Diet-Induced Hypothalamic Inflammation, Phoenixin, and Subsequent Precocious Puberty.

Recent studies have shown a rise in precocious puberty, especially in girls. At the same time, childhood obesity due to overnutrition and energy imbalance is rising too. Nutrition and fertility are currently facing major challenges in our societies, and are interconnected. Studies have shown that high-fat and/or high-glycaemic-index diet can cause hypothalamic inflammation and microglial activation. Molecular and animal studies reveal that microglial activation seems to produce and activate prostaglandins, neurotrophic factors activating GnRH (gonadotropin-releasing hormone expressing neurons), thus initiating precocious puberty. GnRH neurons' mechanisms of excitability are not well understood. In this review, we study the phenomenon of the rise of precocious puberty, we examine the physiology of GnRH neurons, and we review the recent literature regarding the pathophysiological mechanisms that connect diet-induced hypothalamic inflammation and diet-induced phoenixin regulation with precocious puberty.

Transvenous Diaphragm Neurostimulation Mitigates Ventilation-associated Brain Injury.

Rationale: Mechanical ventilation (MV) is associated with hippocampal apoptosis and inflammation, and it is important to study strategies to mitigate them. Objectives: To explore whether temporary transvenous diaphragm neurostimulation (TTDN) in association with MV mitigates hippocampal apoptosis and inflammation after 50 hours of MV. Methods: Normal-lung porcine study comparing apoptotic index, inflammatory markers, and neurological-damage serum markers between never-ventilated subjects, subjects undergoing 50 hours of MV plus either TTDN every other breath or every breath, and subjects undergoing 50 hours of MV (MV group). MV settings in volume control were Vt of 8 ml/kg, and positive end-expiratory pressure of 5 cm H2O. Measurements and Main Results: Apoptotic indices, microglia percentages, and reactive astrocyte percentages were greater in the MV group in comparison with the other groups (P < 0.05). Transpulmonary pressure at baseline and at study end were both lower in the group receiving TTDN every breath, but lung injury scores and systemic inflammatory markers were not different between the groups. Serum concentrations of four neurological-damage markers were lower in the group receiving TTDN every breath than in the MV group (P < 0.05). Heart rate variability declined significantly in the MV group and increased significantly in both TTDN groups over the course of the experiments. Conclusions: Our study found that mechanical ventilation is associated with hippocampal apoptosis and inflammation, independent of lung injury and systemic inflammation. Also, in a porcine model, TTDN results in neuroprotection after 50 hours, and the degree of neuroprotection increases with greater exposure to TTDN.

Orally Administered DHA-Enriched Phospholipids and DHA-Enriched Triglyceride Relieve Oxidative Stress, Improve Intestinal Barrier, Modulate Inflammatory Cytokine and Gut Microbiota, and Meliorate Inflammatory Responses in the Brain in Dextran Sodium Sulfate Induced Colitis in Mice.

SCOPE: Studies based on DHA/EPA supplementation in animal models of inflammatory bowel disease (IBD) reveal controversial results. It is speculated that different forms of DHA may explain the controversial results. Therefore, the effects of DHA-enriched phospholipids (DHA-PL) and DHA-enriched triglyceride (DHA-TG) on IBD are compared. METHODS AND RESULTS: Male C57BL6/J mice are given DHA-PL and DHA-TG for 14 consecutive days, and receive ad libitum a 3.0% dextran sodium sulfate solution on the eighth day to establish IBD model. The results show that both DHA-PL and DHA-TG can reverse the colitis pathological process by decreasing the disease activity indexes (DAI), raising the colon length, suppressing the intestinal permeability, suppressing the oxidative stress, down-regulating pro-inflammatory factors, up-regulating anti-inflammatory factor in colon tissues. DHA-PL and DHA-TG also regulate the composition of gut microbiota via decreasing of the abundance Bacteroidetes and Firmicutes, and DHA-TG increases the abundance of Odoribacter. Importantly, DHA-PL and DHA-TG obviously attenuate the activation of microglia. CONCLUSIONS: DHA-PL shows outstanding advantages in regulating oxidative stress, inflammatory responses, and intestinal barrier permeability. The current research indicates that the existence of DHA affects the improvement, DHA in phospholipid form could be a more effective choice for nutritional intervention to prevent and treat colitis.

