An Eluate of the Medicinal Plant Garcinia kola Displays Strong Antidiabetic and Neuroprotective Properties in Streptozotocin-Induced Diabetic Mice.

Materials and Methods: G. kola methanolic extract was fractionated using increasingly polar solvents. Fractions were administered to streptozotocin (STZ)-induced diabetic mice until marked motor signs developed in diabetic controls. Fine motor skills indicators were measured in the horizontal grid test (HGT) to confirm the prevention of motor disorders in treated animals. Column chromatography was used to separate the most active fraction, and subfractions were tested in turn in the HGT. Gas chromatography-mass spectrometry (GC-MS) technique was used to assess the components of the most active subfraction. Results: Treatment with ethyl acetate fraction and its fifth eluate (F5) preserved fine motor skills and improved the body weight and blood glucose level. At dose 1.71 mg/kg, F5 kept most parameters comparable to the nondiabetic vehicle group values. GC-MS chromatographic analysis of F5 revealed 36 compounds, the most abundantly expressed (41.8%) being the ß-lactam molecules N-ethyl-2-carbethoxyazetidine (17.8%), N,N-dimethylethanolamine (15%), and isoniacinamide (9%). Conclusions: Our results suggest that subfraction F5 of G. kola extract prevented the development of motor signs and improved disease profile in an STZ-induced mouse model of diabetic encephalopathy. Antidiabetic activity of ß-lactam molecules accounted at least partly for these effects.

Evaluation of metabolic, antioxidant and anti-inflammatory effects of Garcinia kola on diabetic rats.

Garcinia kola (G. kola), is a plant characterized by its hypoglycemic properties. We recently reported our findings on the extracts of G. kola, in which we found that it prevented the loss of inflammation-sensible neuronal populations in streptozotocin (STZ)-induced rat models of type 1 diabetes mellitus (T1DM). In the present study we assessed the effect of G. kola bioactive compounds extracted successively with water, hexane, methylene chloride, ethyl acetate, and butanol. through analyzing biochemical markers of oxidative stress, inflammation, and metabolic function in STZ-induced diabetic animals. Animals made diabetic by a single injection with STZ (60 mg/kg, i.p.), were treated daily with either vehicle solution, insulin, or G. kola extracts and its fractions from the first to the 6th-week post-injection. Biochemical markers; glucose, insulin, C-peptide, neuron-specific enolase (NSE), creatinine kinase, glutathione peroxidase, malondialdehyde (MDA), resistin, soluble E-selectin (SE-Selectin), and C-reactive proteins (CRP) levels in the sera were determined in the study groups. A marked increase in blood glucose (209.26% of baseline value), and a decrease in body weight (-12.37%) were observed in diabetic control animals but not in animals treated with either insulin or G. kola extracts and its fractions. The sub-fraction F5, G. kola ethyl acetate had the highest bioactive activities, with a maintenance of blood sugar, malondialdehyde, C-peptide, E-selectin, C-reactive protein (CRP) and neuron-specific enolase (NSE) to levels and responses comparable to healthy non-diabetic vehicle group and the positive control diabetic insulin-treated group. Our findings suggest that G. kola may have a strong therapeutic potential against T1DM and its microvascular complications.

Garcinia kola seeds may prevent cognitive and motor dysfunctions in a type 1 diabetes mellitus rat model partly by mitigating neuroinflammation.

Background We reported recently that extracts of seeds of Garcinia kola, a plant with established hypoglycemic properties, prevented the loss of inflammation-sensible neuronal populations like Purkinje cells in a rat model of type 1 diabetes mellitus (T1DM). Here, we assessed G. kola extract ability to prevent the early cognitive and motor dysfunctions observed in this model. Methods Rats made diabetic by single injection of streptozotocin were treated daily with either vehicle solution (diabetic control group), insulin, or G. kola extract from the first to the 6th week post-injection. Then, cognitive and motor functions were assessed using holeboard and vertical pole behavioral tests, and animals were sacrificed. Brains were dissected out, cut, and processed for Nissl staining and immunohistochemistry. Results Hyperglycemia (209.26 %), body weight loss (-12.37 %), and T1DM-like cognitive and motor dysfunctions revealed behavioral tests in diabetic control animals were not observed in insulin and extract-treated animals. Similar, expressions of inflammation markers tumor necrosis factor (TNF), iba1 (CD68), and Glial fibrillary acidic protein (GFAP), as well as decreases of neuronal density in regions involved in cognitive and motor functions (-49.56 % motor cortex, -33.24 % medial septal nucleus, -41.8 % /-37.34 % cerebellar Purkinje /granular cell layers) were observed in diabetic controls but not in animals treated with insulin or G. kola. Conclusions Our results indicate that T1DM-like functional alterations are mediated, at least partly, by neuroinflammation and neuronal loss in this model. The prevention of the development of such alterations by early treatment with G. kola confirms the neuroprotective properties of the plant and warrant further mechanistic studies, considering the potential for human disease.

