A previously reported study highlighted the neuroprotective potential of the novel benzylideneacetophenone derivative, JC3, in mice. In pursuit of compounds with even more robust neuroprotective and anti-inflammatory properties compared to JC3, we synthesized substituted 1,3-diphenyl-2-propen-1-ones based on chalcones. Molecular modeling studies aimed at discerning the chemical structural features conducive to heightened biological activity revealed that JCII-8,10,11 exhibited the widest HOMOLUMO gap within this category, indicating facile electron and radical transfer between HOMO and LUMO in model assessments.From the pool of synthesized compounds, JCII-8,10,11 were selected for the present investigation. The biological assays involving JCII-8,10,11 demonstrated their concentration-dependent suppression of iNOS and COX-2 protein levels, alongside various cytokine mRNA expressions in LPS-induced murine microglial BV2 cells. Furthermore, western blot analyses were conducted to investigate the MAPK pathways and NF-κB/p65 nuclear translocation. These evaluations conclusively confirmed the inflammatory inhibition effects in both in vitro and in vivo inflammation models. These findings establish JCII-8,10,11 as potent anti-inflammatory agents, hindering inflammatory mediators and impeding NF-κB/p65 nuclear translocation via JNK and ERK MAPK phosphorylation in BV2 cells. The study positions them as potential therapeutics for inflammation-related conditions. Additionally, JCII-11 exhibited greater activity compared to other tested JCII compounds.

A previously reported study highlighted the neuroprotective potential of the novel benzylideneacetophenone derivative, JC3, in mice. In pursuit of compounds with even more robust neuroprotective and anti-inflammatory properties compared to JC3, we synthesized substituted 1,3-diphenyl-2-propen-1-ones based on chalcones. Molecular modeling studies aimed at discerning the chemical structural features conducive to heightened biological activity revealed that JCII-8,10,11 exhibited the widest HOMOLUMO gap within this category, indicating facile electron and radical transfer between HOMO and LUMO in model assessments.From the pool of synthesized compounds, JCII-8,10,11 were selected for the present investigation. The biological assays involving JCII-8,10,11 demonstrated their concentration-dependent suppression of iNOS and COX-2 protein levels, alongside various cytokine mRNA expressions in LPS-induced murine microglial BV2 cells. Furthermore, western blot analyses were conducted to investigate the MAPK pathways and NF-κB/p65 nuclear translocation. These evaluations conclusively confirmed the inflammatory inhibition effects in both in vitro and in vivo inflammation models. These findings establish JCII-8,10,11 as potent anti-inflammatory agents, hindering inflammatory mediators and impeding NF-κB/p65 nuclear translocation via JNK and ERK MAPK phosphorylation in BV2 cells. The study positions them as potential therapeutics for inflammation-related conditions. Additionally, JCII-11 exhibited greater activity compared to other tested JCII compounds.

A previously reported study highlighted the neuroprotective potential of the novel benzylideneacetophenone derivative, JC3, in mice. In pursuit of compounds with even more robust neuroprotective and anti-inflammatory properties compared to JC3, we synthesized substituted 1,3-diphenyl-2-propen-1-ones based on chalcones. Molecular modeling studies aimed at discerning the chemical structural features conducive to heightened biological activity revealed that JCII-8,10,11 exhibited the widest HOMOLUMO gap within this category, indicating facile electron and radical transfer between HOMO and LUMO in model assessments.From the pool of synthesized compounds, JCII-8,10,11 were selected for the present investigation. The biological assays involving JCII-8,10,11 demonstrated their concentration-dependent suppression of iNOS and COX-2 protein levels, alongside various cytokine mRNA expressions in LPS-induced murine microglial BV2 cells. Furthermore, western blot analyses were conducted to investigate the MAPK pathways and NF-κB/p65 nuclear translocation. These evaluations conclusively confirmed the inflammatory inhibition effects in both in vitro and in vivo inflammation models. These findings establish JCII-8,10,11 as potent anti-inflammatory agents, hindering inflammatory mediators and impeding NF-κB/p65 nuclear translocation via JNK and ERK MAPK phosphorylation in BV2 cells. The study positions them as potential therapeutics for inflammation-related conditions. Additionally, JCII-11 exhibited greater activity compared to other tested JCII compounds.

