Minocycline mitigates tau pathology via modulating the TLR-4/NF-Ðºß signalling pathway in the hippocampus of neuroinflammation rat model.

INTRODUCTION: The neuroinflammatory response was seen to impact the formation of phosphorylated tau protein in Alzheimer's disease (AD). This study aims to investigate the molecular mechanism of minocycline in reducing phosphorylated tau protein formation in the hippocampus of lipopolysaccharide (LPS)-induced rats. METHODS: Fifty adult male Sprague Dawley (SD) rats were randomly allocated to 1 of 5 groups: control, LPS (5 mg/kg), LPS + minocycline (25 mg/kg), LPS + minocycline (50 mg/kg) and LPS + memantine (10 mg/kg). Minocycline and memantine were administered intraperitoneally (i.p) for two weeks, and LPS was injected i.p. once on day 5. ELISA was used to determine the level of phosphorylated tau protein in SD rats' hippocampal tissue. The density and expression of Toll-like receptor-4 (TLR-4), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-кß), tumour necrosis factor-alpha (TNF-α), and cyclooxygenase (COX)-2 were determined using Western blot and immunohistochemistry. RESULTS: Minocycline, like memantine, prevented LPS-induced increasein phosphorylated tau protein level suggested via reduced density and expression of TLR-4, NF-кß, TNF-αand COX-2 proteins in rat hippocampal tissue. Interestingly, higher doses were shown to be more neuroprotective than lower doses. CONCLUSION: This study suggests that minocycline suppresses the neuroinflammation signalling pathway and decreased phosphorylated tau protein formation induced by LPS in a dose-dependent manner. Minocycline can be used as a preventative and therapeutic drug for neuroinflammatory diseases such as AD.

Global trends and themes in genetic counseling research.

This article seeks to highlight the most recent trends and themes in genetic counseling that are of broad interest. A total of 3505 documents were published between 1952 and 2021, with a trend toward increase in paper/year. The most common documents are original articles (2515, 71.8%), followed by review articles (341, 9.7%). Journal of Genetic Counseling publishes the highest number of genetic counseling articles (587, 16.7%), followed by Clinical Genetics (103, 2.9%) and the South American Journal of Medical Genetics (95, 2.7%). Co-occurrence analysis revealed five research themes: genetic testing, cancer, genetic counselor, prenatal diagnosis, and psychiatry. The genetic counselor theme contained most of the recent keywords, including "covid-19," "underrepresented population," "service delivery models," "workforce," "disparities," "service delivery," "professional development," "cultural competence," "access," "diversity," "telemedicine," and "health literacy." Genetic counseling researchers may use these keywords to find topics pertinent to their future research and practice.

Minocycline Protects Against Lipopolysaccharide-Induced Cognitive Impairment and Oxidative Stress: Possible Role of the CREB-BDNF Signaling Pathway.

The oxidative stress-induced dysregulation of the cyclic AMP response element-binding protein- brain-derived neurotrophic factor (CREB-BDNF) cascade has been linked to cognitive impairment in several studies. This study aimed to investigate the effect of minocycline on the levels of oxidative stress markers, CREB, and BDNF in lipopolysaccharide (LPS)-induced cognitive impairment. Fifty adult male Sprague Dawley rats were divided randomly into five groups. Group 1 was an untreated control group. Groups 2, 3, 4 and 5 were treated concurrently with LPS (5 mg/kg, i.p) once on day 5 and normal saline (0.7 ml/rat, i.p) or minocycline (25 and 50 mg/kg, i.p) or memantine (10 mg/kg, i.p) once daily from day 1 until day 14, respectively. From day 15 to day 22 of the experiment, Morris Water Maze (MWM) was used to evaluate learning and reference memory in rats. The levels of protein carbonyl (PCO), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD) were determined by enzyme-linked immunosorbent assay (ELISA). CREB and BDNF expression and density were measured by immunohistochemistry and western blot analysis, respectively. LPS administration significantly increased escape latency to the hidden platform with decreased travelled distance, swimming speed, target crossings and time spent in the target quadrant. Besides, the hippocampal tissue of LPS rats showed increased levels of PCO and MDA, decreased levels of CAT and SOD, and reduced expression and density of BDNF and CREB. Treatment with minocycline reversed these effects in a dose-dependent manner, comparable to the effects of memantine. Both doses of minocycline treatment protect against LPS-induced cognitive impairment by reducing oxidative stress and upregulating the CREB-BDNF signalling pathway in the rat hippocampus.

