Publications by authors named "Paul F Seke Etet"

23 Publications

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improves cognitive and motor function of a rat model of acute radiation syndrome in the elevated plus maze.

Brain Commun 2021 28;3(3):fcab170. Epub 2021 Jul 28.

Neuroscience Laboratory, Faculty of Medicine and Biomedical Sciences, The University of Yaoundé I, Yaoundé, Cameroon.

We reported recently that the elevated plus maze is a good tool for evaluating cognitive and motor functional changes in gamma-irradiated rats as a model for new drug evaluation and monitoring. The capacity of to mitigate radiation-induced brain injury is currently unknown. We therefore assessed the effects of the neuroprotective medicinal plant , on the cognitive and motor changes in this murine model of acute radiation syndrome. Wistar rats exposed once to an ionizing dose of Tc99m-generated Gamma radiation were treated with an ethyl acetate fraction of methanolic extract of seeds (content of 100 mg/kg of extract) for 9 weeks. Cognitive and motor function indicators were assessed in the elevated plus maze in these animals and compared with irradiated control groups (vitamin C- and vehicle-treated groups) and the non-irradiated control rats. The irradiated control group displayed cachexia, shaggy and dirty fur, porphyrin deposits around eyes, decreased exploratory activity, reduced social interactions and a loss of thigmotaxis revealed by a marked decrease in rearing episodes and stretch attend posture episodes close to the walls of elevated plus maze closed arm, an increased central platform time, and decreases in open arm time and entries. This group further displayed a decrease in head dips and grooming episodes. Treatment with , and in a lesser extent vitamin C, significantly prevented the body weight loss ( < 0.001) and mitigated the development of elevated plus maze signs of cognitive and motor affections observed in the irradiated control group ( < 0.05). Altogether, our data suggest for the first time that seeds have protective properties against the development of cognitive and motor decline in the acute radiation syndrome-like context. Future studies are warranted to characterize the molecular mechanisms and neuronal networks of this action.
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http://dx.doi.org/10.1093/braincomms/fcab170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361417PMC
July 2021

Influence of HIV infection on the distribution of high-risk HPV types among women with cervical precancerous lesions in Yaounde, Cameroon.

Int J Infect Dis 2021 Sep 29;110:426-432. Epub 2021 Jul 29.

Department of Biochemistry, Faculty of Science, University of Dschang, Dschang, Cameroon.

Objectives: To characterize high-risk HPV types associated with cervical precancerous lesions in women living in Yaounde, Cameroon, and to determine their distribution with HIV status.

Methods: Women with abnormal pap smears recorded from February 2015 to May 2019 at Saint Martin de Porres' Health Centre, Yaounde, Cameroon, were recruited in this study after obtaining informed consent. Pap smears were collected and re-examined. Human immunodeficiency virus (HIV) serology was determined. HPV16, 18, 33, and 45 were assessed using standard PCR.

Results: All included participants (370) were HPV-positive and had either low grade squamous intraepithelial lesions (67.03%) or high grade squamous intraepithelial lesions (31.35%). They were subdivided into HIV-positive (N =102) and HIV-negative (N =268). In the HIV-negative subgroup, we observed 66.04% HPV16-positve, 41.79% HPV18-positve, 21.27% HPV33-positve and 8.21% HPV45-positve. In the HIV-positive subgroup, we observed 22.55% HPV16-positve, 5.88% HPV18-positve, 75.49% HPV33-positve, and 49.02% HPV45-positve. Married HIV-positive participants (47.14 ± 1.19) were older than both their single counterparts (34.94±1.22, P = 0.0008) and HIV-negative participants (41.43 ± 0.79, P = 0.0001). Single HIV-positive women reported higher numbers of miscarriages (P = 0.0023), and had later first sexual intercourse than HIV-negative (P = 0.0079) women.

Conclusion: Our study suggested differential expressions in high-risk HPV types with HIV status and cervical precancerous lesions and warrants more extensive studies.
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http://dx.doi.org/10.1016/j.ijid.2021.07.059DOI Listing
September 2021

Fear and depression during the COVID-19 outbreak in Cameroon: a nation-wide observational study.

BMC Psychiatry 2021 07 15;21(1):356. Epub 2021 Jul 15.

Brain Research Africa Initiative (BRAIN), Yaoundé, Cameroon.

Background: The COVID-19 pandemic has been associated with significant psychological and social distress worldwide. We investigated fear and depression among adults in Cameroon during different phases of the COVID-19 outbreak.