Evaluation of the safety of conventional lighting replacement by artificial daylight.

BACKGROUND: Short morning exposure to high illuminance visible electromagnetic radiations termed as artificial daylight is beneficial for the mental health of people living in geographical areas with important seasonal changes in daylight illuminance. However, the commercial success of high illuminance light sources has raised the question of the safety of long hour exposure. METHODS: We have investigated the effect of the replacement of natural daylight by artificial daylight in Swiss mice raised under natural lighting conditions. Mice were monitored for neurotoxicity and general health changes. They were submitted to a battery of conventional tests for mood, motor and cognitive functions' assessment on exposure day (ED) 14 and ED20. Following sacrifice on ED21 due to marked signs of neurotoxicity, the expression of markers of inflammation and apoptosis was assessed in the entorhinal cortex and neurons were estimated in the hippocampal formation. RESULTS: Signs of severe cognitive and motor impairments, mood disorders, and hepatotoxicity were observed in animals exposed to artificial daylight on ED20, unlike on ED14 and unlike groups exposed to natural daylight or conventional lighting. Activated microglia and astrocytes were observed in the entorhinal cortex, as well as dead and dying neurons. Neuronal counts revealed massive neuronal loss in the hippocampal formation. CONCLUSIONS: These results suggest that long hour exposure to high illuminance visible electromagnetic radiations induced severe alterations in brain function and general health in mice partly mediated by damages to the neocortex-entorhinal cortex-hippocampus axis. These findings raise caution over long hour use of high illuminance artificial light.

Garcinia kola aqueous suspension prevents cerebellar neurodegeneration in long-term diabetic rat - a type 1 diabetes mellitus model.

ETHNOPHARMACOLOGICAL RELEVANCE: The development of compounds able to improve metabolic syndrome and mitigate complications caused by inappropriate glycemic control in type 1 diabetes mellitus is challenging. The medicinal plant with established hypoglycemic properties Garcinia kola Heckel might have the potential to mitigate diabetes mellitus metabolic syndrome and complications. AIM OF THE STUDY: We have investigated the neuroprotective properties of a suspension of G. kola seeds in long-term type 1 diabetes mellitus rat model. MATERIALS AND METHODS: Wistar rats, made diabetic by single injection of streptozotocin were monitored for 8 months. Then, they were administered with distilled water or G. kola oral aqueous suspension daily for 30 days. Body weight and glycemia were determined before and after treatment. After sacrifice, cerebella were dissected out and processed for stereological quantification of Purkinje cells. Histopathological and immunohistochemical analyses of markers of neuroinflammation and neurodegeneration were performed. RESULTS: Purkinje cell counts were significantly increased, and histopathological signs of apoptosis and neuroinflammation decreased, in diabetic animals treated with G. kola compared to diabetic rats given distilled water. Glycemia was also markedly improved and body weight restored to non-diabetic control values, following G. kola treatment. CONCLUSIONS: These results suggest that G. kola treatment improved the general condition of long-term diabetic rats and protected Purkinje cells partly by improving the systemic glycemia and mitigating neuroinflammation.

Signaling pathways bridging fate determination of neural crest cells to glial lineages in the developing peripheral nervous system.

