Effect of probiotics on the maintenance of intestinal homeostasis after chemotherapy: systematic review and meta-analysis of pre-clinical studies.

Gastrointestinal mucositis (GIM) is an inflammation caused by antitumor therapy, especially after chemotherapy and radiotherapy. Currently in the clinical practice, only palliative measures are taken to treat GIM, representing the main clinical limitation in the management of this condition. Several studies have highlighted the potential benefits of probiotics for the management of GIM, but the actual role of these microorganisms in the maintenance of intestinal homeostasis remains elusive. In this context, here we aimed to realise a systematic review with meta-analysis to evaluate the effect of probiotics on experimental GIM. The meta-analysis showed that probiotics significantly suppressed the body weight loss related to GIM in rodents (95% confidence interval (CI): -2.67 to -0.70; I2=98%, P<0.00). Subgroup analysis showed that pre-treatment (≥7 days before chemotherapy) (95% CI: -8.84 to -0.17; I2=98%, P<0.04) with a high dose of probiotics (≥ 109 cfu/day) (95% CI: -2.58 to -0.28; I2=98%, P<0.00) comprising two or more microorganism species (95% CI: -6.49 to -0.28; I2=96%, P=0.03) remedied GIM more effectively. It was also revealed that fungi (specifically Saccharomyces boullardii) are more effective in remedying GIM than bacteria (P=0.03 vs P<0.00), and the mouse models are more receptive than rats to the enteroprotective effects of probiotics (95% CI: -4.76, -0.69; I2=97%, P=0.01). Qualitative analyses highlighted that probiotics suppress GIM through several mechanisms; they reduce the intestinal permeability, suppress the pro-inflammatory cytokine production while stimulating production and secretion of anti-inflammatory cytokines, inhibit the signalling pathways coupled to inflammation and apoptosis, accelerate the proliferation of enterocytes, reduce the levels of reactive oxygen species, and help maintain the protective mucus layer. In conclusion, this review highlights the therapeutic benefits of probiotics in experimental GIM.

Swimming exercise demonstrates advantages over running exercise in reducing proteinuria and glomerulosclerosis in spontaneously hypertensive rats.

Experimental studies in animal models have described the benefits of physical exercise (PE) to kidney diseases associated with hypertension. Land- and water-based exercises induce different responses in renal function. Our aim was to evaluate the renal alterations induced by different environments of PE in spontaneously hypertensive rats (SHRs). The SHRs were divided into sedentary (S), swimming exercise (SE), and running exercise (RE) groups, and were trained for 8 weeks under similar intensities (60 min/day). Arterial pressure (AP) and heart rate (HR) were recorded. The renal function was evaluated through urinary volume at each week of training; sodium and potassium excretions, plasma and urinary osmolarities, glomerular filtration rate (GFR), levels of proteinuria, and renal damage were determined. SE and RE rats presented reduced mean AP, systolic blood pressure, and HR in comparison with S group. SE and RE rats showed higher urine osmolarity compared with S. SE rats showed higher free water clearance (P < 0.01), lower urinary density (P < 0.0001), and increased weekly urine volume (P < 0.05) in comparison with RE and S groups. GFR was increased in both SE and RE rats. The proteinuria of SE (7.0 ± 0.8 mg/24 h) rats was decreased at the 8th week of the PE in comparison with RE (9.6 ± 0.8 mg/24 h) and S (9.8 ± 0.5 mg/24 h) groups. The glomerulosclerosis was reduced in SE rats (P < 0.02). SE produced different response in renal function in comparison with RE, in which only swimming-trained rats had better profile for proteinuria and glomerulosclerosis.

