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The in-situ activation of adaptive immunity at the surgical site has demonstrated remarkable efficacy in inhibiting various forms of tumour recurrence and even holds the promise of a potential cure. However, extensive research and bioinformatic analysis conducted in this study have unveiled the formidable challenge posed by melanoma-intrinsic β-catenin signaling, which hinders the infiltration of cytotoxic T-lymphocytes (CTLs) and their subsequent anti-tumour action. To overcome this obstacle, a β-catenin antagonist called carnosic acid (CA) was co-assembled with a RADA-rich peptide to create a nanonet-derived hydrogel known as Supra-gelδCA. This injectable hydrogel is designed to be retained at the surgical site while simultaneously promoting hemostasis. Importantly, Supra-gelδCA directly releases CA to the site of residual tumour lesions, thereby enhancing infiltration of CTLs and subsequently activating adaptive immunity. Consequently, it effectively suppresses postoperative recurrence of skin cutaneous melanoma (SKCM) in vivo. Collectively, the presented Supra-gelδCA not only provides an efficacious immunotherapy strategy for regulating adaptive immunity by overcoming the obstacle posed by melanoma-intrinsic β-catenin signaling-induced absence of CTLs but also offers a clinically translatable hydrogel that revolutionizes post-surgical management of SKCM. [Display omitted] [ABSTRACT FROM AUTHOR]

ABSTRACT Carnosic acid (CA) is recognized as an antioxidant that confers protection to plants against various forms of oxidative stress, including UV‐B stress. However, limited research has been conducted to elucidate the molecular mechanisms underlying its defence against UV‐B stress. In this study, we demonstrated that CA exhibits more efficacy compared to other antioxidants in UV‐B resistance. Moreover, CA was found to enhance the accumulation of secondary metabolites in Arabidopsis leaves. Through the analysis of differentially expressed genes in response to UV‐B stress with or without CA treatment, we uncovered that the exogenous application of CA effectively activates the flavonoid biosynthesis pathway in Arabidopsis to improve resistance of Arabidopsis to UV‐B stress. [ABSTRACT FROM AUTHOR]

The globus pallidus externus (GPe) is a central component of the basal ganglia circuit that acts as a gatekeeper of cocaine-induced behavioral plasticity. However, the molecular and circuit mechanisms underlying this function are unknown. Here, we show that GPe parvalbumin-positive (GPePV) cells mediate cocaine responses by selectively modulating ventral tegmental area dopamine (VTADA) cells projecting to the dorsomedial striatum (DMS). Interestingly, GPePV cell activity in cocaine-naive mice is correlated with behavioral responses following cocaine, effectively predicting cocaine sensitivity. Expression of the voltage-gated potassium channels KCNQ3 and KCNQ5 that control intrinsic cellular excitability following cocaine was downregulated, contributing to the elevation in GPePV cell excitability. Acutely activating channels containing KCNQ3 and/or KCNQ5 using the small molecule carnosic acid, a key psychoactive component of Salvia rosmarinus (rosemary) extract, reduced GPePV cell excitability and impaired cocaine reward, sensitization, and volitional cocaine intake, indicating its therapeutic potential to counteract psychostimulant use disorder. [Display omitted] • Globus pallidus is part of a 4-node circuit controlling cocaine sensitivity • KCNQ3 and KCNQ5 expression is reduced following cocaine administration • Carnosic acid inhibits GPePV cells through activating KCNQ3/5 heteromers • Carnosic acid reduces cocaine reward, sensitization, and self-administration Tian et al. demonstrate that the activity of cells in the mouse globus pallidus can predict neurophysiological and behavioral responses to cocaine. This discovery leads to the identification of carnosic acid, derived from the ancient medicinal plant rosemary, as a potential therapeutic that reduces cocaine reward and self-administration. [ABSTRACT FROM AUTHOR]

Summary: Rosemary extract (RE) is a natural antioxidant, which has been widely used for preservation of oils. The main lipophilic components of RE are carnosic acid (CA) and carnosol (CN). However, the reports on the method for determining CA and CN in vegetable oils are really rare. Herein, a highly efficient method for quantitative analysis of CA and CN in vegetable oils was developed. The vegetable oil samples were dissolved in n‐hexane saturated using acetonitrile and extracted with acetonitrile saturated using n‐hexane, followed by HPLC analysis using UV detector. Qualitative and quantitative determinations were performed by external standard method. Under the optimised conditions, limit of detection (LOD) and limit of quantitation (LOQ) of CA were 0.11 μg mL−1 and 0.55 μg mL−1, respectively; LOD and LOQ of CN were 0.05 μg mL−1 and 0.20 μg mL−1, respectively. When the method was applied to determine CA and CN in vegetable oils spiked with standards, good recoveries (83.98% ~ 102.80% for CA and 98.29% ~ 114.74% for CN) and RSDs (0.61% ~ 7.36% for CA and 0.40% ~ 2.88% for CN, n = 2) were achieved. Accordingly, this work would efficiently identify and monitor lipophilic RE in vegetable oils, as this advanced method showed sensitive, quantitative, and reliable results suited for vegetable oils. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA) is a component of polycarbonate plastics that has been implicated in memory impairment. The present study investigated the effect of carnosic acid (CA) on memory deficit induced by BPA and the role of Akt in this mechanism. First, SH-SY5Y cells were treated with 20 nM BPA and 1 μM CA for 12 h. The results showed that treatment of CA with BPA improved the alternation of IRS-1/Akt/GSK-3β as well as the induction of ApoE and Ser396p-tau. Moreover, treatment of CA with BPA restored the signaling involved in long-term potentiation (LTP) effect, leading to induction of synaptic-related proteins, such as PSD-95, synapsin1a, and pro-BDNF. Wortmannin treatment alleviated the reversal by CA. Then, C57BL/6 J male mice were orally administered with CA to test the memory function in BPA treatment. The results showed that CA and RE can improve BPA-induced impairment of motor, recognition, and spatial memory by using open-field test (OFT), novel objective recognition test (NOR), and Y-maze test, respectively. Moreover, CA and RE improved the phosphorylation of tau and the reduction of PSD-95, synapsin1a, and pro-BDNF proteins induced by BPA. Therefore, the results indicated that CA decreased the phosphorylated tau and memory impairment induced by BPA through Akt pathway. [ABSTRACT FROM AUTHOR]

BACKGROUND: Carnosic acid, a bioactive compound found in rosemary, has been shown to reduce inflammation and reactive oxygen species (ROS). However, its mechanism of action in osteoclast differentiation remains unclear. OBJECTIVE: To investigate the effects of carnosic acid on osteoclast activation, ROS production, and mitochondrial function. METHODS: Primary bone marrow-derived macrophages from mice were extracted and cultured in vitro. Different concentrations of carnosic acid (0, 10, 15, 20, 25 and 30 μmol/L) were tested for their effects on bone marrow-derived macrophage proliferation and toxicity using the cell counting kit-8 cell viability assay to determine a safe concentration. Bone marrow-derived macrophages were cultured in graded concentrations and induced by receptor activator of nuclear factor-κB ligand for osteoclast differentiation for 5-7 days. The effects of carnosic acid on osteoclast differentiation and function were then observed through tartrate-resistant acid phosphatase staining, F-actin staining, H2DCFDA probe and mitochondrial ROS, and Mito-Tracker fluorescence detection. Western blot and RT-PCR assays were subsequently conducted to examine the effects of carnosic acid on the upstream and downstream proteins of the receptor activator of nuclear factor-κB ligand-induced MAPK signaling pathway. RESULTS AND CONCLUSION: Tartrate-resistant acid phosphatase staining and F-actin staining showed that carnosic acid dose-dependently inhibited in vitro osteoclast differentiation and actin ring formation in the cell cytoskeleton, with the highest inhibitory effect observed in the high concentration group (30 μmol/L). Carnosic acid exhibited the most significant inhibitory effect during the early stages (days 1-3) of osteoclast differentiation compared to other intervention periods. Fluorescence imaging using the H2DCFDA probe, mitochondrial ROS, and Mito-Tracker demonstrated that carnosic acid inhibited cellular and mitochondrial ROS production while reducing mitochondrial membrane potential, thereby influencing mitochondrial function. The results of western blot and RT-PCR revealed that carnosic acid could suppress the expression of NFATc1, CTSK, MMP9, and C-fos proteins associated with osteoclast differentiation, and downregulate the expression of NFATc1, Atp6vod2, ACP5, CTSK, and C-fos genes related to osteoclast differentiation. Furthermore, carnosic acid enhanced the expression of antioxidant enzyme proteins and reduced the generation of ROS during the process of osteoclast differentiation. Overall, carnosic acid exerts its inhibitory effects on osteoclast differentiation by inhibiting the phosphorylation modification of the P38/ERK/JNK protein and activating the MAPK signaling pathway in bone marrow-derived macrophages. [ABSTRACT FROM AUTHOR]

In order to reveal the influence of carnosic acid on the quality characteristics of thermal processed rapeseed oil, the changes of color, acid value, peroxide value, tocopherol, viscosity, fatty acid composition and total polar compound were investigated during thermal processing (180 ℃, 0, 8, 16, 24, 32 h) by adding different concentrations of carnosic acid (0, 200, 400, 700 mg/kg) and 200 mg/kg tert-butylhydroquinone as antioxidants. The results indicated that the addition of 700 mg/kg carnosic acid showed a better performance in the thermal processed rapeseed oil: The color deterioration was delayed and the increase of viscosity was inhibited; the increased value of acid value was the smallest which was from 0.280±0.030 mg/g to 0.757±0.020 mg/g, as well as the minimum peroxide value (0.138 g/100 g) was obtained at 32 h; the loss rate of α-tocopherol and γ-tocopherol were 95.51%±0.96% and 83.37%±0.39%, respectively; the content of polar components was 26.62%±0.03%, prolonging the thermal processing life of rapeseed oil by delaying the increase of total polar compound. It was found that the use of carnosic acid could better control the risk factors in rapeseed oil during thermal processing and reduce the waste of oils.