Methods: An online survey was conducted in Cameroon from June-December 2020 using a structured questionnaire. Socio-demographic data and information regarding COVID-19 history were obtained. Fear and depressive symptoms were assessed using the Fear of COVID-19 score (FCV-19S) and the Patient Health Questionnaire (PHQ-9), respectively. Responses were clustered in weeks to better appreciate their evolution over time.

Results: Overall, 7381 responses from all ten regions of Cameroon were analysed (median age: 30 years, 73.3% male). The prevalence of depression (PHQ-9 score ≥ 10) was 8.4%, and that of high fear of COVID-19 (FCV-19S scores ≥19) was 57.4%. These rates were similar across genders, age-groups, and region of residence. While mean weekly PHQ-9 scores remained fairly stable throughout the study period (range: 2.53-3.21; p = 0.101), mean FCV-19S scores were highest during the early weeks but decreased significantly thereafter (from 20.31 to 18.34; p <  0.001). Multivariate analyses revealed that having a postgraduate degree, a history of quarantine, flu-like symptoms during the past 14 days, and higher FCV-19S scores were associated with more severe depressive symptoms, while obtaining COVID-19 information from various sources reduced the odds for depression.

Conclusion: Depression amidst the COVID-19 crisis is less prevalent in Cameroon than in other countries. Prompt and widespread dissemination of adequate COVID-19 information may reduce the risks for depression by dispelling fear and anxiety among Cameroonians.
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http://dx.doi.org/10.1186/s12888-021-03323-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280628PMC
July 2021

Anticancer Activity of Combretum fragrans F. Hoffm on Glioblastoma and Prostate Cancer Cell Lines.

Asian Pac J Cancer Prev 2021 Apr 1;22(4):1087-1093. Epub 2021 Apr 1.

UFR Sciences Fondamentales et Appliquées, Team "Récepteurs, Régulations, Cellules Tumorales" (2RCT)-EA 3842 CAPTuR, Pôle Biologie Santé-Bât. B36/B37, University of Poitiers, 1 rue Georges Bonnet-TSA, France.

Background: Cancer incidence has been growing in an alarming rate worldwide and new therapeutics are needed, particularly for intractable and chemoresistant cases. We evaluated the cytotoxic effects of Combretum fragrans F. Hoffm (Combretaceae) on glioblastoma (U87MG and C6) and prostate (PC-3) cancer cell lines.

Methods: The cytotoxic effect of the methanolic extract of the stem bark of Combretum fragrans was assessed using XTT (2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide) test. Expressions of Akt and ERK1/2 were determined using Western blot technique, while Caspase-3/7 kits were used to evaluate caspase-3/7 activity.

Results: C. fragrans extract inhibited the proliferation of U87 (IC50 = 20.13 µg/mL), C6 (IC50 = 12.17 µg/mL), and PC-3 (IC50 = 11.50 µg/mL) cells. Treatment with the extract resulted in lower levels (p < 0.001) of phospho-ERK1/2 and phospho-Akt in U87 cells, and instead, higher levels of phospho-ERK1/2 (p < 0.001) in C6 and PC-3 cells. An increase in caspase-3/7 activity was observed, mainly after 24 hours of treatment, indicating the activation of apoptotic processes.

Conclusion: Altogether, these results suggest that C. fragrans have potent anticancer properties. This plant should be further investigated for developing new anticancer drugs.
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http://dx.doi.org/10.31557/APJCP.2021.22.4.1087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325120PMC
April 2021

Characterization of the Cognitive and Motor Changes Revealed by the Elevated Plus Maze in an Experimental Rat Model of Radiation-Induced Brain Injury.

Adv Biomed Res 2020 28;9:72. Epub 2020 Nov 28.

Department of Translational Neuroscience, Brain Research Africa Initiative (BRAIN), Geneva, Switzerland.

Background: Experimental models are needed to better understand the pathophysiology of neurodegenerative diseases to develop novel therapeutics. The neuropathology and clinical signs of acute radiation syndrome resemble those of neurodegenerative conditions. We characterized elevated plus maze (EPM) indicators of cognitive and motor impairment in rats exposed to brain-damaging doses of gamma radiation to develop a model for neurological component of the acute radiation syndrome.

Materials And Methods: Technetium 99 m was administered once through tail vein to male Wistar rats to reach an absorbed dose of Gamma radiation of 667 mGy (66.7Rad). Animal performance in the EPM was assessed every 14 days. Rats were observed for 9 weeks for the occurrence of systemic and neurological signs. Comparisons were done between irradiated and nonirradiated rats, and in each group with baseline performance.