Time-course effects of aerobic exercise training on cardiovascular and renal parameters in 2K1C renovascular hypertensive rats

Exercise training (Ex) has been recommended for its beneficial effects in hypertensive states. The present study evaluated the time-course effects of Ex without workload on mean arterial pressure (MAP), reflex bradycardia, cardiac and renal histology, and oxidative stress in two-kidney, one-clip (2K1C) hypertensive rats. Male Fischer rats (10 weeks old; 150–180 g) underwent surgery (2K1C or SHAM) and were subsequently divided into a sedentary (SED) group and Ex group (swimming 1 h/day, 5 days/week for 2, 4, 6, 8, or 10 weeks). Until week 4, Ex decreased MAP, increased reflex bradycardia, prevented concentric hypertrophy, reduced collagen deposition in the myocardium and kidneys, decreased the level of thiobarbituric acid-reactive substances (TBARS) in the left ventricle, and increased the catalase (CAT) activity in the left ventricle and both kidneys. From week 6 to week 10, however, MAP and reflex bradycardia in 2K1C Ex rats became similar to those in 2K1C SED rats. Ex effectively reduced heart rate and prevented collagen deposition in the heart and both kidneys up to week 10, and restored the level of TBARS in the left ventricle and clipped kidney and the CAT activity in both kidneys until week 8. Ex without workload for 10 weeks in 2K1C rats provided distinct beneficial effects. The early effects of Ex on cardiovascular function included reversing MAP and reflex bradycardia. The later effects of Ex included preventing structural alterations in the heart and kidney by decreasing oxidative stress and reducing injuries in these organs during hypertension.

Time-course effects of aerobic exercise training on cardiovascular and renal parameters in 2K1C renovascular hypertensive rats.

Exercise training (Ex) has been recommended for its beneficial effects in hypertensive states. The present study evaluated the time-course effects of Ex without workload on mean arterial pressure (MAP), reflex bradycardia, cardiac and renal histology, and oxidative stress in two-kidney, one-clip (2K1C) hypertensive rats. Male Fischer rats (10 weeks old; 150-180 g) underwent surgery (2K1C or SHAM) and were subsequently divided into a sedentary (SED) group and Ex group (swimming 1 h/day, 5 days/week for 2, 4, 6, 8, or 10 weeks). Until week 4, Ex decreased MAP, increased reflex bradycardia, prevented concentric hypertrophy, reduced collagen deposition in the myocardium and kidneys, decreased the level of thiobarbituric acid-reactive substances (TBARS) in the left ventricle, and increased the catalase (CAT) activity in the left ventricle and both kidneys. From week 6 to week 10, however, MAP and reflex bradycardia in 2K1C Ex rats became similar to those in 2K1C SED rats. Ex effectively reduced heart rate and prevented collagen deposition in the heart and both kidneys up to week 10, and restored the level of TBARS in the left ventricle and clipped kidney and the CAT activity in both kidneys until week 8. Ex without workload for 10 weeks in 2K1C rats provided distinct beneficial effects. The early effects of Ex on cardiovascular function included reversing MAP and reflex bradycardia. The later effects of Ex included preventing structural alterations in the heart and kidney by decreasing oxidative stress and reducing injuries in these organs during hypertension.

Cardiac and renal effects induced by different exercise workloads in renovascular hypertensive rats

We examined the effect of exercise training (Ex) without (Ex 0 percent) or with a 3 percent workload (Ex 3 percent) on different cardiac and renal parameters in renovascular hypertensive (2K1C) male Fisher rats weighing 150-200 g. Ex was performed for 5 weeks, 1 h/day, 5 days/week. Ex 0 percent or Ex 3 percent induced similar attenuation of baseline mean arterial pressure (MAP, 119 ± 5 mmHg in 2K1C Ex 0 percent, N = 6, and 118 ± 5 mmHg in 2K1C Ex 3 percent, N = 11, vs 99 ± 4 mmHg in sham sedentary (Sham Sed) controls, N = 10) and heart rate (HR, bpm) (383 ± 13 in 2K1C Ex 0 percent, N = 6, and 390 ± 14 in 2K1C Ex 3 percent, N = 11 vs 371 ± 11 in Sham Sed, N = 10,). Ex 0 percent, but not Ex 3 percent, improved baroreflex bradycardia (0.26 ± 0.06 ms/mmHg, N = 6, vs 0.09 ± 0.03 ms/mmHg in 2K1C Sed, N = 11). Morphometric evaluation suggested concentric left ventricle hypertrophy in sedentary 2K1C rats. Ex 0 percent prevented concentric cardiac hypertrophy, increased cardiomyocyte diameter and decreased cardiac vasculature thickness in 2K1C rats. In contrast, in 2K1C, Ex 3 percent reduced the concentric remodeling and prevented the increase in cardiac vasculature wall thickness, decreased the cardiomyocyte diameter and increased collagen deposition. Renal morphometric analysis showed that Ex 3 percent induced an increase in vasculature wall thickness and collagen deposition in the left kidney of 2K1C rats. These data suggest that Ex 0 percent has more beneficial effects than Ex 3 percent in renovascular hypertensive rats.