Worldwide melatonin research: a bibliometric analysis of the published literature between 2015 and 2019.

This study presents a bibliometric analysis of the publications on melatonin research from the Scopus database during the period 2015-2019. Based on the keywords used, which are related to melatonin in the article title, the study retrieved 4411 documents for further analysis using various tools. We used Microsoft Excel to conduct the frequency analysis, VOSviewer for data visualization, and Harzing's Publish or Perish for citation metrics and analysis. This study reports the results using standard bibliometric indicators such as the growth of publications, authorship patterns, collaboration, and prolific authors, country contribution, most active institutions, preferred journals, and top-cited articles. Based on our findings, there is a continuous growth of publications on melatonin research for 5 years since 2015. China was the largest contributor to melatonin research, followed by the United States. The Journal of Pineal Research published the most number of publications related to melatonin research. Our findings suggest that the role of melatonin in plant and food sciences, as well as in cancer, may in later years take over the clusters that earlier dominated melatonin research.

In Silico Analyses and Cytotoxicity Study of Asiaticoside and Asiatic Acid from Malaysian Plant as Potential mTOR Inhibitors.

Natural products remain a popular alternative treatment for many ailments in various countries. This study aimed to screen for potential mammalian target of rapamycin (mTOR) inhibitors from Malaysian natural substance, using the Natural Product Discovery database, and to determine the IC50 of the selected mTOR inhibitors against UMB1949 cell line. The crystallographic structure of the molecular target (mTOR) was obtained from Protein Data Bank, with Protein Data Bank (PDB) ID: 4DRI. Everolimus, an mTOR inhibitor, was used as a standard compound for the comparative analysis. Computational docking approach was performed, using AutoDock Vina (screening) and AutoDock 4.2.6 (analysis). Based on our analysis, asiaticoside and its derivative, asiatic acid, both from Centella asiatica, revealed optimum-binding affinities with mTOR that were comparable to our standard compound. The effect of asiaticoside and asiatic acid on mTOR inhibition was validated with UMB1949 cell line, and their IC50 values were 300 and 60 µM, respectively, compared to everolimus (29.5 µM). Interestingly, this is the first study of asiaticoside and asiatic acid against tuberous sclerosis complex (TSC) disease model by targeting mTOR. These results, coupled with our in silico findings, should prompt further studies, to clarify the mode of action, safety, and efficacy of these compounds as mTOR inhibitors.

Effects of Tualang honey in modulating nociceptive responses at the spinal cord in offspring of prenatally stressed rats.

OBJECTIVE: This study was done to determine whether Tualang honey could prevent the altered nociceptive behaviour, with its associated changes of oxidative stress markers and morphology of the spinal cord, among the offspring of prenatally stressed rats. METHODS: Pregnant rats were divided into three groups: control, stress, and stress treated with Tualang honey. The stress and stress treated with Tualang honey groups were subjected to restraint stress from day 11 of pregnancy until delivery. Ten week old male offspring (n = 9 from each group) were given formalin injection and their nociceptive behaviours were recorded. After 2 h, the rats were sacrificed, and their spinal cords were removed to assess oxidative stress activity and morphology. Nociceptive behaviour was analysed using repeated measures analysis of variance (ANOVA), while the levels of oxidative stress parameters and number of Nissl-stained neurons were analysed using a one-way ANOVA. RESULTS: This study demonstrated that prenatal stress was associated with increased nociceptive behaviour, changes in the oxidative stress parameters and morphology of the spinal cord of offspring exposed to prenatal stress; administration of Tualang honey reduced the alteration of these parameters. CONCLUSION: This study provides a preliminary understanding of the beneficial effects of Tualang honey against the changes in oxidative stress and neuronal damage in the spinal cord of the offspring of prenatally stressed rats.

Enhancement of BDNF concentration and restoration of the hypothalamic-pituitary-adrenal axis accompany reduced depressive-like behaviour in stressed ovariectomised rats treated with either Tualang honey or estrogen.