Results: EPM indicators of cognitive and motor impairment, anxiety, and depression were observed concomitantly and increased with the severity of acute radiation syndrome-like systemic and neurological signs. Alterations in EPM indicators appeared 3 weeks postirradiation and their severity increased with time. Notably, arm transitions and the distance covered in the maze were decreased (-56.71% and -73.62%, < 0.001), as well as open arm entries and time spent in open arms (-77.78% and -76.19%, < 0.05) and the indicator of thigmotaxis rearing (-92.45, < 0.001).

Conclusions: Our results suggest that irradiated rat performance in the EPM paradigm reflects disease severity and could be used to perform both acute and subchronic pharmacological studies in acute radiation syndrome-like diseases in rats.
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http://dx.doi.org/10.4103/abr.abr_62_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012866PMC
November 2020

COVID-19 Preventive Behaviours in Cameroon: A Six-Month Online National Survey.

Int J Environ Res Public Health 2021 03 4;18(5). Epub 2021 Mar 4.

Brain Research Africa Initiative (BRAIN), Yaoundé, Cameroon.

Since March 2020, the Cameroonian government implemented nationwide measures to stall COVID-19 transmission. However, little is known about how well these unprecedented measures are being observed as the pandemic evolves. We conducted a six-month online survey to assess the preventive behaviour of Cameroonian adults during the COVID-19 outbreak. A five-point adherence score was constructed based on self-reported observance of the following preventive measures: physical distancing, face mask use, hand hygiene, not touching one's face, and covering the mouth when coughing or sneezing. Predictors of adherence were investigated using ordinal logistic regression models. Of the 7381 responses received from all ten regions, 73.3% were from male respondents and overall mean age was 32.8 ± 10.8 years. Overall mean adherence score was 3.96 ± 1.11 on a scale of 0-5. Mean weekly adherence scores were initially high, but gradually decreased over time accompanied by increasing incidence of COVID-19 during the last study weeks. Predictors for higher adherence included higher age, receiving COVID-19 information from health personnel, and agreeing with the necessity of lockdown measures. Meanwhile, experiencing flu-like symptoms was associated with poor adherence. Continuous observance of preventive measures should be encouraged among Cameroonians in the medium- to long-term to avoid a resurgence in COVID-19 infections.
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http://dx.doi.org/10.3390/ijerph18052554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967528PMC
March 2021

Hypolipidemic and anti-atherosclerogenic effects of aqueous extract of Ipomoea batatas leaves in diet-induced hypercholesterolemic rats.

J Integr Med 2021 05 2;19(3):243-250. Epub 2021 Mar 2.

Department of Animal Biology and Physiology, University of Yaoundé 1, Yaoundé, Centre Region, Cameroon.

Objective: Ipomoea batatas (L.) Lam. is a food plant used in African traditional medicine to treat cardiovascular diseases and related conditions. We assessed the hypolipidemic and anti-atherosclerogenic properties of the aqueous extract of I. batatas leaves in a rat model of diet-induced hypercholesterolemia.

Methods: Hypercholesterolemia was induced in male Wistar rats by exclusive feeding with a cholesterol-enriched (1%) standard diet for four weeks. Then, rats were treated once daily (per os) with I. batatas extract at doses of 400, 500 and 600 mg/kg or with atorvastatin (2 mg/kg), for four weeks. Following treatment, animals were observed for another four weeks and then sacrificed. Aortas were excised and processed for histopathological studies, and blood glucose level and lipid profile were measured.

Results: Hypercholesterolemic animals experienced a 21.5% faster increase in body weight, significant increases in blood glucose and blood lipids (148.94% triglycerides, 196.97% high-density lipoprotein cholesterol, 773.04% low-density lipoprotein cholesterol, 148.93% very low-density lipoprotein cholesterol and 210.42% total cholesterol), and increases in aorta thickness and atherosclerotic plaque sizes compared to rats fed standard diet. Treatment of hypercholesterolemic rats with the extract mitigated these alterations and restored blood glucose and blood lipid levels to normocholesterolemic values.

Conclusion: Our findings suggest that I. batatas leaves have hypolipidemic and anti-atherosclerogenic properties and justify their use in traditional medicine.
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http://dx.doi.org/10.1016/j.joim.2021.02.002DOI Listing
May 2021

Tumor Microenvironment Uses a Reversible Reprogramming of Mesenchymal Stromal Cells to Mediate Pro-tumorigenic Effects.

Front Cell Dev Biol 2020 19;8:545126. Epub 2020 Nov 19.