Rheumatoid arthritis (RA), a chronic inflammatory disease, is characterized by joint swelling, cartilage erosion, and bone destruction. This study investigated the therapeutic efficacy of Carnosic acid (CA), a natural compound with anti-inflammatory and antioxidant properties, in an adjuvant-induced arthritis model. Paw swelling and arthritis index were measured. Oxidative stress markers, including lipid peroxidation and antioxidant enzyme levels, were assessed. Synovial tissue was analyzed for pro-inflammatory markers using real-time Q-PCR and Western blotting. The expression of mPGES-1 was determined by Western blotting. Peripheral neuropathic pain was assessed using cold and mechanical allodynia tests. Bone loss was quantitatively assessed through microcomputed tomography (μCT) scanning of femurs and X-ray radiography. Indomethacin-induced gastric ulcers were evaluated. Molecular docking studies were conducted to analyze the binding affinity of CA to mPGES-1. The CA treatment not only demonstrated a significant reduction in joint inflammation and paw swelling but also mitigated oxidative stress and improved the antioxidant defence system. CA inhibited microsomal prostaglandin E synthase-1 (mPGES-1) expression and the expression of pro-inflammatory molecules such as inducible nitric oxide synthase (iNOS) and cyclooxygenases-2 (COX-2), thus attenuating the arthritis symptoms without severe gastrointestinal side effects. Additionally, it inhibited the expression of pro-inflammatory molecules such as iNOS and COX-2, contributing to the reduction of arthritis symptoms. Notably, CA treatment prevented the common side effects of traditional RA treatments like corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs), including weight loss, bone degradation, and gastric ulcers. These findings suggest that CA, through specific enzyme inhibition, offers a compelling alternative therapeutic approach for RA. Further research is warranted to explore the potential of CA in other arthritis models and its suitability for human RA treatment. CA significantly reduces inflammation in FCA induced arthritis model. CA treatment inhibits key pro-inflammatory molecules, including mPGES-1 and COX-2 In silico docking studies confirm the affinity of CA to mPGES-1. CA prevents bone loss and avoids side effects seen with standard treatments. Antioxidant properties of CA counteract oxidative stress related to chronic inflammation. [ABSTRACT FROM AUTHOR]

Featured Application: Utilization of Rosmarinus officinalis extracts and/or its bioactives as ingredients in functional products, foods, cosmetics, and pharmaceuticals, with anti-inflammatory health-promoting neuroprotective effects against inflammation-related neurodegenerative disorders, such as Alzheimer's and Parkinson's Diseases. Neurodegenerative disorders (NDs) are conditions marked by progressively escalating inflammation that leads to the degeneration of neuronal structure and function. There is an increasing interest in natural compounds, especially those from pharmaceutical plants, with neuroprotective properties as part of potential therapeutic interventions. Thus, the rich bioactive content of the perennial herb rosemary (Rosmarinus officinalis) is thoroughly reviewed in this article, with an emphasis on its pleiotropic pharmacological properties, including its antioxidant, anti-inflammatory, and neuroprotective health-promoting effects. In addition, a comprehensive analysis of the existing scientific literature on the potential use of rosemary and its bioactive constituents in treating neurodegenerative disorders was also conducted. Rosemary and its bioactives' chemical properties and neuroprotective mechanisms are discussed, focusing on their ability to mitigate oxidative stress, reduce inflammation, and modulate neurotransmitter activity. The role of rosemary in enhancing cognitive function, attenuating neuronal apoptosis, and promoting neurogenesis is outlined. Key bioactive components, such as rosmarinic acid and carnosic acid, are also highlighted for their neuroprotective act. The promising outcomes of the conducted pre-clinical studies or clinical trials confirm the efficacy of rosemary in preventing or alleviating Alzheimer's and Parkinson's diseases both in vitro (in cells) and in vivo (in animal models of NDs). From this perspective, the applications of rosemary's bio-functional compounds and extracts in the food, cosmetics, and pharmaceutical sectors are also presented; in the latter, we discuss their use against neurodegenerative disorders, either alone or as adjuvant therapies. This paper critically evaluates these studies' methodological approaches and outcomes, providing insights into the current state of the clinical research and identifying potential avenues for future investigation. All findings presented herein contribute to the growing body of literature and support the exploration of natural compounds as promising candidates for novel applications and neuroprotective interventions, paving the way for more applied scientific research. [ABSTRACT FROM AUTHOR]

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6‐phosphogluconate dehydrogenase (6PGD) and Glucose‐6‐phosphate dehydrogenase (G6PD) are crucial enzymes involved in generating cellular reducing power. Modifying the balance of reduced NADPH is considered essential for cancer advancement and combined therapeutic strategies. Usnic acid (UA) is a physiologically active dibenzofuran derivative. Carnosic acid (CA) is a phenolic diterpene that has been isolated from several plants. This work evaluated the inhibitory effects of UA and CA on G6PD and 6PGD by in vitro tests. Molecular docking studies were employed to predict the mechanisms of inhibition. IC50 values for UA and CA were determined to be 49.50 μM and 77.00 μM for G6PD, and 69.30 μM and 57.75 μM for 6PGD, respectively. The Ki values for UA and CA were determined to be 35.01±7.69 μM and 43.46±10.48 μM for G6PD, and 104.87±11.86 μM and 31.17±2.55 μM for 6PGD, respectively. UA was identified as the most effective inhibitor against G6PD, whereas CA exhibited the best inhibitory activity against 6PGD, with estimated binding energies of −8.0 and −7.8 kcal/mol, respectively, in molecular docking studies. Ultimately, it was shown that the results obtained from in vitro and in silico methods in the study were strongly associated. These chemicals′ structure might assist in creating medications that focus on the pentose phosphate pathway. [ABSTRACT FROM AUTHOR]

The aims of the present study were (i) to characterize the dichloromethane extract of the fresh aerial parts of S. somalensis, cultivated in Liguria (Italy), (ii) to quantify carnosic acid production and (iii) to find an eco-friendly alternative approach to control diseases caused by phytopathogenic fungi. The phytochemical investigation yielded several known terpenoids, as well as a diterpene, 4α,9α-epoxy-2H-dibenzo[a,d]cyclohepten-7(5H)-one, not previously described as a plant metabolite before. The results showed a noteworthy quantity of carnosic acid (113.90 µg/mg of dried extract). The potential antifungal activity of the plant surface extract and carnosic acid against five phytopathogenic fungi (Colletotrichum coccodes, Fusarium oxysporum, Sclerotinia sclerotiorum, Botrytis cinerea and Rhizoctonia solani) was considered. A complete inhibition of C. coccodes, S. sclerotiorum and R. solani mycelium growth was observed by carnosic acid at 500 µg/mL. High inhibition values were observed against B. cinerea and F. oxysporum compared to reference active ingredients. Four different B. cinerea strains exhibited a pronounced sensitivity to carnosic acid, as well as those originating from agricultural crop scenarios where a high load of active ingredient for gray mold control was historically adopted. Additionally, the formation and development of the germinative tube in B. cinerea were greatly slowed down. [ABSTRACT FROM AUTHOR]