Evolution and resolution of brain involvement associated with SARS- CoV2 infection: A close Clinical - Paraclinical follow up study of a case.

The new severe acute respiratory syndrome- coronavirus 2 is reported to affect the nervous system. Among the reports of the various neurological manifestations, there are a few documented specific processes to explain the neurological signs. We report a para-infectious encephalitis patient with clinical, laboratory, and imaging findings during evolution and convalescence phase of coronavirus infection. This comprehensive overview can illuminate the natural history of similar cases. As the two previously reported cases of encephalitis associated with this virus were not widely discussed regarding the treatment, we share our successful approach and add some recommendations about this new and scarce entity.

Therapeutic effects of hirsutella sinensis on the disease onset and progression of amyotrophic lateral sclerosis in SOD1G93A transgenic mouse model.

AIMS: Although the pathophysiology of amyotrophic lateral sclerosis (ALS) is still not completely understood, the deregulated microglia polarization and neuroinflammation have been shown to contribute to the pathogenesis and progression of this disease. In the present study, we aimed to determine whether hirsutella sinensis (HS) could reduce neuroinflammatory and pathological changes in the spinal cord of SOD1G93A model mice of ALS and consequently ameliorate disease onset and progression. METHODS: SOD1G93A mice were chronically treated with HS by gavage. Their lifespan was recorded, and motor behavior was evaluated by rotarod test. The pathological changes in skeletal muscles and motor neurons in spinal cords were assessed by immunofluorescent staining and hematoxylin-eosin staining. The microglia activation and neuroinflammation were determined by immunofluorescent staining and RT-PCR. RESULTS: Our data suggested that repeated HS administration prolonged the lifespan and extended disease duration of ALS mice without significant delay on disease onset. HS ameliorated the pathological changes in the motor neurons and gastrocnemius muscles. Moreover, HS promoted the transition of microglia from pro-inflammatory M1 to anti-inflammatory M2 phenotype in the spinal cord of ALS mice. CONCLUSION: All these findings indicate that HS may serve as a potential therapeutic candidate for the treatment of ALS.

NF-κB-Mediated Neuroinflammation in Parkinson's Disease and Potential Therapeutic Effect of Polyphenols.

Different animal and human studies from last two decades in the case of Parkinson's disease (PD) have concentrated on oxidative stress due to increased inflammation and cytokine-dependent neurotoxicity leading to induction of dopaminergic (DA) degeneration pathway in the nigrostriatal region. Chronic inflammation, the principle hallmark of PD, forms the basis of neurodegeneration. Aging in association with activation of glia due to neuronal injury, perhaps because of immune alterations and genetic predispositions, leads to deregulation of inflammatory pathways premising the onset of PD. A family of inducible transcription factors, nuclear factor-κB (NF-κB), is found to show expression in various cells and tissues, such as microglia, neurons, and astrocytes which play an important role in activation and regulation of inflammatory intermediates during inflammation. Both canonical and non-canonical NF-κB pathways are involved in the regulation of the stimulated cells. During the prodromal/asymptomatic stage of age-associated neurodegenerative diseases (i.e., PD and AD), chronic neuroinflammation may act silently as the driver of neuronal dysfunction. Though research has provided an insight over age-related neurodegeneration in PD, elaborative role of NF-κB in neuroinflammation is yet to be completely understood and thus requires more investigation. Polyphenols, a group of naturally occurring compound in medicinal plants, have gained attention because of their anti-oxidative and anti-neuroinflammatory properties in neurodegenerative diseases. In this aspect, this review highlights the role of NF-κB and the possible therapeutic roles of polyphenols in NF-κB-mediated neuroinflammation in PD.