Section of Hematology, Stem Cell Research Laboratory, Department of Medicine, University of Verona, Verona, Italy.

The role of mesenchymal stromal cells (MSCs) in the tumor microenvironment is well described. Available data support that MSCs display anticancer activities, and that their reprogramming by cancer cells in the tumor microenvironment induces their switch toward pro-tumorigenic activities. Here we discuss the recent evidence of pro-tumorigenic effects of stromal cells, in particular (i) MSC support to cancer cells through the metabolic reprogramming necessary to maintain their malignant behavior and stemness, and (ii) MSC role in cancer cell immunosenescence and in the establishment and maintenance of immunosuppression in the tumor microenvironment. We also discuss the mechanisms of tumor microenvironment mediated reprogramming of MSCs, including the effects of hypoxia, tumor stiffness, cancer-promoting cells, and tumor extracellular matrix. Finally, we summarize the emerging strategies for reprogramming tumor MSCs to reactivate anticancer functions of these stromal cells.
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http://dx.doi.org/10.3389/fcell.2020.545126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710932PMC
November 2020

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

Saudi J Biol Sci 2020 Dec 11;27(12):3641-3646. Epub 2020 Aug 11.

Faculty of Medicine, King Fahad Medical City, Ministry of Health, Riyadh 11525, Saudi Arabia.

(), is a plant characterized by its hypoglycemic properties. We recently reported our findings on the extracts of , 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 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 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 extracts and its fractions. The sub-fraction F5, 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 may have a strong therapeutic potential against T1DM and its microvascular complications.
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http://dx.doi.org/10.1016/j.sjbs.2020.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714953PMC
December 2020

Emerging data supporting stromal cell therapeutic potential in cancer: reprogramming stromal cells of the tumor microenvironment for anti-cancer effects.

Cancer Biol Med 2020 11 15;17(4):828-841. Epub 2020 Dec 15.

Department of Medicine, University of Verona, Section of Hematology, Stem Cell Research Laboratory, Verona 37134, Italy.

After more than a decade of controversy on the role of stromal cells in the tumor microenvironment, the emerging data shed light on pro-tumorigenic and potential anti-cancer factors, as well as on the roots of the discrepancies. We discuss the pro-tumorigenic effects of stromal cells, considering the effects of tumor drivers like hypoxia and tumor stiffness on these cells, as well as stromal cell-mediated adiposity and immunosuppression in the tumor microenvironment, and cancer initiating cells' cellular senescence and adaptive metabolism. We summarize the emerging data supporting stromal cell therapeutic potential in cancer, discuss the possibility to reprogram stromal cells of the tumor microenvironment for anti-cancer effects, and explore some causes of discrepancies on the roles of stromal cells in cancer in the available literature.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721102PMC
November 2020

The Actigraphy Sleep Score: A New Biomarker for Diagnosis, Disease Staging, and Monitoring in Human African Trypanosomiasis.

Am J Trop Med Hyg 2020 12 15;103(6):2244-2252. Epub 2020 Oct 15.

Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom.

Human African trypanosomiasis (HAT) remains a serious public health problem with diagnostic and treatment challenges in many African countries. The absence of a gold-standard biomarker has been a major difficulty for accurate disease staging and treatment follow-up. We therefore attempted to develop a simple, affordable, and noninvasive biomarker for HAT diagnosis and staging. Simultaneous actigraphy and polysomnography as well as cerebrospinal fluid (CSF) white blood cell (WBC) count, trypanosome presence, and C-X-C motif ligand (CXCL)-10 cytokine levels were performed in 20 HAT patients and nine healthy individuals (controls) using standard procedures. The International HIV Dementia Scale (IHDS) was scored in some patients as a surrogate for clinical assessment. From actigraphic parameters, we developed a novel sleep score and used it to determine correlations with other HAT markers, and compared their performance in differentiating between patients and controls and between HAT stages. The novel actigraphy sleep score (ASS) had the following ranges: 0-25 (healthy controls), 67-103 (HAT stage I), 111-126 (HAT intermediate), and 133-250 (HAT stage II). Compared with controls, stage I patients displayed a 7-fold increase in the ASS ( < 0.01), intermediate stage patients a 10-fold increase ( < 0.001), and HAT stage II patients an almost 20-fold increase ( < 0.001). CXCL-10 showed high interindividual differences. White blood cell counts were only marked in HAT stage II patients with a high interindividual variability. The International HIV Dementia Scale score negatively correlated with the ASS. We report the development and better performance of a new biomarker, ASS, for HAT diagnosis, disease staging, and monitoring that needs to be confirmed in large cohort studies.
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http://dx.doi.org/10.4269/ajtmh.20-0340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695071PMC
December 2020

Effect of Aqueous Extract of Stem Bark on the Development of Hypertension in L-NAME-Induced Hypertensive Rat Model.