A possible interaction between glucocorticoids and estrogen-induced increases in brain-derived-neurotrophic factor (BDNF) expression in enhancing depressive-like behaviour has been documented. Here we evaluated the effects of Tualang honey, a phytoestrogen, and 17 ß -estradiol (E2) on the depressive-like behaviour, stress hormones, and BDNF concentration in stressed ovariectomised (OVX) rats. The animals were divided into six groups: (i) nonstressed sham-operated control, (ii) stressed sham-operated control, (iii) nonstressed OVX, (iv) stressed OVX, (v) stressed OVX treated with E2 (20 µg daily, sc), and (vi) stressed OVX treated with Tualang honey (0.2 g/kg body weight daily, orally). Two months after surgery, the animals were subjected to social instability stress procedure followed by forced swimming test. Struggling time, immobility time, and swimming time were scored. Serum adrenocorticotropic hormone (ACTH) and corticosterone levels, and the BDNF concentration were determined using commercially available ELISA kits. Stressed OVX rats displayed increased depressive-like behaviour with significantly increased serum ACTH and corticosterone levels, while the BDNF concentration was significantly decreased compared to other experimental groups. These changes were notably reversed by both E2 and Tualang honey. In conclusion, both Tualang honey and E2 mediate antidepressive-like effects in stressed OVX rats, possibly acting via restoration of hypothalamic-pituitary-adrenal axis and enhancement of the BDNF concentration.

Tualang honey supplement improves memory performance and hippocampal morphology in stressed ovariectomized rats.

Recently, our research team has reported that Tualang honey was able to improve immediate memory in postmenopausal women comparable with that of estrogen progestin therapy. Therefore the aim of the present study was to examine the effects of Tualang honey supplement on hippocampal morphology and memory performance in ovariectomized (OVX) rats exposed to social instability stress. Female Sprague-Dawley rats were divided into six groups: (i) sham-operated controls, (ii) stressed sham-operated controls, (iii) OVX rats, (iv) stressed OVX rats, (v) stressed OVX rats treated with 17ß-estradiol (E2), and (vi) stressed OVX rats treated with Tualang honey. These rats were subjected to social instability stress procedure followed by novel object recognition (NOR) test. Right brain hemispheres were subjected to Nissl staining. The number and arrangement of pyramidal neurons in regions of CA1, CA2, CA3 and the dentate gyrus (DG) were recorded. Two-way ANOVA analyses showed significant interactions between stress and OVX in both STM and LTM test as well as number of Nissl-positive cells in all hippocampal regions. Both E2 and Tualang honey treatments improved both short-term and long-term memory and enhanced the neuronal proliferation of hippocampal CA2, CA3 and DG regions compared to that of untreated stressed OVX rats.

Effect of melatonin supplementation and cross-fostering on renal glutathione system and development of hypertension in spontaneously hypertensive rats.

Antenatal and postnatal environments are hypothesised to influence the development of hypertension. This study investigates the synergistic effect of cross-fostering and melatonin supplementation on the development of hypertension and renal glutathione system in spontaneously hypertensive rats (SHR). In one experiment, 1-day-old male SHR pups were fostered to either SHR (shr-SHR) or Wistar-Kyoto rats, (shr-WKY). In a concurrent experiment, SHR dams were given melatonin in drinking water (10 mg/kg body weight) from day 1 of pregnancy. Immediately following delivery, 1-day-old male pups were fostered either to SHR (Mel-shr-SHR) or WKY (Mel-shr-WKY) dams receiving melatonin supplementation until weaning on day 21. Upon weaning, melatonin supplementation was continued to these pups until the age of 16 weeks. Systolic blood pressures (SBP) were recorded at the age of 4, 6, 8, 12 and 16 weeks. Renal antioxidant activities were measured. Mean SBP of shr-WKY, Mel-shr-SHR and Mel-shr-WKY was significantly lower than that in shr-SHR until the age of 8 weeks. At 12 and 16 weeks of age, mean SBP of Mel-shr-WKY was lower than those in non-treated shr-SHR and shr-WKY pups but was not significantly different from that in Mel-shr-SHR. Renal glutathione peroxidase (GPx) and glutathione S-transferase (GST) activities were significantly higher in Mel-shr-SHR and Mel-shr-WKY at 16 weeks of age. It appears that combination of cross-fostering and melatonin supplementation exerts no synergistic effect on delaying the rise in blood pressure in SHR. The elevated GPx and GST activities are likely to be due to the effect of melatonin supplementation.

Mood and memory function in ovariectomised rats exposed to social instability stress.