Pharmacologic Overview of Chlorogenic Acid and its Metabolites in Chronic Pain and Inflammation.

BACKGROUND: Natural phenolic compounds in medicinal herbs and dietary plants are antioxidants which play therapeutic or preventive roles in different pathological situations, such as oxidative stress and inflammation. One of the most studied phenolic compounds in the last decade is chlorogenic acid (CGA), which is a potent antioxidant found in certain foods and drinks. OBJECTIVE: This review focuses on the anti-inflammatory and antinociceptive bioactivities of CGA, and the putative mechanisms of action are described. Ethnopharmacological reports related to these bioactivities are also reviewed. MATERIALS AND METHODS: An electronic literature search was conducted by authors up to October 2019. Original articles were selected. RESULTS: CGA has been shown to reduce inflammation and modulate inflammatory and neuropathic pain in animal models. CONCLUSION: The consensus of the literature search was that systemic CGA may facilitate pain management via bolstering antioxidant defenses against inflammatory insults.

Coenzyme Q10 supplementation improves acute outcomes of stroke in rats pretreated with atorvastatin.

OBJECTIVES: Coenzyme Q10 (CoQ10, ubiquinone) stands among the safest supplements in the elderly to protect against cardiovascular disorders. Noteworthy, CoQ10 deficiency is common in many surviving stroke patients as they are mostly prescribed statins for the secondary prevention of stroke incidence lifelong. Accordingly, the current study aims to experimentally examine whether CoQ10 supplementation in animals receiving atorvastatin may affect acute stroke-induced injury. METHODS: Adult rats underwent transient middle cerebral artery occlusion after atorvastatin pretreatment (5 or 10 mg/ kg/day; po; 30 days) with or without CoQ10 (200 mg/kg/day). After 24 hours ischemic/reperfusion injury, animals were subjected to functional assessments followed by cerebral molecular and histological to detect inflammation, apoptosis and oxidative stress. RESULTS: Animals dosed with 10 mg/kg presented the worst neurological function and brain damage in the acute phase of stroke injury. CoQ10 supplementation efficiently improved functional deficit and cerebral infarction in all stroke animals, particularly those exhibiting statin toxicity. Such benefits were associated with remarkable anti-inflammatory and anti-apoptotic effects, based on the analyzed tumor necrosis factor-α, interleukin-6, Bax/Bcl2 and cleaved caspase 3/9 immunoblots. Importantly, our fluoro-jade staining data indicated CoQ10 may revert the stroke-induced neurodegeneration. No parallel alteration was detected in stroke-induced oxidative stress as determined by malondialdehyde and 8-oxo-2'-deoxyguanosine levels. DISCUSSION: These data suggest that all stroke animals may benefit from CoQ10 administration through modulating inflammatory and degenerative pathways. This study provides empirical evidence for potential advantages of CoQ10 supplementation in atorvastatin-receiving patients which may not shadow its antioxidant properties.

Hashimoto's thyroiditis induces neuroinflammation and emotional alterations in euthyroid mice.