Evid Based Complement Alternat Med 2020 18;2020:3678469. Epub 2020 Sep 18.

Department of Animal Biology and Physiology, Laboratory of Animal Physiology, University of Yaoundé I, P.O. Box 812, Yaoundé, Cameroon.

Background: is a plant used against cardiovascular disorders in African folk medicine. We assessed the effects of the aqueous extract of its stem bark on the development of hypertension in L-NAME-induced hypertensive rats.

Methods: The animals were administered L-NAME once daily for 3 weeks (25 mg/kg, i.p.), concomitantly with aqueous extract of stem bark (100 and 200 mg/kg, p.o.) or captopril (20 mg/kg, p.o.). Then, hemodynamic and electrocardiographic parameters, oxidative stress markers, and the lipid profile were assessed in the blood and heart, aorta, and kidney homogenates, and histopathological analyses were performed.

Results: L-NAME-induced hypertensive control animals, but not the animals concomitantly treated with extract, displayed increases in the mean arterial blood pressure (21.64% difference, < 0.001, vs. dose 200 mg/kg), systolic arterial blood pressure (21.33%, < 0.001), and the diastolic arterial blood pressure (21.84%, < 0.001). In addition, hypertensive control animals displayed (i) increases in serum triglycerides, total cholesterol, LDL, and creatinine levels, malondialdehyde and transaminase activities, and atherogenic index; (ii) decreases in serum HDL, catalase, reduced glutathione, and nitric oxide; and (iii) aorta wall thickening, inflammatory cell infiltration, and cell loss in the cardiac muscle and renal tissues. As captopril, the extract prevented hypertension-like changes in lipid profile, cardiac, hepatic, and renal affection indicators, and oxidative stress markers.

Conclusion: Our findings suggest that the extract of has antihypertensive and antioxidant effects in L-NAME-induced hypertension rat models. These effects partly justify the traditional medicine use against cardiovascular disorders.
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http://dx.doi.org/10.1155/2020/3678469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519996PMC
September 2020

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

J Microsc Ultrastruct 2017 Oct-Dec;5(4):206-215. Epub 2017 Jun 1.

Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, 51452 Buraydah, Saudi Arabia.

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.
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http://dx.doi.org/10.1016/j.jmau.2017.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025781PMC
June 2017

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

J Complement Integr Med 2017 Apr 15;14(3). Epub 2017 Apr 15.

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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.
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http://dx.doi.org/10.1515/jcim-2016-0167DOI Listing
April 2017

Expression of interferon-inducible chemokines and sleep/wake changes during early encephalitis in experimental African trypanosomiasis.

PLoS Negl Trop Dis 2017 Aug 18;11(8):e0005854. Epub 2017 Aug 18.

Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.

Background: Human African trypanosomiasis or sleeping sickness, caused by the parasite Trypanosoma brucei, leads to neuroinflammation and characteristic sleep/wake alterations. The relationship between the onset of these alterations and the development of neuroinflammation is of high translational relevance, but remains unclear. This study investigates the expression of interferon (IFN)-γ and IFN-inducible chemokine genes in the brain, and the levels of CXCL10 in the serum and cerebrospinal fluid prior to and during the encephalitic stage of trypanosome infection, and correlates these with sleep/wake changes in a rat model of the disease.

Methodology/principal Findings: The expression of genes encoding IFN-γ, CXCL9, CXCL10, and CXCL11 was assessed in the brain of rats infected with Trypanosoma brucei brucei and matched controls using semi-quantitative end-point RT-PCR. Levels of CXCL10 in the serum and cerebrospinal fluid were determined using ELISA. Sleep/wake states were monitored by telemetric recording. Using immunohistochemistry, parasites were found in the brain parenchyma at 14 days post-infection (dpi), but not at 6 dpi. Ifn-γ, Cxcl9, Cxcl10 and Cxcl11 mRNA levels showed moderate upregulation by 14 dpi followed by further increase between 14 and 21 dpi. CXCL10 concentration in the cerebrospinal fluid increased between 14 and 21 dpi, preceded by a rise in the serum CXCL10 level between 6 and 14 dpi. Sleep/wake pattern fragmentation was evident at 14 dpi, especially in the phase of wake predominance, with intrusion of sleep episodes into wakefulness.