Adipose tissue plays a crucial role in regulating metabolic homeostasis, and its dysfunction in obesity leads to insulin resistance and type 2 diabetes (T2D). White adipose tissue (WAT) primarily stores energy as lipids, while brown adipose tissue (BAT) regulates thermogenesis by dissipating energy as heat. The process of browning involves the transdifferentiation of WAT into brown-like or beige adipocytes, which exhibit a similar phenotype as BAT. The browning of WAT is an attractive approach against obesity and T2D, and the activation of the energy sensor AMP-activated protein kinase (AMPK) has been shown to play a role in browning. Carnosic acid (CA), a polyphenolic diterpene, found in many plants including rosemary, is reported to possess potent antioxidant, anti-inflammatory, and anti-hyperglycemic properties. The limited evidence available indicates that CA activates AMPK and may have anti-obesity and antidiabetic potential; however, the effects in adipocyte browning remain largely unexplored. This study aimed to examine the effects of CA on the markers of adipocyte browning. The treatment of 3T3L1 adipocytes with CA activated AMPK, reduced lipid accumulation, and increased the expression of browning protein markers (UCP-1, PGC-1α, PRDM16, and TFAM) and mitochondrial biogenesis. The use of compound C, an AMPK inhibitor, significantly attenuated the effects of CA, indicating AMPK involvement. These studies demonstrate that CA can activate AMPK and stimulate the browning of white adipocytes. Future animal and human studies are required to examine the effects of CA in vivo. [ABSTRACT FROM AUTHOR]

Ruellia angustiflora is a shrub popularly known as flower of fire, used in traditional medicine as a healing agent. This study aims to verify the presence of characteristics of pharmaceutical interest in extracts from the root, stem and leaves of this species. The ideal time for ultrasound-assisted extraction is 60 min with a solid-liquid ratio of 1% (w/v). The kinetics of the reaction of the extracts with DPPH is biphasic, and IC50 values are related to the total phenolic compounds. Five phenolic compounds were identified in the extracts, where ferulic acid, rutin and quercetin showed to be the main responsible for the antiradical activity. The extracts displayed considerable photoprotective activity, mainly Ra-LE (SPF = 23). Ra-RE showed an inhibition halo similar to erythromycin against Streptococcus pyogenes. Taken together, these data reveal that Ruellia angustiflora is a source of phenolic compounds and has relevant antiradical, photoprotective and antibacterial activities. [ABSTRACT FROM AUTHOR]

Background: Increased level of serum cholic acid (CA) is often accompanied with decreased CYP2E1 expression in hepatocellular carcinoma (HCC) patients. However, the roles of CA and CYP2E1 in hepatocarcinogenesis have not been elucidated. This study aimed to investigate the roles and the underlying mechanisms of CYP2E1 and CA in HCC cell growth. Methods: The proteomic analysis of liver tumors from DEN-induced male SD rats with CA administration was used to reveal the changes of protein expression in the CA treated group. The growth of CA-treated HCC cells was examined by colony formation assays. Autophagic flux was assessed with immunofluorescence and confocal microscopy. Western blot analysis was used to examine the expression of CYP2E1, mTOR, AKT, p62, and LC3II/I. A xenograft tumor model in nude mice was used to examine the role of CYP2E1 in CA-induced hepatocellular carcinogenesis. The samples from HCC patients were used to evaluate the clinical value of CYP2E1 expression. Results: CA treatment significantly increased the growth of HCC cells and promoted xenograft tumors accompanied by a decrease of CYP2E1 expression. Further studies revealed that both in vitro and in vivo, upregulated CYP2E1 expression inhibited the growth of HCC cells, blocked autophagic flux, decreased AKT phosphorylation, and increased mTOR phosphorylation. CYP2E1 was involved in CA-activated autophagy through the AKT/mTOR signaling. Finally, decreased CYP2E1 expression was observed in the tumor tissues of HCC patients and its expression level in tumors was negatively correlated with the serum level of total bile acids (TBA) and gamma-glutamyltransferase (GGT). Conclusions: CYP2E1 downregulation contributes to CA-induced HCC development presumably through autophagy regulation. Thus, CYP2E1 may serve as a potential target for HCC drug development. [ABSTRACT FROM AUTHOR]

Background: Worldwide, more than 125 million people are infected with Shigella each year and develop shigellosis. In our previous study, we provided evidence that Shigella sonnei infection triggers activation of the NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome in macrophages. NLRP3 inflammasome is responsible for regulating the release of the proinflammatory cytokines interleukin (IL)-1β and IL-18 through the protease caspase-1. Researchers and biotech companies have shown great interest in developing inhibitors of the NLRP3 inflammasome, recognizing it as a promising therapeutic target for several diseases. The leaves of Cinnamomum osmophloeum kaneh, an indigenous tree species in Taiwan, are rich in cinnamaldehyde (CA), a compound present in significant amounts. Our aim is to investigate how CA affects the activation of the NLRP3 inflammasome in S. sonnei-infected macrophages. Methods: Macrophages were infected with S. sonnei, with or without CA. ELISA and Western blotting were employed to detect protein expression or phosphorylation levels. Flow cytometry was utilized to assess H2O2 production and mitochondrial damage. Fluorescent microscopy was used to detect cathepsin B activity and mitochondrial ROS production. Additionally, colony-forming units were employed to measure macrophage phagocytosis and bactericidal activity. Results: CA inhibited the NLRP3 inflammasome in S. sonnei-infected macrophages by suppressing caspase-1 activation and reducing IL-1β and IL-18 expression. CA also inhibited pyroptosis by decreasing caspase-11 and Gasdermin D activation. Mechanistically, CA reduced lysosomal damage and enhanced autophagy, while leaving mitochondrial damage, mitogen-activated protein kinase phosphorylation, and NF-κB activation unaffected. Furthermore, CA significantly boosted phagocytosis and the bactericidal activity of macrophages against S. sonnei, while reducing secretion of IL-6 and tumour necrosis factor following infection. Conclusion: CA shows promise as a nutraceutical for mitigating S. sonnei infection by diminishing inflammation and enhancing phagocytosis and the bactericidal activity of macrophages against S. sonnei. [ABSTRACT FROM AUTHOR]

Background Aflatoxin B1 (AFB1) food contamination is a global health hazard that has detrimental effects on both human and animal health. The objective of the current study is to assess the protective impact of carnosic acid against AFB1-induced toxicities in the liver, kidneys, and heart. Methods Forty male Wistar Albino rats (weighting 180 ~ 200 g) were allocated into 5 groups (8 rats each); the 1st group received saline as served as a control, the 2nd group received carnosic acid (CA100) at a dose of 100 mg/kg bw/day by gavage for 14 days, the 3rd group received AFB1 at a dose of 2.5 mg/kg bw, orally twice on days 12 and 14, the 4th group (AFB1-CA50) received AFB1 as in the 3rd group and CA at a dose of 50 mg/kg bw/day, and the 5th group (AFB1-CA100) received AFB1 as in the 3rd group and CA as in the 2nd group. Results CA significantly decreased the liver enzymes (ALT, AST. ALP), renal function products (LDH, BUN, creatinine), and cardiac enzymes (CK and CK-MB) to control levels after the high increment by AFB1 exposure. Moreover, CA significantly decreased the oxidative stress (MDA, NO, 8-OHdG) and increased the antioxidant enzyme activities (CAT, GSH, GSH-Px, and SOD) after severe disruption of oxidant/antioxidant balance by AFB1 exposure. Interestingly, CA significantly decreased the proinflammatory mediators (IL-6, IL-1β, and TNF-α) to the control levels after severe inflammation induced by AFB1 exposure. Conclusions Conclusively, CA had antioxidant, anti-inflammatory, and anti-DNA damage effects against hepatic, renal, and cardiac AFB1-induced toxicities. [ABSTRACT FROM AUTHOR]

The potential therapeutic effects of carnosic acid (CA) on postinflammatory hyperpigmentation (PIH) were evaluated, including its effects on melanin deposition in zebrafish, melanogenesis and melanosome transfer in skin cells and skin wound healing in mice. Our results demonstrated that CA dose-dependently decreased melanin deposition in the skin of juvenile zebrafishes. It also inhibited melanogenesis in melanoma cells and melanosome transfer to keratinocytes. Next, CA was loaded in a liposome-hydrogel system (LP-GEL) to treat skin wounds in mice. The results showed that CA-LP-GEL, as well as LP-GEL, could accelerate skin wound healing and repair the structure of healing skins in mice. Comparatively, the levels of inflammatory factors (IL-1β and TNF-a) in healing skins were significantly increased by LP-GEL, but reduced by CA-LP-GEL. In addition, Fontana-Masson staining analysis of healing skin showed that the melanoma cells were restored by the treatment of LP-GEL and CA-LP-GEL, while the melanin content was significantly increased only by LP-GEL. Real-time PCR data showed that CA decreased the gene expression related with melanogenesis (MITF, TYR and TRP-1), melanosome transfer (MLPH, Myova and Rab27a) and inflammatory cytokines (IL-1β and TNF-α) in vitro and in vivo. In conclusion, CA could reduce melanin deposition in the skin by inhibiting melanogenesis and melanosome transfer. CA-LP-GEL was found to accelerate skin wound healing and suppress inflammation and hyperpigmentation in mice. These results suggest that CA has a big developing potentiality for PIH treatment.