BACKGROUND: Although studies have reported an increased risk for mood disorders in Hashimoto's thyroiditis (HT) patients even in the euthyroid state, the mechanisms involved remain unclear. Neuroinflammation may play a key role in the etiology of mood disorders in humans and behavioral disturbances in rodents. Therefore, this study established a euthyroid HT model in mice and investigated whether HT itself was capable of triggering neuroinflammation accompanied by emotional alterations. METHODS: Experimental HT was induced by immunizing NOD mice with thyroglobulin and adjuvant twice. Four weeks after the last challenge, mice were tested for anxiety-like behavior in the open field and elevated plus maze tests and depression-like behavior in the forced swimming and tail suspension tests. Then, animals were sacrificed for thyroid-related parameter measure as well as detection of cellular and molecular events associated with neuroinflammation. The changes in components of central serotonin signaling were also investigated. RESULTS: HT mice showed intrathyroidal monocyte infiltration and rising serum thyroid autoantibody levels accompanied by normal thyroid function, which defines euthyroid HT in humans. These mice displayed more anxiety- and depressive-like behaviors than controls. HT mice further showed microglia and astrocyte activation in the frontal cortex detected by immunohistochemistry, real-time RT-PCR, and transmission electron microscopy (TEM). These observations were also accompanied by enhanced gene expression of proinflammatory cytokines IL-1ß and TNF-α in the frontal cortex. Despite this inflammatory response, no signs of neuronal apoptosis were visible by the TUNEL staining and TEM in the frontal cortex of HT mice. Additionally, IDO1 and SERT, key serotonin-system-related genes activated by proinflammatory cytokines, were upregulated in HT mice, accompanied by reduced frontal cortex serotonin levels. CONCLUSIONS: Our results are the first to suggest that HT induces neuroinflammation and alters related serotonin signaling in the euthyroid state, which may underlie the deleterious effects of HT itself on emotional function.

Role of Curcumin in Regulation of TNF-α Mediated Brain Inflammatory Responses.

BACKGROUND: Inflammation is a protective response of the body system that protects the body from the various kinds of external and internal insults; however, it has been found that most chronic illnesses are caused by dysregulated and excessive inflammation. Inflammation plays a major role in developing neurological diseases. In the brain cytokines, TNF-α and TNF-ß are known to mediate inflammation in many diseases. Functions of these cytokines are regulated by the activation of transcription factor NF-κb. Recent evidence suggest that curcumin has an immense therapeutic potential because of its anti-inflammatory and anti-oxidant properties. It has been tested for treating various chronic illnesses associated with the brain. OBJECTIVE: The study aims to elucidate the role of curcumin in alleviating the inflammatory reactions initiated by TNF-α and NF-κb signaling. METHODS: This study is a survey of literature from sources like PubMed central, science direct, medline and available scientific databases to determine how inflammation plays an important role in the development of neurodegenerative diseases and the role of curcumin as an anti-inflammatory agent. Looking into the importance of curcumin in alleviating inflammatory responses, several patents are filed and accepted which are referenced in this article. RESULTS: Neuro-inflammation mediated by TNF-α plays a major role in the development of pathologies like Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis etc. Curcumin appears to subside or reduce the inflammatory responses. Thus, it appears to have therapeutic potential for treating various neuroinflammatory diseases. CONCLUSION: Cytokines get upregulated during neurodegenerative diseases as a result of which inflammatory responses are initiated in the brain. Curcumin is reported to have anti-inflammatory properties and thereby its supplementation may help in reducing the inflammation. Future research on this area will further explain the mode of action of curcumin in alleviating neuroinflammation.

Cell and molecular mechanisms behind diet-induced hypothalamic inflammation and obesity.

Diet-induced obesity (DIO) is associated with chronic, low-grade inflammation in the hypothalamus, a key regulator of energy homeostasis. Current studies have revealed the involvement of different cell types, as well as cell and molecular mechanisms, that contribute to diet-induced hypothalamic inflammation (DIHI) and DIO. Subsequent to the discovery that high-fat diet and saturated fatty acids increase the expression of hypothalamic cytokines prior to weight gain, research has focused on understanding the cellular and molecular mechanisms underlying these changes, in addition to the role of inflammation in the pathogenesis of obesity. Recent studies have proposed that the inhibition of pro-inflammatory pathways in microglia and astrocytes is sufficient to protect against DIHI and prevent obesity. In addition, impairment of intracellular and epigenetic mechanisms, such as hypothalamic autophagy and changes in the methylation pattern of certain genes, have been implicated in susceptibility to DIHI and DIO. Interestingly, a sexual dimorphism has been found during DIO in hypothalamic inflammation, glial activation and metabolic diseases, and recent data support an important role of sex steroids in DIHI. These new exciting findings uncover novel obesity pathogenic mechanisms and provide targets to develop therapeutic approaches.