Conclusions/significance: The results show a modest increase in Cxcl9 and Cxcl11 transcripts in the brain and the emergence of sleep/wake cycle fragmentation in the initial encephalitic stage, followed by increases in Ifn-γ and IFN-dependent chemokine transcripts in the brain and of CXCL10 in the cerebrospinal fluid. The latter parameter and sleep/wake alterations could provide combined humoral and functional biomarkers of the early encephalitic stage in African trypanosomiasis.
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http://dx.doi.org/10.1371/journal.pntd.0005854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576758PMC
August 2017

Trypanosoma brucei Invasion and T-Cell Infiltration of the Brain Parenchyma in Experimental Sleeping Sickness: Timing and Correlation with Functional Changes.

PLoS Negl Trop Dis 2016 12 21;10(12):e0005242. Epub 2016 Dec 21.

Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.

Background: The timing of Trypanosoma brucei entry into the brain parenchyma to initiate the second, meningoencephalitic stage of human African trypanosomiasis or sleeping sickness is currently debated and even parasite invasion of the neuropil has been recently questioned. Furthermore, the relationship between neurological features and disease stage are unclear, despite the important diagnostic and therapeutic implications.

Methodology: Using a rat model of chronic Trypanosoma brucei brucei infection we determined the timing of parasite and T-cell neuropil infiltration and its correlation with functional changes. Parasite DNA was detected using trypanosome-specific PCR. Body weight and sleep structure alterations represented by sleep-onset rapid eye movement (SOREM) periods, reported in human and experimental African trypanosomiasis, were monitored. The presence of parasites, as well as CD4+ and CD8+ T-cells in the neuropil was assessed over time in the brain of the same animals by immunocytochemistry and quantitative analyses.

Principal Findings: Trypanosome DNA was present in the brain at day 6 post-infection and increased more than 15-fold by day 21. Parasites and T-cells were observed in the parenchyma from day 9 onwards. Parasites traversing blood vessel walls were observed in the hypothalamus and other brain regions. Body weight gain was reduced from day 7 onwards. SOREM episodes started in most cases early after infection, with an increase in number and duration after parasite neuroinvasion.

Conclusion: These findings demonstrate invasion of the neuropil over time, after an initial interval, by parasites and lymphocytes crossing the blood-brain barrier, and show that neurological features can precede this event. The data thus challenge the current clinical and cerebrospinal fluid criteria of disease staging.
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http://dx.doi.org/10.1371/journal.pntd.0005242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5217973PMC
December 2016

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

J Ethnopharmacol 2017 Jan 5;195:159-165. Epub 2016 Nov 5.

Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, UAE. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jep.2016.11.001DOI Listing
January 2017

The Emerging Roles of the Calcineurin-Nuclear Factor of Activated T-Lymphocytes Pathway in Nervous System Functions and Diseases.

J Aging Res 2016 15;2016:5081021. Epub 2016 Aug 15.

Department of Basic Health Sciences, Qassim University, Buraydah, Al-Qassim 51452, Saudi Arabia.

The ongoing epidemics of metabolic diseases and increase in the older population have increased the incidences of neurodegenerative diseases. Evidence from murine and cell line models has implicated calcineurin-nuclear factor of activated T-lymphocytes (NFAT) signaling pathway, a Ca(2+)/calmodulin-dependent major proinflammatory pathway, in the pathogenesis of these diseases. Neurotoxins such as amyloid-β, tau protein, and α-synuclein trigger abnormal calcineurin/NFAT signaling activities. Additionally increased activities of endogenous regulators of calcineurin like plasma membrane Ca(2+)-ATPase (PMCA) and regulator of calcineurin 1 (RCAN1) also cause neuronal and glial loss and related functional alterations, in neurodegenerative diseases, psychotic disorders, epilepsy, and traumatic brain and spinal cord injuries. Treatment with calcineurin/NFAT inhibitors induces some degree of neuroprotection and decreased reactive gliosis in the central and peripheral nervous system. In this paper, we summarize and discuss the current understanding of the roles of calcineurin/NFAT signaling in physiology and pathologies of the adult and developing nervous system, with an emphasis on recent reports and cutting-edge findings. Calcineurin/NFAT signaling is known for its critical roles in the developing and adult nervous system. Its role in physiological and pathological processes is still controversial. However, available data suggest that its beneficial and detrimental effects are context-dependent. In view of recent reports calcineurin/NFAT signaling is likely to serve as a potential therapeutic target for neurodegenerative diseases and conditions. This review further highlights the need to characterize better all factors determining the outcome of calcineurin/NFAT signaling in diseases and the downstream targets mediating the beneficial and detrimental effects.
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http://dx.doi.org/10.1155/2016/5081021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5002468PMC
September 2016

New insights in staging and chemotherapy of African trypanosomiasis and possible contribution of medicinal plants.

