IVC combined therapy showed remarkable anti-parasitic and immunostimulatory effects, specifically towards the CD4 population that seem to be promising in controlling cryptosporidiosis in diabetic individuals. Further research is required to explore other effective treatment strategies for those comorbid patients.

Resumo O presente trabalho tem como objetivo investigar os efeitos anti-parasitários e imunomodulantes da nitazoxanida (NTZ) e ivermectina (IVC), isoladas ou em associação, e do selênio (SE), associado à NTZ ou à IVC, sobre a infecção por Cryptosporidium em camundongos diabéticos. Os resultados revelaram que a terapia combinada com NTZ e IVC resultou em maior redução de oocistos fecais, enquanto a NTZ isolada mostrou a menor redução de oocistos fecais (63%). Além disso, a associação do SE com a NTZ ou IVC resultou em redução do número de oocistos fecais de 63% para 71% e de 82% para 84%, respectivamente. Todos os tratamentos, com exceção da monoterapia com NTZ, mostraram uma melhora significativa nos índices relacionados à histopatologia intestinal. Os resultados da imuno-histoquímica mostraram reversão da razão celular CD4/CD8 T normal nos camundongos infectados não tratados, no entanto, após a terapia, houve retorno à razão celular CD4/CD8 T normal. O tratamento combinado (NTZ+ IVC) demonstrou o mais alto nível de expressão celular CD4 T. Em conclusão, a terapia combinada com NTZ e IVC mostrou efeitos anti-parasitários e imunoestimuladores notáveis, especificamente para a população CD4, que parecem ser promissores para o controle da criptosporidiose em indivíduos diabéticos.