Naringenin Decreases α-Synuclein Expression and Neuroinflammation in MPTP-Induced Parkinson's Disease Model in Mice.

The present study was designed to ascertain the role of naringenin (NGN), a citrus fruit flavanone, against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced α-synuclein (SYN) pathology and neuroinflammation in a mouse model. NGN was administered to C57BL/6J mice once a day for 5 consecutive days prior to the MPTP intoxication. On day 5, 40-50 min after the NGN or vehicle administration, MPTP was injected in two divided doses (2× 40 mg/kg, i.p. at 16 h apart). The animals were observed for motor functions 48 h after the first MPTP injection. The animals were then euthanized, the brains collected to analyze SYN pathology, cytokines, and oxidative stress levels in the substantia nigra region. The NGN significantly downregulated SYN and upregulated dopamine transporter (DAT) and tyrosine hydroxylase (TH) protein expressions. It also downregulated tumor necrosis factor-α (TNFα) and interleukin 1ß (IL1ß) mRNA expressions and improved superoxide dismutase levels. It also reduced glutathione levels when compared to vehicle-treated PD animals. The upregulation of TH corroborates to an increase in dopamine, DOPAC, and homovanillic acid turnover and motor functions with NGN treatment. To summarize, NGN, a dietary flavone, has the potential to counteract MPTP-induced dopaminergic degeneration by regulating SYN pathology, neuroinflammation, and oxidative stress. This warrants the investigation of NGN's potential effects in a genetic model of PD.

Patchouli alcohol protects against ischemia/reperfusion-induced brain injury via inhibiting neuroinflammation in normal and obese mice.

Almost all of the candidate drugs for ischemic stroke failed to be translated from bench to beside. One important reason is that animals used in experimental studies cannot mimic ischemic patients due to lack of comorbidities like hypertension, diabetes and obesity. Therefore, it is better to test candidate drugs not only in normal animals but also in animals with comorbidities. Patchouli alcohol (PA), a natural tricyclic sesquiterpene in the traditional Chinese herb Pogostemonisherba, is well recognized for its anti-inflammation function in various inflammatory diseases. And as inflammation plays a very important role in cerebral ischemia/reperfusion (I/R) injury process and determines the ultimate brain damage, we hypothesized that PA could protect against cerebral I/R injury through its anti-inflammation ability. In this study, the effects of PA on cerebral I/R injury were evaluated in normal mice and obese mice. In normal mice with cerebral I/R injury, PA treatment reduced the infarct volume and neurological deficits in a dose- and time-dependent manner. PA treatment alleviated BBB dysfunction, inhibited mRNA and protein levels of TNF-α and IL-1ß and modulated the activation of MAPKs signaling pathways. Moreover, PA also reduced infarct volume, alleviated the BBB dysfunction and inhibited inflammation in ob/ob mice with cerebral I/R injury. In conclusion, we demonstrated for the first time that PA could protect against cerebral I/R injury not only in normal mice but also in obese mice via inhibiting inflammation, suggesting that PA can be a potential drug for clinical treatment of ischemic stroke.

Withania somnifera as a potential candidate to ameliorate high fat diet-induced anxiety and neuroinflammation.