Cardiac and renal effects induced by different exercise workloads in renovascular hypertensive rats.

We examined the effect of exercise training (Ex) without (Ex 0%) or with a 3% workload (Ex 3%) on different cardiac and renal parameters in renovascular hypertensive (2K1C) male Fisher rats weighing 150-200 g. Ex was performed for 5 weeks, 1 h/day, 5 days/week. Ex 0% or Ex 3% induced similar attenuation of baseline mean arterial pressure (MAP, 119 ± 5 mmHg in 2K1C Ex 0%, N = 6, and 118 ± 5 mmHg in 2K1C Ex 3%, N = 11, vs 99 ± 4 mmHg in sham sedentary (Sham Sed) controls, N = 10) and heart rate (HR, bpm) (383 ± 13 in 2K1C Ex 0%, N = 6, and 390 ± 14 in 2K1C Ex 3%, N = 11 vs 371 ± 11 in Sham Sed, N = 10,). Ex 0%, but not Ex 3%, improved baroreflex bradycardia (0.26 ± 0.06 ms/mmHg, N = 6, vs 0.09 ± 0.03 ms/mmHg in 2K1C Sed, N = 11). Morphometric evaluation suggested concentric left ventricle hypertrophy in sedentary 2K1C rats. Ex 0% prevented concentric cardiac hypertrophy, increased cardiomyocyte diameter and decreased cardiac vasculature thickness in 2K1C rats. In contrast, in 2K1C, Ex 3% reduced the concentric remodeling and prevented the increase in cardiac vasculature wall thickness, decreased the cardiomyocyte diameter and increased collagen deposition. Renal morphometric analysis showed that Ex 3% induced an increase in vasculature wall thickness and collagen deposition in the left kidney of 2K1C rats. These data suggest that Ex 0% has more beneficial effects than Ex 3% in renovascular hypertensive rats.

Enalapril prevents cardiac immune-mediated damage and exerts anti-Trypanosoma cruzi activity during acute phase of experimental Chagas disease.

Chagas heart disease (CHD), caused by Trypanosoma cruzi infection, is a significant cause of morbidity and mortality in South and Central America. Enalapril, an angiotensin converting enzyme (ACE) inhibitor, is an important drug used to ameliorate heart functional capacity and its remodelling in individuals presenting CHD. In this study, we evaluated the effects of enalapril on systemic and cardiac immune response during experimental acute CHD. C57BL/6 mice infected with 50 trypomastigote forms of T. cruzi (Colombian strain) were treated daily with enalapril (25 mg/kg) and, after 30 days, a reduction in seric levels of IFN-gamma, TNF-alpha, CCL5/RANTES and nitric oxide, but not in that of IL-10, was detected. This imbalance of cytokines reflects in a reduction of heart mononuclear infiltration and in an increasing of cardiac mast cells. Enalapril also presents a new and interesting in vitro and in vivo anti-T. cruzi activity probably acting on parasite oxidative pathway via cytochrome-P450. Our data show that enalapril exerts an important anti-T. cruzi and anti-inflammatory activity during acute CHD reducing inflammatory cells and, possibly, preventing fibrotic process in the chronic phase. Nevertheless, further studies are still necessary to clarify the mechanisms by which this drug is acting on the parasites and on the immune pathways.