ScientificWorldJournal 2012 19;2012:343652. Epub 2012 Apr 19.

Department of Neurological Sciences (DNNMMS), University of Verona, Via Delle Grazie 8, 37134 Verona, Italy.

Human African trypanosomiasis (HAT) is a fatal if untreated fly-borne neuroinflammatory disease caused by protozoa of the species Trypanosoma brucei (T.b.). The increasing trend of HAT cases has been reversed, but according to WHO experts, new epidemics of this disease could appear. In addition, HAT is still a considerable burden for life quality and economy in 36 sub-Saharan Africa countries with 15-20 million persons at risk. Following joined initiatives of WHO and private partners, the fight against HAT was re-engaged, resulting in considerable breakthrough. We present here what is known at this day about HAT etiology and pathogenesis and the new insights in the development of accurate tools and tests for disease staging and severity monitoring in the field. Also, we elaborate herein the promising progresses made in the development of less toxic and more efficient trypanocidal drugs including the potential of medicinal plants and related alternative drug therapies.
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http://dx.doi.org/10.1100/2012/343652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3349134PMC
October 2012

Sleep and rhythm changes at the time of Trypanosoma brucei invasion of the brain parenchyma in the rat.

Chronobiol Int 2012 May 12;29(4):469-81. Epub 2012 Apr 12.

Department of Neurological Sciences, University of Verona, Italy.

Human African trypanosomiasis (HAT), or sleeping sickness, is a severe disease caused by Trypanosoma brucei (T.b.). The disease hallmark is sleep alterations. Brain involvement in HAT is a crucial pathogenetic step for disease diagnosis and therapy. In this study, a rat model of African trypanosomiasis was used to assess changes of sleep-wake, rest-activity, and body temperature rhythms in the time window previously shown as crucial for brain parenchyma invasion by T.b. to determine potential biomarkers of this event. Chronic radiotelemetric monitoring in Sprague-Dawley rats was used to continuously record electroencephalogram, electromyogram, rest-activity, and body temperature in the same animals before (baseline recording) and after infection. Rats were infected with T.b. brucei. Data were acquired from 1 to 20 d after infection (parasite neuroinvasion initiates at 11-13 d post-infection in this model), and were compared to baseline values. Sleep parameters were manually scored from electroencephalographic-electromyographic tracings. Circadian rhythms of sleep time, slow-wave activity, rest-activity, and body temperature were studied using cosinor rhythmometry. Results revealed alterations of most of the analyzed parameters. In particular, sleep pattern and sleep-wake organization plus rest-activity and body temperature rhythms exhibited early quantitative and qualitative alterations, which became marked around the time interval crucial for parasite neuroinvasion or shortly after. Data derived from actigrams showed close correspondence with those from hypnograms, suggesting that rest-activity could be useful to monitor sleep-wake alterations in African trypanosomiasis.
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http://dx.doi.org/10.3109/07420528.2012.660713DOI Listing
May 2012

Actigraphy in human African trypanosomiasis as a tool for objective clinical evaluation and monitoring: a pilot study.

PLoS Negl Trop Dis 2012 14;6(2):e1525. Epub 2012 Feb 14.

Neurology Department, Central Hospital Yaoundé/Faculty of Medicine, University of Yaoundé I, Yaoundé, Cameroon.

Background: Human African trypanosomiasis (HAT) or sleeping sickness leads to a complex neuropsychiatric syndrome with characteristic sleep alterations. Current division into a first, hemolymphatic stage and second, meningoencephalitic stage is primarily based on the detection of white blood cells and/or trypanosomes in the cerebrospinal fluid. The validity of this criterion is, however, debated, and novel laboratory biomarkers are under study. Objective clinical HAT evaluation and monitoring is therefore needed. Polysomnography has effectively documented sleep-wake disturbances during HAT, but could be difficult to apply as routine technology in field work. The non-invasive, cost-effective technique of actigraphy has been widely validated as a tool for the ambulatory evaluation of sleep disturbances. In this pilot study, actigraphy was applied to the clinical assessment of HAT patients.