Fate determination of neural crest cells is an essential step for the development of different crest cell derivatives. Peripheral glia development is marked by the choice of the neural crest cells to differentiate along glial lineages. The molecular mechanism underlying fate acquisition is poorly understood. However, recent advances have identified different transcription factors and genes required for the complex instructive signaling process that comprise both local environmental and cell intrinsic cues. Among others, at least the roles of Sox10, Notch, and neuregulin 1 have been documented in both in vivo and in vitro models. Cooperative interactions of such factors appear to be necessary for the switch from multipotent neural crest cells to glial lineage precursors in the peripheral nervous system. This review summarizes recent advances in the understanding of fate determination of neural crest cells into different glia subtypes, together with the potential implications in regenerative medicine.

Azadirachta indica ethanolic extract protects neurons from apoptosis and mitigates brain swelling in experimental cerebral malaria.

BACKGROUND: Cerebral malaria is a rapidly developing encephalopathy caused by the apicomplexan parasite Plasmodium falciparum. Drugs currently in use are associated with poor outcome in an increasing number of cases and new drugs are urgently needed. The potential of the medicinal plant Azadirachta indica (Neem) for the treatment of experimental cerebral malaria was evaluated in mice. METHODS: Experimental cerebral malaria was induced in mice by infection with Plasmodium berghei ANKA. Infected mice were administered with Azadirachta indica ethanolic extract at doses of 300, 500, or 1000 mg/kg intraperitoneally (i.p.) in experimental groups, or with the anti-malarial drugs chloroquine (12 mg/kg, i.p.) or artemether (1.6 mg/kg, i.p.), in the positive control groups. Treatment was initiated at the onset of signs of brain involvement and pursued for five days on a daily basis. Mice brains were dissected out and processed for the study of the effects of the extract on pyramidal cells' fate and on markers of neuroinflammation and apoptosis, in the medial temporal lobe. RESULTS: Azadirachta indica ethanolic extract mitigated neuroinflammation, decreased the severity of brain oedema, and protected pyramidal neurons from apoptosis, particularly at the highest dose used, comparable to chloroquine and artemether. CONCLUSIONS: The present findings suggest that Azadirachta indica ethanolic extract has protective effects on neuronal populations in the inflamed central nervous system, and justify at least in part its use in African and Asian folk medicine and practices.

Insulin resistance and cancer: the role of insulin and IGFs.

Insulin, IGF1, and IGF2 are the most studied insulin-like peptides (ILPs). These are evolutionary conserved factors well known as key regulators of energy metabolism and growth, with crucial roles in insulin resistance-related metabolic disorders such as obesity, diseases like type 2 diabetes mellitus, as well as associated immune deregulations. A growing body of evidence suggests that insulin and IGF1 receptors mediate their effects on regulating cell proliferation, differentiation, apoptosis, glucose transport, and energy metabolism by signaling downstream through insulin receptor substrate molecules and thus play a pivotal role in cell fate determination. Despite the emerging evidence from epidemiological studies on the possible relationship between insulin resistance and cancer, our understanding on the cellular and molecular mechanisms that might account for this relationship remains incompletely understood. The involvement of IGFs in carcinogenesis is attributed to their role in linking high energy intake, increased cell proliferation, and suppression of apoptosis to cancer risks, which has been proposed as the key mechanism bridging insulin resistance and cancer. The present review summarizes and discusses evidence highlighting recent advances in our understanding on the role of ILPs as the link between insulin resistance and cancer and between immune deregulation and cancer in obesity, as well as those areas where there remains a paucity of data. It is anticipated that issues discussed in this paper will also recover new therapeutic targets that can assist in diagnostic screening and novel approaches to controlling tumor development.

Signaling pathways bridging microbial-triggered inflammation and cancer.

Microbial-triggered inflammation protects against pathogens and yet can paradoxically cause considerable secondary damage to host tissues that can result in tissue fibrosis and carcinogenesis, if persistent. In addition to classical pathogens, gut microbiota bacteria, i.e. a group of mutualistic microorganisms permanently inhabiting the gastrointestinal tract and which plays a key role in digestion, immunity, and cancer prevention, can induce inflammation-associated cancer following the alterations of their microenvironment. Emerging experimental evidence indicates that microbiota members like Escherichia coli and several other genotoxic and mutagenic pathogens can cause DNA damage in various cell types. In addition, the inflammatory response induced by chronic infections with pathogens like the microbiota members Helicobacter spp., which have been associated with liver, colorectal, cervical cancers and lymphoma, for instance, can also trigger carcinogenic processes. A microenvironment including active immune cells releasing high amounts of inflammatory signaling molecules can favor the carcinogenic transformation of host cells. Pivotal molecules released during immune response such as the macrophage migration inhibitory factor (MMIF) and the reactive oxygen and nitrogen species' products superoxide and peroxynitrite, can further damage DNA and cause the accumulation of oncogenic mutations, whereas pro-inflammatory cytokines, adhesion molecules, and growth factors may create a microenvironment promoting neoplastic cell survival and proliferation. Recent findings on the implication of inflammatory signaling pathways in microbial-triggered carcinogenesis as well as the possible role of microbiota modulation in cancer prevention are herein summarized and discussed.