This study aims to compare the effects of social instability stress on memory and anxiety- and depressive-like behaviour between sham-operated controls and ovariectomised (OVX) rats. Forty adult female Sprague-Dawley rats (8 weeks old) were randomly divided into four groups, (n = 10 per group). These were non-stressed sham-operated control rats, stressed sham-operated control rats, non-stressed OVX rats, and stressed OVX rats. The rats were subjected to social instability stress procedure for 15 days. Novel object recognition, open field, and forced swim tests were conducted after the stress procedure. Serum estradiol, ACTH and corticosterone levels were measured using commercially available ELISA kits. Lower serum estradiol level and uterine weight with higher weight gain were observed in OVX rats compared to sham-operated controls. Serum ACTH, and corticosterone levels were higher in stressed compared to non-stressed groups. Memory deficit and anxiety- and depressive-like behaviour were significantly increased in stressed compared to non-stressed OVX rats but these changes were not seen in sham-operated controls. These results suggest that the high circulating corticosterone acts synergistically with low circulating estradiol to exert negative effects on mood and memory function.

Association of oxidative stress and memory performance in postmenopausal women receiving estrogen-progestin therapy.

OBJECTIVE: The aim of this study was to examine the association between changes in blood oxidative stress level/activity and changes in memory performance among postmenopausal women. METHODS: This study involved 39 postmenopausal women who received estrogen-progestin therapy (EPT) for 16 weeks. Verbal learning and memory performance were assessed using the Malay Version of Auditory Verbal Learning Test before and after 16 weeks of EPT. Oxidative stress levels/activities before and after 16 weeks of EPT were determined using commercially available kits. Data were analyzed using paired t test and r. P < 0.05 was considered significant. RESULTS: The activities of glutathione peroxidase and catalase were considerably increased (P < 0.05), but the level of 4-hydroxynonenal was notably decreased (P < 0.05), after 16 weeks of EPT. There were positive correlations between changes in plasma superoxide dismutase and changes in trial A2 scores (r = 0.36, P < 0.05), and between changes in the ratio of blood reduced glutathione to oxidized glutathione and changes in trial A2 scores (r = 0.34, P < 0.05). CONCLUSIONS: Sixteen weeks of EPT increase blood antioxidant capacity. However, most of the changes in oxidative stress level/activity are not significantly associated with changes in the memory performance of postmenopausal women.

Metabolic syndrome, its pathophysiology and the role of melatonin.

Metabolic syndrome (MetS) is characterised by symptoms of obesity, insulin resistance, hypertension, dyslipidemia and diabetes mellitus. The pathophysiological mechanisms involved in MetS are complex and involved dysregulation of many biochemical and physiological regulatory mechanisms of the body. Elevated levels of low density lipoproteins like VLDL, and LDL with reduction of HDL seen in patients with MetS contribute to atherogenic dyslipedemia. Melatonin has been suggested to be effective in improving MetS through its anti-hyperlipidemic action. Melatonin reduced both adiposity, and body weight in experimental animal studies and also attenuated weight gain and obesityinduced metabolic alterations and this effect of melatonin is attributed to its anti-oxidative effects. Melatonin administration has been shown to inhibit insulin release by acting through both MT1 and MT2 melatonin receptors present in pancreatic ß-cells. Melatonin also increased insulin sensitivity and glucose tolerance in animals fed with either high fat or high sucrose diet. Melatonin exerts most of its beneficial actions by acting through MT1 and MT2 melatonin receptors present in various tissues of the body and some of the metabolic actions of melatonin have been blocked by melatonin antagonist like luzindole. Ramelteon, the newly available melatonin agonist will also have more promising role in the control of MetS. The numbers of patents are available with regard to treatment of MetS. Drug related to antidepressant fluoxetine is used for treatment of MetS (US Patent No. 2008001400450). Anti-oxidants like S-adenosyl-methionine, Vitamin E, and Vitamin C have been found beneficial in treating MetS (US Patent No. 8063024). Melatonin being a powerful Antioxidant will have a promising role in treating patients with metabolic syndrome.

Melatonin in antinociception: its therapeutic applications.

The intensity of pain sensation exhibits marked day and night variations. Since the intensity of pain perception is low during dark hours of the night when melatonin levels are high, this hormone has been implicated as one of the prime antinociceptive substances. A number of studies have examined the antinociceptive role of melatonin in acute, inflammatory and neuropathic pain animal models. It has been demonstrated that melatonin exerts antinociceptive actions by acting at both spinal cord and supraspinal levels. The mechanism of antinociceptive actions of melatonin involves opioid, benzodiazepine, α(1)- and α(2)-adrenergic, serotonergic and cholinergic receptors. Most importantly however, the involvement of MT(1)/MT(2) melatonergic receptors in the spinal cord has been well documented as an antinociceptive mechanism in a number of animal models of pain perception. Exogenous melatonin has been used effectively in the management of pain in medical conditions such as fibromyalgia, irritable bowel syndrome and migraine and cluster headache. Melatonin has been tried during surgical operating conditions and has been shown to enhance both preoperative and post-operative analgesia. The present review discusses the available evidence indicating that melatonin, acting through MT(1)/MT(2) melatonin receptors, plays an important role in the pathophysiological mechanism of pain.