Alcohol use disorder (AUD) is the most prevalent substance use disorder but there is incomplete knowledge of the underlying molecular etiology. Here, we examined the cytosolic proteome from the nucleus accumbens core (NAcC) of ethanol drinking rhesus macaques to identify ethanol-sensitive signaling proteins. The targets were subsequently investigated using bioinformatics, genetic, and pharmacological manipulations in mouse models of ethanol drinking. Of the 1000+ cytosolic proteins identified in our screen, 50 proteins differed significantly between control and ethanol drinking macaques. Gene Ontology analysis of the differentially expressed proteins identified enrichment in pathways regulating metabolic processes and proteasome activity. Because the family of Glutathione S-transferases (GSTs) was enriched in these pathways, validation studies targeted GSTs using bioinformatics and genetically diverse mouse models. Gstp1 and Gstm2 were identified in Quantitative Trait Loci and published gene sets for ethanol-related phenotypes (e.g., ethanol preference, conditioned taste aversion, differential expression), and recombinant inbred strains that inherited the C57BL/6J allele at the Gstp2 interval consumed higher amounts of ethanol than those that inherited the DBA/2J allele. Genetic deletion of Gstp1/2 led to increased ethanol consumption without altering ethanol metabolism or sucrose preference. Administration of the pharmacologic activator of Gstp1/2, carnosic acid, decreased voluntary ethanol drinking. Proteomic analysis of the NAcC cytosolic of heavy drinking macaques that were validated in mouse models indicate a role for glutathione-mediated redox regulation in ethanol-related neurobiology and the potential of pharmacological interventions targeting this system to modify excessive ethanol drinking.

旨在为迷迭香脂溶性提取物在食用油保鲜方面的应用提供参考，以玉米油提取的迷迭香脂溶性提取物（可作为抗氧化剂）为原料，对其进行脱色处理，以脱色率为指标，通过单因素试验和响应面试验优化脱色工艺条件，并采用高效液相色谱法测定脱色前后迷迭香脂溶性提取物中脂溶性抗氧化成分（鼠尾草酸和鼠尾草酚）的含量。结果表明：与活性白土及活性白土与活性炭复配（质量比1∶ 1、1∶ 2、2∶ 1）脱色剂相比，活性炭对迷迭香脂溶性提取物的脱色效果最好，最佳脱色工艺为活性炭添加量2.1%、脱色温度50 ℃、脱色时间59 min，在此条件下脱色率为(75.02±0.37)%；脱色前后迷迭香脂溶性提取物中脂溶性抗氧化成分含量分别为4.065 5%和3.883 6%。综上，优化条件下迷迭香脂溶性提取物的脱色效果较好，且脱色对其脂溶性抗氧化成分含量影响较小。In order to provide a reference for the application of rosemary fat-soluble extract in the preservation of edible oil, the rosemary fat-soluble extract (which can be used as an antioxidant) extracted by corn oil was decolorized. With the decolorization rate as the index, the decolorization process conditions were optimized by single factor experiment and response surface methodology, and the content of fat-soluble antioxidant components (carnosic acid and carnosic phenol) in rosemary fat-soluble extract before and after decolorization was determined by high performance liquid chromatography. The results showed that activated carbon had the best decolorization effect on rosemary fat-soluble extract compared with activated clay and compound decolorant of activated clay and activated carbon (mass ratio 1∶ 1,1∶ 2,2∶ 1). The optimal decolorization process conditions were as follows: activated carbon dosage2.1%, decolorization temperature 50 ℃, decolorization time 59 min. Under the optimal conditions, the decolorization rate was (75.02±0.37)%. The antioxidant content before and after decolorization in rosemary fat-soluble extract was 4.065 5% and 3.883 6%, respectively. In summary, the decolorization effect of rosemary fat-soluble extract under optimized conditions was better, and the decolorization had little effect on the content of fat-soluble antioxidant components.

Carnosic acid (CA), a diterpene obtained mainly from Rosmarinus officinalis and Salvia officinalis, exerts antioxidant, anti-inflammatory, and anti-apoptotic effects in mammalian cells. At least in part, those benefits are associated with the ability that CA modulates mitochondrial physiology. CA attenuated bioenergetics collapse and redox impairments in the mitochondria obtained from brain cells exposed to several toxicants in both in vitro and in vivo experimental models. CA is a potent inducer of the major modulator of the redox biology in animal cells, the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which controls the expression of a myriad of genes whose products are involved with cytoprotection in different contexts. Moreover, CA upregulates signaling pathways related to the degradation of damaged mitochondria (mitophagy) and with the synthesis of these organelles (mitochondrial biogenesis). Thus, CA may be considered an agent that induces mitochondrial renewal, depending on the circumstances. In this review, we discuss about the mechanisms of action by which CA promotes mitochondrial protection in brain cells. [ABSTRACT FROM AUTHOR]

Fungi are eukaryotic organisms with relatively few pathogenic members dangerous for humans, usually acting as opportunistic infections. In the last decades, several life-threatening fungal infections have risen mostly associated with the worldwide extension of chronic diseases and immunosuppression. The available antifungal therapies cannot combat this challenge because the arsenal of compounds is scarce and displays low selective action, significant adverse effects, and increasing resistance. A growing isolation of outbreaks triggered by fungal species formerly considered innocuous is being recorded. From ancient times, natural substances harvested from plants have been applied to folk medicine and some of them recently emerged as promising antifungals. The most used are briefly revised herein. Combinations of chemotherapeutic drugs with natural products to obtain more efficient and gentle treatments are also revised. Nevertheless, considerable research work is still necessary before their clinical use can be generally accepted. Many natural products have a highly complex chemical composition, with the active principles still partially unknown. Here, we survey the field underlying lights and shadows of both groups. More studies involving clinical strains are necessary, but we illustrate this matter by discussing the potential clinical applications of combined carnosic acid plus propolis formulations. [ABSTRACT FROM AUTHOR]

The presence of mutagenic and carcinogenic N-nitrosamine impurities in medicinal products poses a safety risk. While incorporating antioxidants in formulations is a potential mitigation strategy, concerns arise regarding their interference with drug absorption by inhibiting intestinal drug transporters. Our study screened thirty antioxidants for inhibitory effects on key intestinal transporters—OATP2B1, P-gp, and BCRP in HEK-293 cells (OATP2B1) or membrane vesicles (P-gp, BCRP) using 3H-estrone sulfate, 3H-N-methyl quinidine, and 3H-CCK8 as substrates, respectively. The screen identified that butylated hydroxyanisole (BHA) and carnosic acid inhibited all three transporters (OATP2B1, P-gp, and BCRP), while ascorbyl palmitate (AP) inhibited OATP2B1 by more than 50%. BHA had IC50 values of 71 ± 20 µM, 206 ± 14 µM, and 182 ± 49 µM for OATP2B1, BCRP, and P-gp, respectively. AP exhibited IC50 values of 23 ± 10 µM for OATP2B1. The potency of AP and BHA was tested with valsartan, an OATP2B1 substrate, and revealed IC50 values of 26 ± 17 µM and 19 ± 11 µM, respectively, in HEK-293-OATP2B1 cells. Comparing IC50 values of AP and BHA with estimated intestinal concentrations suggests an unlikely inhibition of intestinal transporters at clinical concentrations of drugs formulated with antioxidants. [ABSTRACT FROM AUTHOR]

Acquiring resistance against antiviral drugs is a significant problem in antimicrobial therapy. In order to identify novel antiviral compounds, the antiviral activity of eight plants indigenous to the southern region of Hungary against herpes simplex virus-2 (HSV-2) was investigated. The plant extracts and the plant compound carnosic acid were tested for their effectiveness on both the extracellular and intracellular forms of HSV-2 on Vero and HeLa cells. HSV-2 replication was measured by a direct quantitative PCR (qPCR). Among the tested plant extracts, Salvia rosmarinus (S. rosmarinus) exhibited a 90.46% reduction in HSV-2 replication at the 0.47 μg/mL concentration. Carnosic acid, a major antimicrobial compound found in rosemary, also demonstrated a significant dose-dependent inhibition of both extracellular and intracellular forms of HSV-2. The 90% inhibitory concentration (IC90) of carnosic acid was between 25 and 6.25 μg/mL. Proteomics and high-resolution respirometry showed that carnosic acid suppressed key ATP synthesis pathways such as glycolysis, citrate cycle, and oxidative phosphorylation. Inhibition of oxidative phosphorylation also suppressed HSV-2 replication up to 39.94-fold. These results indicate that the antiviral action of carnosic acid includes the inhibition of ATP generation by suppressing key energy production pathways. Carnosic acid holds promise as a potential novel antiviral agent against HSV-2. [ABSTRACT FROM AUTHOR]