BACKGROUND: The epidemic of obesity has reached alarming levels in both developing and developed nations. Excessive calorie intake and sedentary lifestyle due to technological advancements are the main causal factors for overweight and obesity among the human population. Obesity has been associated with a number of co-morbidities such as hypertension, type 2 diabetes mellitus, cardiovascular diseases, and neurodegeneration and dementia. The progression of neurological disorders in obese subjects has been mainly attributed to neuroinflammation. Withania somnifera has been used in numerous Ayurvedic formulations owing to its wide array of health-promoting properties. The current study was designed to test the hypothesis whether dry leaf powder of W. somnifera has anxiolytic and anti-neuroinflammatory potential in diet-induced obesity. METHODS: Young adult female rats were divided into four groups: low fat diet group (LFD) fed with regular chow feed, high fat diet group (HFD) fed with diet containing 30% fat by weight, low fat diet plus extract group (LFDE) fed with regular chow feed supplemented with dry leaf powder of W. somnifera 1 mg/g of body weight (ASH), and high fat diet plus extract group (HFDE) fed with diet containing 30% fat by weight and supplemented with ASH. All the animals were kept on respective feeding regimen for 12 weeks; following which, the animals were tested for their anxiety-like behavior using elevated plus maze test. The animals were sacrificed and used to study various inflammatory markers such as GFAP, Iba1, PPARγ, iNOS, MCP-1, TNFα, IL-1ß, IL-6, and various markers of NF-κB pathway by Western blotting and quantitative real-time PCR. Serum levels of leptin, insulin and pro-inflammatory cytokines were also assayed. RESULTS: ASH treated rats showed less anxiety levels as compared to HFD animals. At molecular level, ASH ameliorated the HFD-induced reactive gliosis and microgliosis and suppressed the expression of inflammatory markers such as PPARγ, iNOS, MCP-1, TNFα, IL-1ß, and IL-6. Further, ASH ameliorated leptin and insulin resistance and prevented HFD-induced apoptosis. CONCLUSIONS: Dry leaf powder of W. somnifera may prove to be a potential therapeutic agent to attenuate neuroinflammation associated with obesity and may prevent its co-morbidities.

Leonurine Exerts Antidepressant-Like Effects in the Chronic Mild Stress-Induced Depression Model in Mice by Inhibiting Neuroinflammation.

Background: Leonurine is an active alkaloid that is extracted from Traditional Chinese Medicine Herba leonuri. Emerging evidence indicates that leonurine produces neuroprotective effects in ischemic stroke, Parkinson's disease, and Alzheimer's disease. However, the effect of leonurine in neuropsychiatric disorders, especially in major depression, remains unknown. Methods: We used the chronic mild stress mouse model to explore the antidepressant effects of leonurine and the potential mechanisms. Behavioral tests including sucrose preference test, forced swimming test, and tail suspension test were taken to evaluate depression symptoms. Moreover, the contents of monoamine neurotransmitters in hippocampus and prefrontal cortex were measured by high-performance liquid chromatography. Neuronal morphology was detected by transmission electron microscopy. Results: Administration of leonurine (60 mg/kg) for 4 weeks significantly alleviated depression-like behaviors of chronic mild stress mice, including increased sucrose preference and reduced immobility time in forced swimming test and tail suspension test. We further found that leonurine (60 mg/kg) effectively restored the levels of 5-hydroxytryptamine, noradrenaline, and dopamine in the hippocampus and prefrontal cortex of chronic mild stress mice, accompanied by amelioration of hippocampal neuronal damage. Furthermore, leonurine (60 mg/kg) significantly inhibited the production of proinflammatory cytokine interleukin-1ß, interleukin-6 and TNF-α, and suppressed the nuclear factor kappa B signaling pathway. Conclusions: These findings demonstrate that leonurine exerts antidepressant-like effects, which may be mediated, at least in part, by improving monoamine neurotransmitters and inhibiting neuroinflammation. Our study provides insight into the potential of leonurine in depression therapy.

Resolution of inflammation, n-3 fatty acid supplementation and Alzheimer disease: A narrative review.