Cervical, mandibular, and parotid lymph nodes of dogs naturally infected with Leishmania infantum: a histopathologic and immunohistochemistry study and its correlation with facial skin lesions.

The parasite load in cervical, mandibular, and parotid lymph nodes and in the skin of the nose and the pinna from dogs infected with Leishmania infantum were investigated by histologic and immunohistochemical studies. Twenty-two infected dogs with and without signs of infection were examined to demonstrate correlation of signs with parasite load and the correlation of facial skin lesions with parasites in regional lymph nodes. Chronic inflammation of the skin was demonstrated in infected dogs that had no gross skin lesions, confirming that normal-appearing skin can harbor the parasite, likely playing a role in transmission. Dogs with facial skin lesions showed a higher parasite load in parotid lymph nodes than dogs without lesions of the facial skin, based on Leishman-Donovan unit analysis. Based on immunohistochemical analysis, parasite load in parotid and cervical nodes was correlated with that of skin of the nose and pinna, as was the parasite load in mandibular lymph nodes and skin of the external nose. We demonstrated a logical involvement of the lymphatic vessels and their specific anatomic draining sites.

Hepatic granulomas in canine visceral leishmaniasis and clinical status

The histopathological description of intralobular hepatic granulomas in animals with a defined clinical status (asymptomatic, oligosymptomatic and symptomatic animals) was reported. Seventy-one mongrel dogs naturally infected with Leishmania chagasi were obtained from two Brazilian endemic areas: João Pessoa, PB and Belo Horizonte, MG. The hepatic parasite load was determined and compared to granuloma formation. Liver fragments from all infected animals showed remarkable leishmaniotic granulomatous inflammatory reaction. Granulomas with variable size were constituted by macrophages (parasitized or not with amastigotes of L. chagasi), some epithelioid cells, small numbers of lymphocytes, plasma cells, and rare neutrophils. Asymptomatic dogs had higher numbers of granulomas than oligosymptomatic and symptomatic animals from both geographical regions. However, the average diametric size of granulomas was very heterogeneous in all groups, independently of the geographic region (P>0.05). Parasite tissue load did not show any difference among liver fragments of all animals, especially when considering the defined clinical status and/or their geographic origin

Descreve-se a formação de granulomas hepáticos na leishmaniose canina em animais com classificação clínica definida - assintomáticos, oligossintomáticos e sintomáticos. Setenta e um animais, sem raça definida e naturalmente infectados com Leishmania chagasi, foram obtidos de duas regiões endêmicas brasileiras: João Pessoa, PB e Belo Horizonte, MG. A carga parasitária tecidual foi determinada mediante emprego do Leishmania Donovani Units (LDU) e comparada com a formação de granulomas hepáticos. Fragmentos de fígado de todos os animais infectados mostraram reação granulomatosa notadamente leishmaniótica. Granulomas de variáveis tamanhos eram constituídos por macrófagos, parasitados ou não com formas amastigotas de L. chagasi, algumas células epitelióides, pequeno número de linfócitos e plasmócitos, e raros neutrófilos. Cães assintomáticos apresentaram maior número de granulomas do que os animais oligossintomáticos e sintomáticos, em ambas as regiões geográficas. As médias dos diâmetros foram heterogêneas em todos os grupos, independente da região geográfica (P>0,05). Quanto ao parasitismo (LDU), não houve diferença entre as amostras de fígado, especialmente quando se consideraram a classificação clínica e a região geográfica

Histopathological and immunohistochemical study of type 3 complement receptors (CD11b/CD18) in livers and spleens of asymptomatic and symptomatic dogs naturally infected with Leishmania (Leishmania) chagasi.