Prostate cancer, accounting for 375,304 deaths in 2020, is the second most prevalent cancer in men worldwide. While many treatments exist for prostate cancer, novel therapeutic agents with higher efficacy are needed to target aggressive and hormone-resistant forms of prostate cancer, while sparing healthy cells. Plant-derived chemotherapy drugs such as docetaxel and paclitaxel have been established to treat cancers including prostate cancer. Carnosic acid (CA), a phenolic diterpene found in the herb rosemary (Rosmarinus officinalis) has been shown to have anticancer properties but its effects in prostate cancer and its mechanisms of action have not been examined. CA dose-dependently inhibited PC-3 and LNCaP prostate cancer cell survival and proliferation (IC50: 64, 21 µM, respectively). Furthermore, CA decreased phosphorylation/activation of Akt, mTOR, and p70 S6K. A notable increase in phosphorylation/activation of AMP-activated kinase (AMPK), acetyl-CoA carboxylase (ACC) and its upstream regulator sestrin-2 was seen with CA treatment. Our data indicate that CA inhibits AKT-mTORC1-p70S6K and activates Sestrin-2-AMPK signaling leading to a decrease in survival and proliferation. The use of inhibitors and small RNA interference (siRNA) approaches should be employed, in future studies, to elucidate the mechanisms involved in carnosic acid's inhibitory effects of prostate cancer. [ABSTRACT FROM AUTHOR]

Objective(s): Utilization of doxorubicin (DOX) as a chemotherapy medication is limited due to its cardiotoxic effects. Carnosic acid exerts antioxidant, anti-inflammatory, besides cytoprotective effects. The objective of this study was to investigate the ability of carnosic acid to protect rat hearts and the MCF7 cell line against cardiotoxicity induced by DOX. Materials and Methods: The study involved the classification of male Wistar rats into seven groups: 1) Control 2) DOX (2 mg/kg, every 48h, IP, 12d), 3-5) Carnosic acid (10, 20, 40 mg/kg/day, IP, 16d)+ DOX, 6) Vitamin E (200 mg/kg, every 48h, IP, 16d)+ DOX 7) Carnosic acid (40 mg/kg/day, IP, 16d). Finally, cardiac histopathological alterations, ECG factors, carotid blood pressure, left ventricular function, heart-to-body weight ratio, oxidative (MDA, GSH), inflammatory (IL-1β, TNF-α), plus apoptosis (caspase 3, 8, 9, Bcl-2, Bax) markers were evaluated. DOX toxicity and carnosic acid ameliorative effect were evaluated on MCF7 cells using the MTT assay. Results: DOX augmented the QRS duration, QA, RRI, STI, and heart-to-body weight ratio, and reduced HR, LVDP, Min dP/dt, Max dP/dt, blood pressure, boosted MDA, TNF-a, IL1-ß, caspase 3,8,9, Bax/Bcl-2 ratio, decreased GSH content, caused fibrosis, necrosis, and cytoplasmic vacuolization in cardiac tissue but carnosic acid administration reduced the toxic effects of DOX. The cytotoxic effects of DOX were not affected by carnosic acid at concentrations of 5 and 10 μM. Conclusion: Carnosic acid as an anti-inflammatory and antioxidant substance is effective in reducing DOX-induced damage by enhancing antioxidant defense and modifying inflammatory signal pathway activity and can be used as an adjunct in treating DOX cardiotoxicity. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Health Sciences / Sağlık Bilimleri Dergisi is the property of Erciyes Universitesi Saglik Bilimleri Dergisi and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Biofungicides arise as a promising alternative to the indiscriminate use of harmful synthetic fungicides in crop management. Results: The present study reports the bio‐guided fractionation of an endemic plant from the Canary Islands, Salvia canariensis against the phytopathogens, Alternaria alternata, Botrytis cinerea, and Fusarium oxysporum. This procedure allowed identifying a series of diterpenoids with an abietane skeleton (1–5), which exhibited remarkable activity against the phytopathogenic fungi assayed. Their structures were established by means of spectroscopic and spectrometric methods, as well as comparison with reported data. Compounds 2 (carnosic acid), 4 (11‐acetoxy carnosic acid) and 5 (11,12‐diacetoxy carnosic acid) showed significant mycelium growth inhibition (%GI > 50 at 0.1 mg/mL concentration) on all the assayed fungi, and with a potency also higher than the positive control, Fosbel‐Plus, a fungicide commonly used in agriculture. A preliminary structure–activity relationship is also discussed. Conclusions: These findings underline the aromatic abietane diterpenoids as promising eco‐friendly alternatives to conventional fungicides to use in integrated pest management. © 2024 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Background: Cardiac arrest (CA) is a significant public health concern. There is the high imminent mortality and survival in those who are resuscitated is substantively compromised by the post-CA syndrome (PCAS), characterized by multiorgan ischemia-reperfusion injury (IRI). The inflammatory response in PCAS is complex and involves various immune cell types, including lymphocytes and myeloid cells that have been shown to exacerbate organ IRI, such as myocardial infarction. Purinergic signaling, as regulated by CD39 and CD73, has emerged as centrally important in the context of organ-specific IRI. Hence, comprehensive understanding of such purinergic responses may be likewise imperative for improving outcomes in PCAS. Methods: We have investigated alterations of immune cell populations after CA by utilizing rodent models of PCAS. Blood and spleen were collected after CA and resuscitation and underwent flow cytometry analysis to evaluate shifts in CD3+CD4+ helper T cells, CD3+CD8a+ cytotoxic T cells, and CD4/CD8a ratios. We then examined the expression of CD39 and CD73 across diverse cell types, including myeloid cells, T lymphocytes, and B lymphocytes. Results: In both rat and mouse models, there were significant increases in the frequency of CD3+CD4+ T lymphocytes in PCAS (rat, P < 0.01; mouse, P < 0.001), with consequently elevated CD4/CD8a ratios in whole blood (both, P < 0.001). Moreover, CD39 and CD73 expression on blood leukocytes were markedly increased (rat, P < 0.05; mouse, P < 0.01 at 24h). Further analysis in the experimental mouse model revealed that CD11b+ myeloid cells, with significant increase in their population (P < 0.01), had high level of CD39 (88.80 ± 2.05 %) and increased expression of CD73 (P < 0.05). CD19+ B lymphocytes showed slight increases of CD39 (P < 0.05 at 2h) and CD73 (P < 0.05 at 2h), while, CD3+ T lymphocytes had decreased levels of them. These findings suggested a distinct patterns of expression of CD39 and CD73 in these specific immune cell populations after CA. Conclusions: These data have provided comprehensive insights into the immune response after CA, highlighting high-level expressions of CD39 and CD73 in myeloid cells. [ABSTRACT FROM AUTHOR]

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The use of various herbs and their compounds has been a strategy widely used in the fight against various human diseases. For example, rosmarinic acid, a bioactive phenolic compound commonly found in Rosemary plants (Rosmarinus officinalis Labiatae), has multiple therapeutic benefits in different diseases, such as cancer. Therefore, the study aimed to evaluate in silico and in vitro the inhibition potential of the enzyme Elastase from the porcine pancreas by rosmarinic acid isolated from the plant species R. officinalis Linn. Through Molecular Docking, the mechanism of action was investigated. In addition, rosmarinic acid presented a range of 5–60 µg/mL and significantly inhibited Elastase. At 60 µg/mL, there was an inhibition of 55% on the enzymatic activity. The results demonstrate the inhibition of Elastase by rosmarinic acid, which can lead to the development of new enzyme inhibitors that can be an inspiration for developing various drugs, including anticancer drugs. [ABSTRACT FROM AUTHOR]

The quality and stability of oil during thermal processing reflect the reactions in vegetable oil. The deterioration of the oil is close to the viscosity, fatty acid composition (FA), total polar compounds (TPC), etc. Carnosic acid (CA) is the main antioxidant component of rosemary extract; it is a natural and clean-label antioxidant that is allowed to be added to prolong oil processing and storage. To achieve a clear correlation of this situation, a novel stability evaluation model was used to predict the thermal degradation of rapeseed oil (RSO) with CA. The RSO with CA (200 mg/kg, 400 mg/kg, and 700 mg/kg), the tert-Butylhydroquinone (TBHQ, 200 mg/kg), and the fresh RSO (without additives) during thermal processing (180 ± 5 °C) were studied. The temperature dependency of viscosity fits well with the Lioumbas model (R2 ≥ 0.999). The parameter b value in the Lioumbas model showed a decrease linearly with the processing time (tP, R2 ≥ 0.965). The multiple linear regression analysis showed that the accuracy of the model in predicting viscosity was less than ±2 mPa·s−1, and the deviation% was less than ±10% in all the samples. After 32 h of thermal degradation, the addition of 700 mg/kg CA showed the lowest degradation rate (13.84%) of polyunsaturated fatty acids (PUFAs), and the TPC content was 26.00 ± 0.50%. The TPC showed a positive relationship with viscosity (r = 0.99, p < 0.01), tP (r = 0.97, p < 0.01), and effective carbon numbers (ECN, r = 0.84, p < 0.05). In conclusion, this study can make a potential prediction for the stability of RSO. [ABSTRACT FROM AUTHOR]