In patients with Alzheimer's disease (AD), a persistent and unresolved neuroinflammatory process can contribute to neuronal loss and a decline in their cognitive and functional abilities. Recent studies have demonstrated that the ability to resolve inflammation is impaired in the brains of patients with AD. Preclinical evidence demonstrates the potential of therapeutic interventions on the resolution phase of inflammation in AD. Supplementation of omega-3 fatty acids (n-3 FAs), precursors for specialized pro-resolving mediators, emerged as a possibility for prevention and management of AD. Here, we provide a narrative review of resolving inflammation in AD and the role of n-3 FA supplementation in AD.

Omega-3 fatty acids revert high-fat diet-induced neuroinflammation but not recognition memory impairment in rats.

Neuroinflammation is a consequence of overeating and may predispose to the development of cognitive decline and neurological disorders. This study aimed to evaluate the impact of omega-3 supplementation on memory and neuroinflammatory markers in rats fed a high-fat diet. Male Wistar rats were divided into four groups: standard diet (SD); standard diet + omega-3 (SD + O); high fat diet (HFD); and high fat diet + omega-3 (HFD + O). Diet administration was performed for 20 weeks and omega-3 supplementation started at the 16th week. HFD significantly increased body weight, while omega-3 supplementation did not modify the total weight gain. However, animals from the HFD + O group showed a lower level of visceral fat along with an improvement in insulin sensitivity following HFD. Thus, our results demonstrate a beneficial metabolic role of omega-3 following HFD. On the other hand, HFD animals presented an impairment in object recognition memory, which was not recovered by omega-3. In addition, there was an increase in GFAP-positive cells in the cerebral cortex of the HFD group, showing that omega-3 supplementation can be effective to decrease astrogliosis. However, no differences in GFAP number of cells were found in the hippocampus. We also demonstrated a significant increase in gene expression of pro-inflammatory cytokines IL-6 and TNF-α in cerebral cortex of the HFD group, reinforcing the anti-inflammatory role of this family of fatty acids. In summary, omega-3 supplementation was not sufficient to reverse the memory deficit caused by HFD, although it played an important role in reducing the neuroinflammatory profile. Therefore, omega-3 fatty acids may play an important role in the central nervous system, preventing the progression of neuroinflammation in obesity.

Omega-3 polyunsaturated fatty acid supplementation attenuates microglial-induced inflammation by inhibiting the HMGB1/TLR4/NF-κB pathway following experimental traumatic brain injury.

BACKGROUND: Microglial activation and the subsequent inflammatory response in the central nervous system play important roles in secondary damage after traumatic brain injury (TBI). High-mobility group box 1 (HMGB1) protein, an important mediator in late inflammatory responses, interacts with transmembrane receptor for advanced glycation end products (RAGE) and toll-like receptors (TLRs) to activate downstream signaling pathways, such as the nuclear factor (NF)-κB signaling pathway, leading to a cascade amplification of inflammatory responses, which are related to neuronal damage after TBI. Omega-3 polyunsaturated fatty acid (ω-3 PUFA) is a commonly used clinical immunonutrient, which has antioxidative and anti-inflammatory effects. However, the effects of ω-3 PUFA on HMGB1 expression and HMGB1-mediated activation of the TLR4/NF-κB signaling pathway are not clear. METHODS: The Feeney DM TBI model was adopted to induce brain injury in rats. Modified neurological severity scores, brain water content, and Nissl staining were employed to determine the neuroprotective effects of ω-3 PUFA supplementation. Assessment of microglial activation in lesioned sites and protein markers for proinflammatory, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, interferon (IFN)-γ, and HMGB1 were used to evaluate neuroinflammatory responses and anti-inflammation effects of ω-3 PUFA supplementation. Immunofluorescent staining and western blot analysis were used to detect HMGB1 nuclear translocation, secretion, and HMGB1-mediated activation of the TLR4/NF-κB signaling pathway to evaluate the effects of ω-3 PUFA supplementation and gain further insight into the mechanisms underlying the development of the neuroinflammatory response after TBI. RESULTS: It was found that ω-3 PUFA supplementation inhibited TBI-induced microglial activation and expression of inflammatory factors (TNF-α, IL-1ß, IL-6, and IFN-γ), reduced brain edema, decreased neuronal apoptosis, and improved neurological functions after TBI. We further demonstrated that ω-3 PUFA supplementation inhibited HMGB1 nuclear translocation and secretion and decreased expression of HMGB1 in neurons and microglia in the lesioned areas. Moreover, ω-3 PUFA supplementation inhibited microglial activation and the subsequent inflammatory response by regulating HMGB1 and the TLR4/NF-κB signaling pathway. CONCLUSIONS: The results of this study suggest that microglial activation and the subsequent neuroinflammatory response as well as the related HMGB1/TLR4/NF-κB signaling pathway play essential roles in secondary injury after TBI. Furthermore, ω-3 PUFA supplementation inhibited TBI-induced microglial activation and the subsequent inflammatory response by regulating HMGB1 nuclear translocation and secretion and also HMGB1-mediated activation of the TLR4/NF-κB signaling pathway, leading to neuroprotective effects.