Arterial stiffness, inflammatory and pro-atherogenic markers in gestational diabetes mellitus.

BACKGROUND: This study aims to determine whether gestational diabetes mellitus (GDM) is associated with increased arterial stiffness, inflammatory and pro-atherogenic markers compared to age matched controls. PATIENTS AND METHODS: This is a cross-sectional study involving 53 pregnant women in the early third trimester of pregnancy consisting of 31 women with normal pregnancy and 22 women with GDM. Subjects were grouped into GDM and control groups based on modified oral glucose tolerance test results; they were considered GDM if fasting blood glucose (FBG) was ≥ 6.1 mmol/L and/or the two hours post-glucose intake was ≥ 7.8 mmol/L. Arterial stiffness was assessed non-invasively using the parameters augmentation index (AIx) obtained via pulse wave analysis and carotid femoral pulse wave velocity (PWV). Tumor necrosis factor alpha (TNF-alpha), high sensitivity C- reactive protein (hsCRP) and plasminogen activator inhibitor-1 (PAI-1) were measured using enzyme linked immunoassay technique (ELISA). Aortic and brachial blood pressure (BP) indices were also recorded. RESULTS: Mean ages and gestational ages (GA) for the control and GDM groups showed no significant differences (31.1 ± 5.68 vs. 32.9 ± 8.46 years; 29.0 ± 2.43 vs. 29.6 ± 1.54 weeks respectively). FBG and 2 hour post-glucose levels were significantly higher in GDM; (5.27 ± 1.19 vs. 3.94 ± 0.44 mmol/L, p < 0.001; 9.66 ± 1.76 vs. 5.68 ± 1.10 mmol/L, p < 0.001). TNF-alpha, PAI-1 and hsCRP levels were significantly higher in GDM compared to controls (0.81 ± 0.15 vs. 0.72 ± 0.13 pg/ml, 54.48 ± 13.07 vs. 36.16 ± 15.58 cm/ml, 7.91 ± 1.16 vs. 6.70 ± 1.45 mg/l respectively). PWV (8.28 ± 1.48 vs. 7.97 ± 1.12) and AIx (16.73 ± 10.98 vs. 16.13 ± 9.64 %) were not significantly different between the two groups. No significant differences were seen for aortic and brachial BP, mean arterial pressure and body mass index. CONCLUSIONS: The inflammatory markers TNF-alpha and hsCRP, and the pro-atherogenic marker PAI-1 were elevated in GDM compared to age matched controls. No significant difference was seen between the two groups in their arterial stiffness.

Improvement in immediate memory after 16 weeks of tualang honey (Agro Mas) supplement in healthy postmenopausal women.

OBJECTIVE: The aim of this study was to evaluate the verbal learning and memory performance of postmenopausal women who received tualang honey (Agro Mas) in comparison with women receiving estrogen plus progestin therapy and untreated controls. METHODS: A total of 102 postmenopausal women were recruited and randomly assigned to three groups: tualang honey (20 g/d)[corrected], estrogen plus progestin therapy (Femoston 1/5), and untreated control. Their verbal learning and memory performances were assessed using the Malay version of the Auditory Verbal Learning Test before and after 16 weeks of intervention. Data were analyzed using the repeated-measures analysis of variance, and a P value of less than 0.05 was considered significant. RESULTS: There were significant differences in the mean scores of total learning as well as the mean scores of trials A1, A5, A6, and A7 between the three groups. There were also significant differences in the overall mean scores of total learning and trials A1 and A5 between both estrogen plus progestin therapy and tualang honey groups when compared with the untreated control group. However, significant differences in the mean score for trials A6 and A7 were only observed between the estrogen plus progestin therapy and untreated control groups. CONCLUSIONS: Postmenopausal women who received tualang honey showed improvement in their immediate memory but not in immediate memory after the interference and delayed recall. This is comparable with the improvement seen in women receiving estrogen plus progestin therapy.