Cancer is a serious global public health issue, and a great deal of research has been made to treat cancer. Of these, discovery of promising compounds that effectively fight cancer always has been the main point of interest in pharmaceutical research. Carnosic acid (CA) is a phenolic diterpenoid compound widely present in Lamiaceae plants such as Rosemary (Rosmarinus officinalis L.). In recent years, there has been increasing evidence that CA has significant anti-cancer activity, such as leukaemia, colorectal cancer, breast cancer, lung cancer, liver cancer, pancreatic cancer, stomach cancer, lymphoma, prostate cancer, oral cancer, etc. The potential mechanisms involved by CA, including inhibiting cell proliferation, inhibiting metastasis, inducing cell apoptosis, stimulating autophagy, regulating the immune system, reducing inflammation, regulating the gut microbiota, and enhancing the effects of other anti-cancer drugs. This article reviews the biosynthesis, pharmacokinetics and metabolism, safety and toxicity, as well as the molecular mechanisms and signaling pathways of the anticancer activity of CA. This will contribute to the development of CA or CA-containing functional foods for the prevention and treatment of cancer, providing important advances in the advancement of cancer treatment strategies.

IntroductionThis study aimed to investigate the regulatory effects of mulberry leaf flavonoids and carnosic acid complex (MCC) on the growth performance, intestinal morphology, antioxidant, and p38 MAPK/Nrf2 pathway in broilers.MethodsA total of 256 healthy 8-day-old female yellow-feathered broilers were randomly divided into 4 equal groups: a control group (CON) fed a basal diet, an antibiotic group (CTC) supplemented with 50 mg/kg chlortetracycline, and two experimental groups (MCC75, MCC150) fed basal diets with 75 mg/kg and 150 mg/kg of MCC, respectively. The experiment lasted for 56 days, with days 1–28 designated as the initial phase and days 29–56 as the growth phase.ResultsThe results on the growth performance showed that diets supplemented with MCC and CTC decreased the feed-to-gain ratio (F/G), diarrhea rate, and death rate, while significantly increasing the average daily weight gain (ADG) (p

Active vitamin D derivatives (VDDs)—1α,25-dihydroxyvitamin D3/D2 and their synthetic analogs—are well-known inducers of cell maturation with the potential for differentiation therapy of acute myeloid leukemia (AML). However, their dose-limiting calcemic activity is a significant obstacle to using VDDs as an anticancer treatment. We have shown that different activators of the NF-E2-related factor-2/Antioxidant Response Element (Nrf2/ARE) signaling pathway, such as the phenolic antioxidant carnosic acid (CA) or the multiple sclerosis drug monomethyl fumarate (MMF), synergistically enhance the antileukemic effects of various VDDs applied at low concentrations in vitro and in vivo. This study aimed to investigate whether glutathione, the major cellular antioxidant and the product of the Nrf2/ARE pathway, can mediate the Nrf2-dependent differentiation-enhancing activity of CA and MMF in HL60 human AML cells. We report that glutathione depletion using L-buthionine sulfoximine attenuated the enhancing effects of both Nrf2 activators concomitant with downregulating vitamin D receptor (VDR) target genes and the activator protein-1 (AP-1) family protein c-Jun levels and phosphorylation. On the other hand, adding reduced glutathione ethyl ester to dominant negative Nrf2-expressing cells restored both the suppressed differentiation responses and the downregulated expression of VDR protein, VDR target genes, as well as c-Jun and P-c-Jun levels. Finally, using the transcription factor decoy strategy, we demonstrated that AP-1 is necessary for the enhancement by CA and MMF of 1α,25-dihydroxyvitamin D3-induced VDR and RXRα protein expression, transactivation of the vitamin D response element, and cell differentiation. Collectively, our findings suggest that glutathione mediates, at least in part, the potentiating effect of Nrf2 activators on VDDs-induced differentiation of AML cells, likely through the positive regulation of AP-1. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) represents 80% of all lung cancer cases and is characterized by low survival rates due to chemotherapy and radiation resistance. Novel treatment strategies for NSCLC are urgently needed. Liver kinase B1 (LKB1), a tumor suppressor prevalently mutated in NSCLC, activates AMP-activated protein kinase (AMPK) which in turn inhibits mammalian target of rapamycin complex 1 (mTORC1) and activates unc-51 like autophagy activating kinase 1 (ULK1) to promote autophagy. Sestrin-2 is a stress-induced protein that enhances LKB1-dependent activation of AMPK, functioning as a tumor suppressor in NSCLC. In previous studies, rosemary (Rosmarinus officinalis) extract (RE) activated the AMPK pathway while inhibiting mTORC1 to suppress proliferation, survival, and migration, leading to the apoptosis of NSCLC cells. In the present study, we investigated the anticancer potential of carnosic acid (CA), a bioactive polyphenolic diterpene compound found in RE. The treatment of H1299 and H460 NSCLC cells with CA resulted in concentration and time-dependent inhibition of cell proliferation assessed with crystal violet staining and 3H-thymidine incorporation, and concentration-dependent inhibition of survival, assessed using a colony formation assay. Additionally, CA induced apoptosis of H1299 cells as indicated by decreased B-cell lymphoma 2 (Bcl-2) levels, increased cleaved caspase-3, -7, poly (ADP-ribose) polymerase (PARP), Bcl-2-associated X protein (BAX) levels, and increased nuclear condensation. These antiproliferative and proapoptotic effects coincided with the upregulation of sestrin-2 and the phosphorylation/activation of LKB1 and AMPK. Downstream of AMPK signaling, CA increased levels of autophagy marker light chain 3 (LC3), an established marker of autophagy; inhibiting autophagy with 3-methyladenine (3MA) blocked the antiproliferative effect of CA. Overall, these data indicate that CA can inhibit NSCLC cell viability and that the underlying mechanism of action of CA involves the induction of autophagy through a Sestrin-2/LKB1/AMPK signaling cascade. Future experiments will use siRNA and small molecule inhibitors to better elucidate the role of these signaling molecules in the mechanism of action of CA as well as tumor xenograft models to assess the anticancer properties of CA in vivo. [ABSTRACT FROM AUTHOR]

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Cholestenoic acid (CA) has been reported as an important biomarker of many severe diseases, but its physiological and pathological roles remain unclear. This study aimed to investigate the potential role of CA in hepatic lipid homeostasis. Enzyme kinetic studies revealed that CA specifically activates DNA methyltransferases 1 (DNMT1) at low concentration with EC50 = 1.99 10-6 M and inhibits the activity at higher concentration with IC50 = 9.13 106 M, and specifically inhibits DNMT3a, and DNMT3b activities with IC50= 8.41 10-6 M and IC50= 4.89 10-6 M, respectively. In a human hepatocyte in vitro model of high glucose (HG)- induced lipid accumulation, CA significantly increased demethylation of 5mCpG in the promoter regions of over 7,000 genes, particularly those involved in master signaling pathways such as calcium-AMPK and 0.0027 at 6 h. RNA sequencing analysis showed that the downregulated genes are affected by CA encoding key enzymes, such as PCSK9, MVK, and HMGCR, which are involved in cholesterol metabolism and steroid biosynthesis pathways. In addition, untargeted lipidomic analysis showed that CA significantly reduced neutral lipid levels by 60% in the cells cultured in high-glucose media. Administration of CA in mouse metabolic dysfunction-associated steatotic liver disease (MASLD) models significantly decreases lipid accumulation, suppresses the gene expression involved in lipid biosynthesis in liver tissues, and alleviates liver function. This study shows that CA as an endogenous epigenetic regulator decreases lipid accumulation via epigenetic regulation. The results indicate that CA can be considered a potential therapeutic target for the treatment of metabolic disorders. NEW & NOTEWORTHY To our knowledge, this study is the first to identify the mitochondrial monohydroxy bile acid cholestenoic acid (CA) as an endogenous epigenetic regulator that regulates lipid metabolism through epigenome modification in human hepatocytes. The methods used in this study are all big data analysis, and the results of each part show the global regulation of CA on human hepatocytes rather than narrow point effects. [ABSTRACT FROM AUTHOR]