Leishmania promastigotes interact with macrophages through the association of multiple membrane surface receptors. Macrophage complement receptor CR3 (CD11b/CD18 or Mac-1) has been implicated in the interaction of both human and murine macrophages with serum-opsonized promastigotes. The aim of this study was to determine CR3 expression in the livers and spleens of dogs naturally infected with Leishmania (Leishmania) chagasi. CR3 expression in liver was higher in asymptomatic than in symptomatic animals. Moreover, the hepatic parasitism load determined by immunocytochemical analysis was lower in parallel with higher numbers of granulomas. In contrast, in spleens, CR3 expression was higher in symptomatic animals than in asymptomatic ones. However, the tissue parasite load was greater in spleens of symptomatic dogs. There was a strict correlation between the parasite load and cellular CR3 expression in the spleens of dogs naturally infected with L. chagasi. CR3 macrophage integrins could be essential receptors for Leishmania survival. Considering that the symptomatic animals showed higher parasite loads and higher CD11b/CD18 expression in their spleens, we can conclude that these splenic cells (monocyte-macrophages) might serve to perpetuate intracellular infection.

Canine visceral leishmaniasis: a remarkable histopathological picture of one asymptomatic animal reported from Belo Horizonte, Minas Gerais, Brazil

A remarkable histopathological picture of one asymptomatic dog naturally infected with Leishmania infantum (syn. chagasi) has been presented. Intracellular parasites were ease found in macrophages of all exanimated organs, especially in skin. Embedded paraffin tissues of liver, spleen, axillary and popliteal lymph nodes, and skin (ear, muzzle and abdomen) were stained by hematoxylin and eosin and by immunocytochemical reaction (streptoavidin-peroxidase method) to detect parasites. All organs showed an intense parasitism associated to severe pathological changes. All lymph nodes had conspicuous histological architecture alterations. Lymphocytes were replaced by macrophages stuffed with an intense number of amastigotes forms of Leishmania. The lymphoid nodules (without germinal centers) and the mantle zones in the cortex that surround the follicles were markedly attenuated. Livers showed small intralobular granulomas composed by macrophages loaded with amastigotes. Spleens had an intense depression of the white pulp whereas the lymphocytes were replaced by parasitized macrophages. All fragments of different anatomical region of skin (ear, muzzle and abdomen) showed a diffuse chronic inflammation. The cellular exudate was composed by macrophages, plasmocytes and lymphocytes. Macrophages loaded with amastigotes were ease found in all tissue fragments, but more intense in ear and muzzle. Thus, this fact enhances the importance of asymptomatic dogs in the epidemiology of visceral leishmaniasis.

Relata-se um quadro histológico caracterizado por lesões acentuadas em tecidos de um cão assintomático naturalmente infectado por Leishmania infantum (sin. chagasi). Cortes parafinados de fígado, baço, linfonodos (cervical, axilar e poplíteo) e pele (orelha, espelho nasal e abdome) foram corados pela técnica de hematoxilina-eosina e pela técnica imunoistoquímica de estreptoavidina-peroxidase para detecção de formas amastigotas de Leishmania. Os linfonodos apresentaram profundas alterações estruturais. Em todos observou-se depleção linfocitária, principalmente da córtex, com substituição dos linfócitos por macrófagos abarrotados de formas amastigotas de Leishmania. No fígado, observou-se a presença de pequenos granulomas intralobulares compostos por macrófagos intensamente parasitados, plasmócitos e raros linfócitos. No baço, a alteração marcante foi a depressão da polpa branca. Os folículos linfóides foram substituídos por macrófagos intensamente parasitados com as formas amastigotas de Leishmania. Fragmentos de pele de orelha, espelho nasal e abdome apresentaram reação inflamatória crônica e difusa com exsudato celular composto por macrófagos, plasmócitos e linfócitos. Parasitos foram detectados em todos os tecidos estudados e mais numerosos na pele da orelha e focinho. Os achados mostram a importância de cães assintomáticos na epidemiologia da leishmaniose visceral.