Phytoceramide (Pcer) is found mainly in plants and yeast. It can be neuroprotective and immunostimulatory on various cell types. In this study, the therapeutic effect of Pcer was explored using the carrageenan/kaolin (C/K)-induced arthritis rat model and fibroblast-like synoviocytes (FLS). Pcer treatment (1, 10, and 30 mg/kg/day) were given to the arthritic rats for 6 days after disease induction. Weight distribution ration (WDR), knee thickness, squeaking score, serum levels of proinflammatory mediators, and histological analysis were measured and performed to evaluate arthritic symptoms in the rat model. In interleukin (IL)‑1β‑stimulated FLS, proinflammatory mediators were measured after Pcer (1-30 µM) treatment. Arthritic symptoms in rats with Pcer treatment were significantly decreased at days 4 to 6 after C/K arthritis induction. Inflammation in the knee joints were also significantly decreased in rats with Pcer treatment. Furthermore, in IL-1β‑stimulated FLS, the expressions of proinflammatory mediators were also inhibited by Pcer. As shown by the results, Pcer has anti-arthritic effects in the C/K rat model and in synovial cells, suggesting that Pcer has the potential to be a useful agent in arthritis treatment.

Fumonisin B1 (FB1) structurally resembles sphingolipids and interferes with their metabolism leading to sphingolipid dysregulation. We questioned if FB1 could exacerbate liver or kidney toxicities in glutathione peroxidase 1 (Gpx1) and catalase (Cat) knockout mice. While higher serum levels of thiobarbituric acid reactive substances (TBARS) and sphinganine (Sa) were measured in Gpx1/Cat knockout mice (Gpx1/Cat KO) than wild type mice after 5 days of FB1 treatment, serum levels of alanine aminotransferase (ALT), sphingosine-1 phosphate (So-1-P), and sphinganine-1 phosphate (Sa-1-P) were found to be relatively low. Although Sa was highly elevated in Gpx1/Cat KO mice and wild mice, lower levels of So and Sa were found in both the kidney and liver tissues of Gpx/Cat KO mice than wild type mice after FB1 treatment. Paradoxically, FB1-induced cellular apoptosis and necrosis were hastened under oxidative stress in Gpx1/Cat KO mice.

Fangchinoline (FAN) is a bisbenzylisoquinoline alkaloid that is widely known for its anti-tumor properties. The goal of this study is to examine the effects of FAN on arthritis and the possible pathways it acts on. Human fibroblast-like synovial cells (FLS), carrageenan/kaolin arthritis rat model (C/K), and collagen-induced arthritis (CIA) mice model were used to establish the efficiency of FAN in arthritis. Human FLS cells were treated with FAN (1, 2.5, 5, 10 μM) 1 h before IL-1β (10 ng/mL) stimulation. Cell viability, reactive oxygen species measurement, and western blot analysis of inflammatory mediators and the MAPK and NF-κB pathways were performed. In the animal models, after induction of arthritis, the rodents were given 10 and 30 mg/kg of FAN orally 1 h before conducting behavioral experiments such as weight distribution ratio, knee thickness measurement, squeaking score, body weight measurement, paw volume measurement, and arthritis index measurement. Rodent knee joints were also analyzed histologically through H&E staining and safranin staining. FAN decreased the production of inflammatory cytokines and ROS in human FLS cells as well as the phosphorylation of the MAPK pathway and NF-κB pathway in human FLS cells. The behavioral parameters in the C/K rat model and CIA mouse model and inflammatory signs in the histological analysis were found to be ameliorated in FAN-treated groups. Cartilage degradation in CIA mice knee joints were shown to have been suppressed by FAN. These findings suggest that fangchinoline has the potential to be a therapeutic source for the treatment of rheumatoid arthritis.

Sleep is the most basic and essential physiological requirement for mental health, and sleep disorders pose potential risks of metabolic and neurodegenerative diseases. Tryptic hydrolysate of α(S1)-casein (α(S1)-CH) has been shown to possess stress relieving and sleep promoting effects. However, the differential effects of α(S1)-CH on electroencephalographic wave patterns and its effects on the protein levels of γ-aminobutyric acid A (GABA(A)) receptor subtypes in hypothalamic neurons are not well understood. We found α(S1)-CH (120, 240 mg/kg) increased sleep duration in mice and reduced sleep-wake cycle numbers in rats. While α(S1)-CH (300 mg/kg) increased total sleeping time in rats, it significantly decreased wakefulness. In addition, electroencephalographic theta (θ) power densities were increased whereas alpha (α) power densities were decreased by α(S1)-CH (300 mg/kg) during sleep-wake cycles. Furthermore, protein expressions of GABA(A) receptor β1 subtypes were elevated in rat hypothalamus by α(S1)-CH. These results suggest α(S1)-CH, through GABA(A) receptor modulation, might be useful for treating sleep disorders.
Animals ; Caseins* ; Electroencephalography ; Hypothalamus ; Mental Health ; Mice ; Neurodegenerative Diseases ; Neurons ; Rats ; Receptors, GABA-A* ; Sleep Wake Disorders ; Wakefulness