The objective of this study was the optimization of the extraction process and the qualitative and quantitative determination of the bioactive metabolites: 12-O-methylcarnosic acid (12MCA), carnosic acid (CA), carnosol (CS), 7-O-methyl-epi-rosmanol (7MER) and rosmanol (RO) in infusions, decoctions, turbulent flow extracts, tinctures and oleolites from three Salvia species: Salvia officinalis L. (common sage, SO), Salvia fruticosa Mill. (Greek sage, SF) and Salvia rosmarinus Spenn (syn Rosmarinus officinalis L.) (rosemary, SR), using Quantitative Proton Nuclear Magnetic Resonance Spectroscopy (1H-qNMR). Regarding the aqueous extracts, decoctions appeared to be richer sources of the studied metabolites than infusions among the three plants. For SR, the turbulent flow extraction under heating was the most efficient one. The optimum time for the preparation of decoctions was found to be 5 min for SF and SO and 15 min for SR. It is noteworthy that SR tinctures were not stable in time due to decomposition of the abietane-type diterpenes CA and CS because of the polar solvent used for their preparation. Contrary to this finding, the oleolites of SR appeared to be very stable. Olive oil as a solvent for extraction was very protective for the contained abietane-type diterpenes. A preliminary stability study on the effect of the storage time of the SF on the abietane-type diterpenes content showed that the total quantity of abietanes decreased by 16.51% and 40.79% after 12 and 36 months, respectively. The results of this investigation also demonstrated that 1H-qNMR is very useful for the analysis of sensitive metabolites, like abietane-type diterpenes, that can be influenced by solvents used in chromatographic analysis. [ABSTRACT FROM AUTHOR]

Background: Hepatic steatosis, which involves the excessive accumulation of lipid droplets in hepatocytes, presents a significant global health concern due to its association with obesity and metabolic disorders. Inflammation plays a crucial role in the progression of hepatic steatosis; however, the precise molecular mechanisms responsible for this process remain unknown. Methods: This study investigated the involvement of the nucleotide-binding oligomerization domain-like receptor pyrin domain-containing-3 (NLRP3) inflammasome and the forkhead box O6 (FoxO6) transcription factor in the pathogenesis of hepatic steatosis. We monitored the NLRP3 inflammasome and lipogenesis in mice overexpressing the constitutively active (CA)-FoxO6 allele and FoxO6- null mice. In an in vitro study, we administered palmitate to liver cells overexpressing CA-FoxO6 and measured changes in lipid metabolism. Results: We administered palmitate treatment to clarify the mechanisms through which FoxO6 activates cytokine interleukin (IL)-1β through the NLRP3 inflammasome. The initial experiments revealed that dephosphorylation led to palmitate-induced FoxO6 transcriptional activity. Further palmitate experiments showed increased expression of IL-1β and the hepatic NLRP3 inflammasome complex, including adaptor protein apoptotic speck protein containing a caspase recruitment domain (ASC) and pro-caspase-1. Furthermore, thioredoxin-interacting protein (TXNIP), a key regulator of cellular redox conditions upstream of the NLRP3 inflammasome, was induced by FoxO6 in the liver and HepG2 cells. Conclusion: The findings of this study shed light on the molecular mechanisms underpinning the FoxO6-NLRP3 inflammasome axis in promoting inflammation and lipid accumulation in the liver. [ABSTRACT FROM AUTHOR]

Rosmarinus officinalis L. is a Mediterranean medicinal and aromatic plant, widely used in several industries. The present study aimed to characterize the chemical composition of volatile compounds, encompassing essential oils (EO): hydrosol extract (HE): and water residue extract (WRE1). Additionally, the investigation focused on non-volatile components, including powder phenolic extract (PPE): water residue extract (WRE2): and solid residue extract (SRE): while also assessing their antioxidant and antibacterial activities. The chemical compositions of volatile components were determined by using a Gas Chromatograph equipped with a Mass Spectrometer (GC/MS): while polyphenol extracts were analyzed using Ultra-High-Performance Liquid Chromatograph equipped with a photodiode array detection Mass Spectrometer (UHPLC-DAD-ESI/MS). The antioxidant activity was determined by 1,1-diphenyl-2-picrylhydrazyl free radical scavenging (DPPH) and ferric reducing antioxidant power (FRAP): while the antibacterial effect was evaluated against four pathogenic bacterial strains using disc diffusion and broth microdilution methods. The GC/MS analysis showed that R. officinalis EO was dominated by 1,8-cineole (47.70%) and α-pinene (15.50%). 1,8-cineole (56.67%) and camphor (26.27%) were found as the predominant constituents of HE, while volatile components of WRE1 were mainly dominated by camphor (10.11%). The UHPLC-DAD-ESI/MS analysis revealed the existence of a plethora of polyphenolic components. In PPE and SRE, the predominating compounds were carnosic acid and carnosol, respectively. Rosmarinic acid was the main constituent in WRE2. The results of DPPH free radical scavenging and FRAP activities showed that PPE exhibited strong antioxidant activity, followed by SRE and WRE2. EO and HE showed moderate antioxidant activity, while volatile components of WRE1 exhibited the lowest antioxidant effect. Regarding the antibacterial activity, PPE and SRE indicated the highest effect against the pathogenic bacteria, while WRE1 volatile components had the weakest antibacterial activity. The conducted study showed that material plant left after hydrodistillation of R. officinalis may be used as a new source of bioactive volatile and polyphenolic components with valuable pharmacological activities. [ABSTRACT FROM AUTHOR]

Clinically, the immune checkpoint inhibitor anti-PD-1 antibody has shown a certain effect in the treatment of hepatocellular carcinoma (HCC), which is limited to a small number of patients with HCC. This study aims to reveal whether carnosic acid nanocluster-based framework (CA-NBF) has a sensitization effect on anti-PD-1 antibody in the treatment of HCC at the cellular and animal levels. MHCC97H cells were treated with CA-NBF, anti-PD-1 and their combination. The effects of CA-NBF and anti-PD-1 on cell proliferation, cell cycle, apoptosis, invasion, and migration were evaluated by MTT assay, flow cytometry, and scratch test. The effects of CA-NBF and anti-PD-1 on Wnt/β-catenin signaling pathway in MHCC97H cells were detected. A BALB/C nude mouse model of hepatocellular carcinoma was established, and the tumor growth was observed at different time points. The expression of cytotoxic T lymphocyte and helper T lymphocyte markers CD8 and CD4 in tumor tissues was detected by immunohistochemistry. Western blotting was used to detect the Wnt/β-catenin signaling pathway proteins (Wnt-3a, β-catenin, and GSK-3β) level in tumor tissues after CA-NBF and anti-PD-1 treatment. CA-NBF activity was significantly higher than CA, which could prominently reduce the proliferation, migration and invasion of MHCC97H cells and enhance apoptosis by inactivating Wnt/β-catenin signaling pathway. CA-NBF combined with anti-PD-1 antibody further enhanced cell proliferation, migration, invasion and pro-apoptosis but had no significant effect on Wnt/β-catenin signaling pathway. CA-NBF in vivo improved the tumor response to PD1 immune checkpoint blockade in HCC, manifested by reducing tumor size and weight, promoting CD4 and CD8 expression. CA-NBF combined with anti-PD-1 have stronger immunomodulatory and anticancer effects without increasing biological toxicity. [ABSTRACT FROM AUTHOR]

Although the transcription factor nuclear factor κB (NF-κB) plays a central role in the regulation of senescence-associated secretory phenotype (SASP) acquisition, our understanding of the involvement of NF-κB in the induction of cellular senescence is limited. Here, we show that activation of the canonical NF-κB pathway suppresses senescence in murine dermal fibroblasts. IκB kinase β (IKKβ)-depleted dermal fibroblasts showed ineffective NF-κB activation and underwent senescence more rapidly than control cells when cultured under 20% oxygen conditions, as indicated by senescence-associated β-galactosidase (SA-β-gal) staining and p16INK4a mRNA levels. Conversely, the expression of constitutively active IKKβ (IKKβ-CA) was sufficient to drive senescence bypass. Notably, the expression of a degradation-resistant form of inhibitor of κB (IκB), which inhibits NF-κB nuclear translocation, abolished senescence bypass, suggesting that the inhibitory effect of IKKβ-CA on senescence is largely mediated by NF-κB. We also found that IKKβ-CA expression suppressed the derepression of INK4/Arf genes and counteracted the senescence-associated loss of Ezh2, a catalytic subunit of the Polycomb repressive complex 2 (PRC2). Moreover, pharmacological inhibition of Ezh2 abolished IKKβ-CA-induced senescence bypass. We propose that NF-κB plays a suppressive role in the induction of stress-induced senescence through sustaining Ezh2 expression. [ABSTRACT FROM AUTHOR]

