Therapeutic implications and clinical manifestations of thymoquinone.

Thymoquinone (TQ), a natural phytochemical predominantly found in Nigella sativa, has been investigated for its numerous health benefits. TQ showed anti-cancer, anti-oxidant, and anti-inflammatory properties, validated in various disease models. The anti-cancer potential of TQ is goverened by anti-proliferation, cell cycle arrest, apoptosis induction, ROS production, anti-metastasis and anti-angiogenesis, inhibition of cell migration and invasion action. Additionally, TQ exhibited antitumor activity via the modulation of multiple pathways and molecular targets, including Akt, ERK1/2, STAT3, and NF-κB. The present review highlighted the anticancer potential of TQ . We summarize the anti-cancer, anti-oxidant, and anti-inflammatory properties of TQ, focusing on its molecular targets and its promising action in cancer therapy. We further described the molecular mechanisms by which TQ prevents signaling pathways that mediate cancer progression, invasion, and metastasis.

N-acetyl cysteine in the treatment of cannabis use disorder: A systematic review of clinical trials.

BACKGROUND AND AIM: Cannabis is the most consumed illicit drug globally, with a high risk of developing cannabis use disorder (CUD). No approved pharmacological treatment exists for CUD, but N-Acetyl Cysteine (NAC) has shown promising results in different clinical studies. This study aims to conduct a systematic review of NAC clinical trials for the treatment of CUD. METHODS: Systematic review of randomized controlled trials (RCTs) was conducted to determine the effect of NAC for the treatment of cannabis dependence/cannabis use disorder (CUD). Articles were electronically searched across different databases using PubMed, Google Scholar, EMBASE, Cochrane Library, Medline and PsycINFO from inception to June 2021. Several study characteristics, including study duration, sample size, study population and age group, intervention, adverse effects, and outcome measure were extracted. A PICO table was used for data extraction. RESULTS: We included 08 RCTs in the qualitative analysis. The risk of bias (RoB) was assessed according to Cochrane RoB criteria, and a 5 point grading system according to the Oxford Centre for Evidence-Based Medicine was used to rate the methodological quality (level of evidence) of the included articles. Mild and well-tolerated adverse events were reported in the placebo and NAC group. CONCLUSIONS: The studies collectively offer mixed results, although the strength of the evidence available on which to make a recommendation is strong. NAC has shown to be effective in promoting abstinence, medication adherence and reducing cannabis use and craving among cannabis dependent users. This review also suggests recommendations for future research.

Orexin gene expression is downregulated in alcohol dependent rats during acute alcohol withdrawal.

Alcohol use disorders (AUD) are chronic relapsing brain disorder characterized by compulsive and heavy alcohol consumption. During acute withdrawal, patients with AUD display excessive daytime sleepiness, a condition linked to serious life-threatening complications, however, the mechanism is not known. Orexin and melanin-concentrating hormone (MCH) are the two hypothalamic neuropeptides that regulate many behaviors including sleep-wakefulness, and alcohol consumption, reinforcement, and reinstatement. Importantly, loss of orexin neurons causes narcolepsy, a severe sleep disorder with excessive daytime sleepiness. Does acute alcohol withdrawal reduce orexin gene expression? To investigate this, male Sprague-Dawley rats were divided in two groups: Rats were either administered with alcohol, mixed with infant formula (alcohol group) or control mixture containing water and infant formula (Controls) by gastric intubation every 8 h for 4 days using Majchrowicz's chronic binge drinking protocol. The doses of alcohol were adjusted depending on degree of intoxication, exhibited by animals, prior to each dose. The animals were euthanized after 12 h of last alcohol/water administration. During withdrawal, the hypothalamus was rapidly dissected out, and the expressions of orexin and MCH genes were examined by Real-time PCR. There was a significant reduction in orexin gene expression in rats subjected to alcohol withdrawal as compared to controls. No such change was observed in the MCH gene expression. These results suggest that downregulation of orexin gene expression may be a possible mechanism responsible for excessive daytime sleepiness associated with alcohol withdrawal in patients with AUD.

Melatonin promotes sleep in mice by inhibiting orexin neurons in the perifornical lateral hypothalamus.

Melatonin promotes sleep. However, the underlying mechanisms are unknown. Orexin neurons in the perifornical lateral hypothalamus (PFH) are pivotal for wake promotion. Does melatonin promote sleep by inhibiting orexin neurons? We used C57BL/6J mice and designed 4 experiments to address this question. Experiment 1 used double-labeled immunofluorescence and examined the presence of melatonin receptors on orexin neurons. Second, mice, implanted with bilateral guides targeted toward PFH and sleep-recording electrodes, were infused with melatonin (500 pmole/50 nL/side) at dark onset (onset of active period), and spontaneous bouts of sleep-wakefulness were examined. Third, mice, implanted with bilateral guides into the PFH, were infused with melatonin (500 pmole/50 nL/side) at dark onset and euthanized 2 hours later, to examine the activation of orexin neurons using c-Fos expression in orexin neurons. Fourth, mice, implanted with PFH bilateral guides and sleep-recording electrodes, were infused with melatonin receptor antagonist, luzindole (10 pmol/50 nL/side), at light onset (onset of sleep period), and spontaneous bouts of sleep-wakefulness were examined. Our results suggest that orexin neurons express MT1, but not MT2 receptors. Melatonin infusion into the PFH, at dark onset, site-specifically and significantly increased NREM sleep (43.7%, P = .003) and reduced wakefulness (12.3%, P = .013). Local melatonin infusion at dark onset inhibited orexin neurons as evident by a significant reduction (66%, P = .0004) in the number of orexin neurons expressing c-Fos. Finally, luzindole infusion-induced blockade of melatonin receptors in PFH at sleep onset significantly increased wakefulness (44.1%, P = .015). Based on these results, we suggest that melatonin may act via the MT1 receptors to inhibit orexin neurons and promote sleep.