Although drugs such as barbiturates and benzodiazepines are often used for the treatment of insomnia, they are associated with various side effects such as habituations, tolerance and addiction. Alternatively, natural products with minimal unwanted effects have been preferred for the treatment of acute and/or mild insomnia, with additional benefits of overall health-promotion. Basic and clinical researches on the mechanisms of action of natural products have been carried out so far in insomnia treatments. Recent studies have been focusing on diverse chemical components available in natural products, with an interest of developing drugs that can improve sleep duration and quality. In the last 15 years, our co-workers have been actively looking for candidate substances from natural products that can relieve insomnia. This review is, therefore, intended to bring pharmacological data regarding to the effects of natural products on sleep duration and quality, mainly through the activation of GABAA receptors. It is imperative that phytochemicals will provide useful information during electroencephalography (EEG) analysis and serve as an alternative medications for insomnia patients who are reluctant to use conventional drugs.
Barbiturates ; Benzodiazepines ; Biological Products* ; Electroencephalography ; Humans ; Phytochemicals ; Sleep Initiation and Maintenance Disorders

Cocaine- and amphetamine-regulated transcript (CART) peptide is a widely distributed neurotransmitter expressed in the central nervous systems. Previously, several reports demonstrated that nucleus accumbal-injected CART peptide positively modulated behavioral sensitization induced by psychostimulants and regulated the mesocorticolimbic dopaminergic pathway. It is confirmed that CART peptide exerted inhibitory effect on psychostimulant-enhanced dopamine receptors signaling, Ca2+/calmodulin-dependent kinase signaling and crucial transcription factors expression. Besides modulation of dopamine receptors-related pathways, CART peptide also exhibited elaborated interactions with other neurotransmitter receptors, such as glutamate receptors and γ-aminobutyric acid receptors, which further account for attribution of CART peptide to inhibition of psychostimulant-potentiated locomotor activity. Recently, CART peptide has been shown to have anxiolytic functions on the aversive mood and uncontrolled drug-seeking behaviors following drug withdrawal. Moreover, microinjection of CART peptide has been shown to have an anti-depressant effect, which suggests its potential utility in the mood regulation and avoidance of depression-like behaviors. In this review, we discuss CART pathways in neural circuits and their interactions with neurotransmitters associated with psychostimulant-induced depression.
Central Nervous System ; Depression* ; Dopamine ; Drug-Seeking Behavior ; Microinjections ; Motor Activity ; Neurotransmitter Agents ; Phosphotransferases ; Receptors, Dopamine ; Receptors, Glutamate ; Receptors, Neurotransmitter ; Transcription Factors

The aim of the present study was to identify a new candidate anti-inflammatory compound for use in the active stage of thyroid-associated ophthalmopathy (TAO). Benzylideneacetophenone compound JC3 [(2E)-3-(4-hydroxy-3-methoxyphenyl)phenylpro-2-en-l-one] was synthesized based on a structural modification of yakuchinone B, a constituent of the seeds of Alpinia oxyphylla, which belongs to the ginger family (Zingiberaceae), has been widely used in folk medicine as an anti-inflammatory phytochemical. Orbital fibroblasts were primarily cultured from patients with TAO, and the potential of JC3 to suppress the interferon (IFN)-gamma-induced protein (IP)-10/CXCL10 production in these cells was determined. IFN-gamma strongly increased the level of IP-10/CXCL10 in orbital fibroblasts from patients with TAO. JC3 exerted a significant inhibitory effect on the IFN-gamma-induced increase in IP-10/CXCL10 in a dose-dependent manner; its potency was greater than that of an identical concentration of yakuchinone B with no toxicity to cells at the concentration range used. Moreover, the constructed dimer and trimer polystructures of JC3, showed greater potency than JC3 in suppressing the IFN-gamma-induced production of IP-10/CXCL10. JC3 significantly attenuated the IP-10/CXCL10 mRNA expression induced by IFN-gamma, and a gel-shift assay showed that JC3 suppressed IFN-gamma-induced DNA binding of signal transducer and activator of transcription-1 (STAT-1) in TAO orbital fibroblasts. Our results provide initial evidence that the JC3 compound reduces the levels of IP-10/CXCL10 protein and mRNA induced by IFN-gamma in orbital fibroblasts of TAO patients. Therefore, JC3 might be considered as a future candidate for therapeutic application in TAO that exerts its effects by modulating the pathogenic mechanisms in orbital fibroblasts.
Cells, Cultured ; Chalcone/chemical synthesis/*pharmacology ; Chemokine CXCL10/genetics/*metabolism ; Diarylheptanoids/chemistry/pharmacology ; Fibroblasts/*drug effects/metabolism ; Graves Ophthalmopathy/*metabolism ; Humans ; Interferon-gamma/*metabolism ; Orbit/cytology ; RNA, Messenger/genetics/metabolism ; STAT1 Transcription Factor/genetics/*metabolism