Two new phenolic compounds Fusagunolics A (1) and B (2) were isolated from the plant endophytic fungus Fusarium guttiforme, in addition to the previously known metabolites (3-6). The structures of these compounds was elucidated using a combination of spectroscopic analyses, including UV, HRESIMS, 1 D, and 2 D NMR, as well as electronic circular dichroism (ECD) and the optical rotatory dispersion (ORD). Further, the anti-inflammatory activity of all the compounds was evaluated to assess their capability to inhibit nitric oxide (NO) production by RAW 264.7 macrophages. The bioactive screening revealed that compounds 2 and 6 exhibited moderate inhibitory effects against NO production with the IC50 values 28.6 and 37.6 μM, respectively. [ABSTRACT FROM AUTHOR]

An HPLC method with UV detection was developed for the determination of carnosic acid in human plasma and applied to a pharmacokinetic study after oral administration of Rosemary extract to a healthy volunteer. Sample preparation depends on liquid–liquid extraction with hexane. Chromatographic separation was achieved with C18 column (150 mm × 4.6 mm × 5 μm), at 25°C with isocratic elution, mobile phase composed of solution A (methanol), and solution B (2% o-phosphoric acid in water) (90:10, v/v) at flow rate of 1.0 mL/min. The analyte was detected at 230 nm. The retention time is 4.20 ± 0.03 min. The method was validated in terms of accuracy, precision, specificity, robustness and detection and quantification limits, in accordance with European Medicines Agency guidelines. LOD and LOQ were found to be 0.075 and 0.25 ng/mL, respectively. The method was applied to the analysis of carnosic acid in human plasma with good recovery as 91.7%. The plasma concentration-time profile and pharmacokinetic parameters: AUC0– t , AUC0–∞, C max, t max, t 1/2 were calculated according to the assays. The method can certainly be used for routine analysis of carnosic acid in human plasma after oral administration of Rosemary extract, and for phase I clinical studies and bioavailability-bioequivalance studies as well. [ABSTRACT FROM AUTHOR]

This study compared the neuroprotective efficacy of three antioxidants—the plant-derived carnosic acid (CA), and two synthetic free radical scavengers: edaravone (ED) and ebselen (EB)—in in vitro models of neuronal cell damage. Results showed that CA protected mouse primary neuronal cell cultures against hydrogen peroxide-induced damage more efficiently than ED or EB. The neuroprotective effects of CA were associated with attenuation of reactive oxygen species level and increased mitochondrial membrane potential but not with a reduction in caspase-3 activity. None of the tested substances was protective against glutamate or oxygen-glucose deprivation-evoked neuronal cell damage, and EB even increased the detrimental effects of these insults. Further experiments using the human neuroblastoma SH-SY5Y cells showed that CA but not ED or EB attenuated the cell damage induced by hydrogen peroxide and that the composition of culture medium is the critical factor in evaluating neuroprotective effects in this model. Our data indicate that the neuroprotective potential of CA, ED, and EB may be revealed in vitro only under specific conditions, with their rather narrow micromolar concentrations, relevant cellular model, type of toxic agent, and exposure time. Nevertheless, of the three compounds tested, CA displayed the most consistent neuroprotective effects. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to evaluate the possible anticancer and apoptotic effect of carnosol and carnosic acid on non-small cell lung cancer (NSCLC) cell lines in vitro. Materials and Methods: Three different NSCLC cell lines (H441, H520, and H661) were used in the study and treatment (carnosol and carnosic acid treatment) and control (no treatment) groups were established in all cell lines. The IC50 doses were determined by MTT method on NSCLC cell lines and the changes in expression levels of apoptosis-related genes (Bax, Bak, caspase-3, p53, c-Myc, Bcl-2, and Bcl-XL) were demonstrated by real-time polymerase chain reaction (qPCR), and apoptosis was confirmed by flow cytometry. The treatment group and control group results were compared. Results: The IC50 doses of carnosol and carnosic acid were determined; 60 µM for the H441, 20 µM for the H661, 40 µM for the H520, 20 µM for the H441, 40 µM for the H661, 40 µM for the H520, respectively. Carnosol treatment increased Bax, Bak, caspase-3, and p53 expression but decreased Bcl-XL expression in studied lung cancer cell lines. Carnosic acid treatment increased apoptotic Bax, Bak, caspase-3, and p53 expression but decreased antiapoptotic Bcl-2 and Bcl-XL expression (p<0.05). Conclusion: In this study showed that carnosol and carnosic acid have apoptotic effects on NSCLC cells. With more detailed studies on these agents, these come become a promising agent that can be used in NSCLC cancer treatment in the future. [ABSTRACT FROM AUTHOR]

Simple Summary: The spleen, traditionally associated with its role in immune surveillance and blood cell turnover, nowadays is known to be engaged in metabolic control processes, e.g., in the metabolism of lipids. While input of energy sources is essential during animal ratio' formulation, exploring the lipid composition of the spleen and its potential modulation by antioxidant supplements becomes particularly relevant. Our results may be practically applied in the food industry, as they may provide animal food, ensuring the nutritional requirements of especially poorly nourished consumers. Moreover, our findings could bridge the existing knowledge gap about the interplay of diet and lipid composition in the spleen. As this organ is considered to have an essential role in the development of atherosclerosis, obesity, nonalcoholic liver disease, nonalcoholic steatohepatitis, and fatty liver, understanding the function of this internal organ may be a starting point for developing efficient prevention strategies in order to counteract these disorders. The purpose of our study was to investigate the effect of 0.35 mg Se/kg basal diet (BD) (Se as sodium selenate (Se6) and yeast rich in seleno-methionine (SeYe)) and 0.1% carnosic acid (CA) supplementation to the diet containing 1% fish oil (F-O) and 2% rapeseed oil (R-O) on the contents of fatty acids (FA), malondialdehyde (MDA), tocopherols (Ts), and total cholesterol (TCh) in lambs' spleens. A total of 24 male lambs (4 groups per 6 animals) have been fed: the control diet—the basal diet (BD) enriched in F-O and R-O; the CA diet—BD enriched in F-O, R-O, and CA; the SeYeCA diet—BD enriched in F-O, R-O, CA, and SeYe; the Se6CA diet—BD enriched in F-O, R-O, CA, and Se6. Dietary modifications affected the profiles of saturated (SFA), monounsaturated (MUFA), and polyunsaturated (PUFA) fatty acids in spleens. The SeYeCA and Se6CA diets increased the docosapentaenoic acid preference in Δ4-desaturase; hence, a higher content of docosahexaenoic acid was found in the spleens of SeYe- or Se6-treated lambs than in spleens of animals receiving the CA and control diets. The SeYeCA and Se6CA diets increased the concentration ratio of n-3long-chain PUFA (n-3LPUFA) to FA (n-3LPUFA/FA) in spleens compared to the control and CA diets. The content of n-3PUFA was higher in the spleens of Se6 treated lambs than in spleens of animals receiving the SeYeCA, CA, and control diets. The Se6CA diet increased the content of c9t11CLA in the spleen compared to the control, CA, and SeYeCA diets. Experimental diets reduced the level of atherogenic FA, the content ratios of n-6PUFA/n-3PUFA and n-6LPUFA/n-3LPUFA, and improved the content ratio of MUFA/FA and the value of the hypocholesterolemic/hypercholesterolemic FA ratio in the spleen in comparison with the control diet. The experimental diets supplemented with SeYe or Se6 increased levels of TCh and Ts in spleens in comparison with the CA and control CA diets. The present studies documented that Se6, SeYe, and CA influenced the metabolism of FA, Ts, and cholesterol in spleens. [ABSTRACT FROM AUTHOR]

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Rosmarinus officinalis L. compounds, especially its main polyphenolic compounds, carnosic acid (CA) and rosmarinic acid (RA), influence various facets of cancer biology, making them valuable assets in the ongoing fight against cancer. These two secondary metabolites exhibit formidable antioxidant properties that are a pivotal contributor against the development of cancer. Their antitumor effect has been related to diverse mechanisms. In the case of CA, it has the capacity to induce cell death of cancer cells through the rise in ROS levels within the cells, the inhibition of protein kinase AKT, the activation of autophagy-related genes (ATG) and the disrupt mitochondrial membrane potential. Regarding RA, its antitumor actions encompass apoptosis induction through caspase activation, the inhibition of cell proliferation by interrupting cell cycle progression and epigenetic regulation, antioxidative stress-induced DNA damage, and interference with angiogenesis to curtail tumor growth. To understand the molecular interaction between rosemary compounds (CA and RA) and a protein that is involved in cancer and inflammation, S100A8, we have performed a series of molecular docking analyses using the available three-dimensional structures (PDBID: 1IRJ, 1MR8, and 4GGF). The ligands showed different binding intensities in the active sites with the protein target molecules, except for CA with the 1MR8 protein. [ABSTRACT FROM AUTHOR]