Adenovirus-mediated suppression of hypothalamic glucokinase affects feeding behavior.

Glucokinase (GK), the hexokinase involved in glucosensing in pancreatic ß-cells, is also expressed in arcuate nucleus (AN) neurons and hypothalamic tanycytes, the cells that surround the basal third ventricle (3V). Several lines of evidence suggest that tanycytes may be involved in the regulation of energy homeostasis. Tanycytes have extended cell processes that contact the feeding-regulating neurons in the AN, particularly, agouti-related protein (AgRP), neuropeptide Y (NPY), cocaine- and amphetamine-regulated transcript (CART) and proopiomelanocortin (POMC) neurons. In this study, we developed an adenovirus expressing GK shRNA to inhibit GK expression in vivo. When injected into the 3V of rats, this adenovirus preferentially transduced tanycytes. qRT-PCR and Western blot assays confirmed GK mRNA and protein levels were lower in GK knockdown animals compared to the controls. In response to an intracerebroventricular glucose injection, the mRNA levels of anorexigenic POMC and CART and orexigenic AgRP and NPY neuropeptides were altered in GK knockdown animals. Similarly, food intake, meal duration, frequency of eating events and the cumulative eating time were increased, whereas the intervals between meals were decreased in GK knockdown rats, suggesting a decrease in satiety. Thus, GK expression in the ventricular cells appears to play an important role in feeding behavior.

Fenugreek Seed Powder Attenuated Aluminum Chloride-Induced Tau Pathology, Oxidative Stress, and Inflammation in a Rat Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a common neurodegenerative disorder that mainly affects the aged population and is characterized by the progressive loss of the hippocampal and cortical neurons, which results in memory and cognitive impairments. Trigonella foenum-graecum (fenugreek) has been reported to have hypoglycemic, hypocholesterolemic, hyperinsulinemic and anti-diabetic properties. Traditionally, it was used as a galactagogue and to treat anorexia, fever gastritis, gastric ulcers, and various nervous disorders. However, the neuroprotective effect of fenugreek seed powder against aluminum chloride (AlCl3) induced AD rats has not been analyzed. The result of the present study indicated that the chronic administration of AlCl3 induced significant learning and memory impairments, oxidative stress, and alterations in the protein immunocontent patterns of IDE and CDK5 (enzymes involved in the metabolism of tau and amyloid proteins), pTau, GFAP and Iba-1, IL-1ß, IL-6, TNF-α, iNOS, NF-κB, COX-2, CDK5, BDNF, and STAT3. Our behavioral, biochemical, and molecular studies revealed that the co-administration of fenugreek seed powder significantly attenuated the AlCl3 induced memory deficits, amyloid and tau pathology, oxidative stress, and inflammation in AD rats could be due to the synergistic action of its active components.