Methods/principal Findings: Actigraphy was recorded in patients infected by Trypanosoma brucei gambiense, and age- and sex-matched control subjects. Simultaneous nocturnal polysomnography was also performed in the patients. Nine patients, including one child, were analyzed at admission and two of them also during specific treatment. Parameters, analyzed with user-friendly software, included sleep time evaluated from rest-activity signals, rest-activity rhythm waveform and characteristics. The findings showed sleep-wake alterations of various degrees of severity, which in some patients did not parallel white blood cell counts in the cerebrospinal fluid. Actigraphic recording also showed improvement of the analyzed parameters after treatment initiation. Nocturnal polysomnography showed alterations of sleep time closely corresponding to those derived from actigraphy.

Conclusions/significance: The data indicate that actigraphy can be an interesting tool for HAT evaluation, providing valuable clinical information through simple technology, well suited also for long-term follow-up. Actigraphy could therefore objectively contribute to the clinical assessment of HAT patients. This method could be incorporated into a clinical scoring system adapted to HAT to be used in the evaluation of novel treatments and laboratory biomarkers.
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http://dx.doi.org/10.1371/journal.pntd.0001525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3279345PMC
June 2012

Modulation of fronto-cortical activity by modafinil: a functional imaging and fos study in the rat.

Neuropsychopharmacology 2012 Feb 2;37(3):822-37. Epub 2011 Nov 2.

Center for Nanotechnology Innovation @NEST, Istituto Italiano di Tecnologia, Pisa, Italy.

Modafinil (MOD) is a wake-promoting drug with pro-cognitive properties. Despite its increasing use, the neuronal substrates of MOD action remain elusive. In particular, animal studies have highlighted a putative role of diencephalic areas as primary neuronal substrate of MOD action, with inconsistent evidence of recruitment of fronto-cortical areas despite the established pro-cognitive effects of the drug. Moreover, most animal studies have employed doses of MOD of limited clinical relevance. We used pharmacological magnetic resonance imaging (phMRI) in the anesthetized rat to map the circuitry activated by a MOD dose producing clinically relevant plasma exposure, as here ascertained by pharmacokinetic measurements. We observed prominent and sustained activation of the prefrontal and cingulate cortex, together with weaker but significant activation of the somatosensory cortex, medial thalamic domains, hippocampus, ventral striatum and dorsal raphe. Correlation analysis of phMRI data highlighted enhanced connectivity within a neural network including dopamine projections from the ventral tegmental area to the nucleus accumbens. The pro-arousing effect of MOD was assessed using electroencephalographic recording under anesthetic conditions comparable to those used for phMRI, together with the corresponding Fos immunoreactivity distribution. MOD produced electroencephalogram desynchronization, resulting in reduced delta and increased theta frequency bands, and a pattern of Fos induction largely consistent with the phMRI study. Altogether, these findings show that clinically relevant MOD doses can robustly activate fronto-cortical areas involved in higher cognitive functions and a network of pro-arousing areas, which provide a plausible substrate for the wake-promoting and pro-cognitive effects of the drug.
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http://dx.doi.org/10.1038/npp.2011.260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260987PMC
February 2012

The aging brain, neuroinflammatory signaling and sleep-wake regulation.

Ital J Anat Embryol 2010 ;115(1-2):31-8

Section of Anatomy and Histology, Department of Neuroscience, University of Verona.

Tissues and organs change over time, regulated by intrinsic (genetic) determinants and environmental (and microenvironmental) adaptation. Brain changes during lifetime are especially critical, as the brain is the effector of cognition and the vast majority of neurons live throughout the life of the individual. In addition, brain aging mechanisms are especially critical for disease vulnerability, given the aging-related prevalence of pathologies that include neurodegenerative diseases. In this context, the present contribution concisely highlights data yielded by recent trends of research on the normal aging brain, and specifically: the occurrence of synaptic changes (rather than neuronal loss) and the altered regulation of adult neurogenesis (which represents a novel exciting field of knowledge); the development of a low-grade chronic inflammatory state which primes glial cells and may lead to changes in intercellular crosstalk, thus playing a potential role in the brain susceptibility to neurodegeneration; changes occurring in state-dependent behavior, sleep and wake, which are products of global brain functioning and underlie consciousness and cognitive performance; changes in the biological clock, the hypothalamic suprachiasmatic nucleus, which regulates sleep-wake alternation and other endogenous rhythms. Altogether, the present synopsis of recent studies at the molecular, cellular, and functional levels emphasizes the idea that the normal aging brain should be viewed as an example of adaptation and plasticity rather than as an obligatory decline.
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January 2011
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