Neural activation patterns underlying basolateral amygdala influence on intra-accumbens opioid-driven consummatory versus appetitive high-fat feeding behaviors in the rat.

The present study explored the role of the amygdala in mediating a unique pattern of feeding behavior driven by intra-accumbens (intra-Acb) opioid activation in the rat. Temporary inactivation of the basolateral amygdala (BLA), via GABAA agonist muscimol administration prevents increased consumption following intra-Acb opioid administration of the selective µ-opioid agonist D-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO), yet leaves food approach behaviors intact, particularly after consumption has ended. One interpretation is that inactivation of the BLA selectively blocks neural activity underlying DAMGO-driven consummatory (consumption) but not appetitive (approach) behaviors. The present experiments take advantage of this temporal dissociation of consumption and approach behaviors to investigate their associated neural activity. Following either intra-Acb saline or DAMGO administration, with or without BLA muscimol administration, rats were given 2-hr access to a limited amount of high-fat diet. Immediately following the feeding session, rats were sacrificed and brains assayed for neural activity patterns across critical brain regions known to regulate both appetitive and consummatory feeding behaviors. The results show that intra-Acb DAMGO administration increased c-Fos activation in orexin neurons within the perifornical area of the hypothalamus and that this increase in activation is blocked by BLA muscimol inactivation. Intra-Acb DAMGO administration significantly increased c-Fos activation within dopaminergic neurons of the ventral tegmental area, compared to saline controls, and BLA inactivation had no effect on this increase. Overall, these data provide underlying circuitry that may mediate the selective influence of the BLA on driving consummatory, but not appetitive, feeding behaviors in a model of hedonically driven feeding behavior.

Is previous exposure to hepatitis B a risk factor for pancreatic cancer or hepatocellular carcinoma?

GOALS: We evaluated whether prior infection with the hepatitis B virus (HBV) influences the development of pancreatic cancer or hepatocellular carcinoma (HCC). BACKGROUND: Prior infection with HBV may predispose patients to developing pancreatic cancer or HCC. STUDY: We conducted a retrospective cohort study using administrative data from an integrated health care system. We identified all patients who had HBV testing over a 13-year period. These patients were divided into 1 of 3 cohorts based on HBV status: negative infection (n=28,719), previous exposure (n=5141), or active infection (n=404). Pancreatic cancer and HCC data were obtained from pathology reports in the health system's cancer registry. RESULTS: In a multivariable model, age [hazards ratio (HR), 1.08; confidence interval (CI), 1.06-1.09; P<0.001)] and presence of diabetes (HR, 1.88; CI, 1.27-2.80; P=0.002) were identified to have significant influence on pancreatic cancer development, whereas previous HBV exposure did not have a significant influence (HR, 1.41; CI, 0.88-2.27; P=0.16). In a separate multivariable model, male sex (HR, 2.05; CI, 1.35-3.11; P<0.001), age (HR, 1.08; CI, 1.06-1.09; P<0.001), being hepatitis C positive (HR, 5.40; CI, 3.51-8.33; P<0.001), and presence of cirrhosis (HR, 27.84; CI, 17.43-44.46, P<0.001) were all significant predictors of HCC. However, previous HBV exposure was not associated with HCC development (HR, 1.03; CI, 0.68-1.56; P=0.88). CONCLUSIONS: Data from this study indicate that previous HBV exposure is not a risk factor for the development of either pancreatic cancer or HCC.

Role of adenosine and the orexinergic perifornical hypothalamus in sleep-promoting effects of ethanol.

STUDY OBJECTIVES: Strong clinical and preclinical evidence suggests that acute ethanol promotes sleep. However, very little is known about how and where ethanol acts to promote sleep. We hypothesized that ethanol may induce sleep by increasing extracellular levels of adenosine and inhibiting orexin neurons in the perifornical hypothalamus. DESIGN: Experiments 1 and 2: Within-Subject Design; Experiment 3: Between-Subject Design. SETTING: N/A. PATIENTS OR PARTICIPANTS: N/A. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Using adult male Sprague-Dawley rats as our animal model, we performed three experiments to test our hypothesis. Our first experiment examined the effect of A1 receptor blockade in the orexinergic perifornical hypothalamus on sleep- promoting effects of ethanol. Bilateral microinjection of the selective A1 receptor antagonist 1,3-dipropyl-8-phenylxanthine (500 µM; 250 nL/side) into orexinergic perifornical hypothalamus significantly reduced nonrapid eye movement sleep with a concomitant increase in wakefulness, suggesting that blockade of adenosine A1 receptor attenuates ethanol-induced sleep promotion. Our second experiment examined adenosine release in the orexinergic perifornical hypothalamus during local ethanol infusion. Local infusion of pharmacologically relevant doses of ethanol significantly and dose-dependently increased adenosine release. Our final experiment used c-Fos immunohistochemistry to examine the effects of ethanol on the activation of orexin neurons. Acute ethanol exposure significantly reduced the number of orexin neurons containing c-Fos, suggesting an inhibition of orexin neurons after ethanol intake. CONCLUSIONS: Based on our results, we believe that ethanol promotes sleep by increasing adenosine in the orexinergic perifornical hypothalamus, resulting in A1 receptor-mediated inhibition of orexin neurons.