Anti-plasmodial effects of Azadirachta indica in experimental cerebral malaria: Apoptosis of cerebellar Purkinje cells of mice as a marker.

BACKGROUND: Malaria is a major public health problem in the world, but treatment of malaria is becoming more difficult due to increasing drug resistance. Therefore, the need for alternative drugs is acute. AIMS: This study investigated the antiplasmodial and protective effect of an ethanolic extract of the leaves from a traditionally used medicinal plant, Azadirachta indica (Neem) in a mouse model of malaria. MATERIALS AND METHODS: Swiss albino mice were intraperitoneally infected with 10×10(6)Plasmodium berghei ANKA, a rodent malaria parasite. The presence of parasites was checked by microscopic examination of blood samples daily. Ethanolic extracts of Neem at 300, 500 and 1000 mg/kg were administered intraperitoneally daily for five days from the day parasitaemia reach 5% of parasite inoculation. Intraperitoneal chloroquine and artemether were used as standard drug treatment controls. Symptoms of neurological or respiratory disorder, mortality, weight and temperature were recorded. Histological sections of brain were prepared and examined after staining with hematoxylin-eosin and immunohistochemistry for apoptotic cells. RESULTS: All Neem treatment groups displayed parasitaemia that gradually increased during treatment, and showed signs of terminal illness (i.e. hypothermia, ptosis and convulsions) within 2-4 days post-treatment. In contrast, the chloroquine and artemether groups showed no cerebral malaria symptoms and no deaths. Apoptosis in Purkinje cells, cerebral haemorrhage and oedema were found in some of the mice treated with Neem and chloroquine. CONCLUSIONS: Azadirachta indica (Neem) extract was not protective against malaria symptoms and signs in this mouse model. However, a difference in the number of apoptotic Purkinje cells between the untreated control group and Neem treatment at 500 mg/kg suggests that Neem may have some neuronal protective effect.

High fiber probiotic fermented mare's milk reduces the toxic effects of mercury in rats.

BACKGROUND: Since the advent of the Industrial Revolution in the late 19th century, we have all been unfortunately exposed to an increasingly toxic and polluted world. Among the most dangerous of these pollutants is mercury, which is considered to be the most toxic non-radioactive heavy metal. Fermented foods may help cleanse the body of heavy metals. Fermentation breaks down the nutrients in foods by the action of beneficial microorganisms and creates natural chelators that are available to bind toxins and remove them from the body. AIMS: The current study was designed to determine the impact of feeding a high fiber probiotic fermented mare's milk on the biological effects of mercury toxicity in rat model. METHODS AND MATERIALS: The high fiber fermented mare's milk containing probiotics was prepared and its sensory properties, chemical composition, and antioxidant activity were determined. A rat model of mercury toxicity was used. The effect of feeding the high fiber probiotic fermented mare's milk to rats, along with mercury ingestion, was determined by the analysis of several biochemical markers in serum and histopathological examinations of brain and kidney. RESULTS: The high fiber fermented mare's milk containing probiotics was found to be acceptable by all test panels and volunteers. Mercury ingestion was found to cause biochemical and histopathological alterations in rat serum and tissues. The mercury-treated rats showed a decrease in body weight and an increase in kidney weight. Sera of the mercury treated rats showed alterations in biochemical parameters, and histopathological changes in brain and kidney. However, the rats fed high fiber fermented mare`s milk along with mercury ingestion showed improved histopathology of kidney and brain, and there was restoration of the biochemical parameters in serum to almost normal values. CONCLUSIONS: Feeding high fiber fermented mare`s milk may reduce the toxic effects of mercury.