Carnosic acid attenuates ventilator-induced diaphragmatic dysfunction via activation of the Nrf2/HO-1 pathway.

Oxidative stress arises from an imbalance between reactive oxygen species (ROS) and antioxidant defense mechanisms and disrupts the structural integrity of macromolecules such as lipids, proteins, and DNA. This biochemical imbalance triggers the pathogenesis of cardiovascular and neurodegenerative diseases and leads to lipid oxidation and quality degradation in food systems. Plant-derived bioactive compounds (BACs) such as polyphenols and terpenes develop versatile molecular strategies to mitigate this oxidative damage. In addition to their direct radical scavenging effects, polyphenols stimulate the synthesis of endogenous antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) by activating the Nrf2-Keap1 signaling pathway. Terpenes, on the other hand, create a specialized protective shield in lipid-based matrices through "chain-breaking" reactions and a "slingshot" mechanism that externally halts the oxidation of γ-terpinene. In food engineering applications, these compounds meet the demand for "clean-label" products by providing alternatives to synthetic antioxidants such as BHA and BHT. Specific terpenes, such as carnosic acid, demonstrate higher performance in inhibiting lipid oxidation compared to their synthetic counterparts. Although BAC use extends the shelf life of products while maintaining color and flavor stability, potential interactions with protein digestibility necessitate dosage management. From a clinical perspective, these compounds suppress inflammatory responses by inhibiting the NF-κB pathway and contribute to the prevention of chronic diseases by modulating the gut microbiota. This review evaluates the capacity of BACs to manage oxidative stress in food preservation technologies and human health through a mechanistic and application-based approach.

Background NeuroAIDS remains a significant clinical challenge due to the restricted ability of antiretroviral drugs to cross the blood-brain barrier (BBB), leading to persistent viral reservoirs within the central nervous system (CNS). Atazanavir, a protease inhibitor, exhibits poor aqueous solubility and limited CNS penetration, necessitating innovative delivery strategies to enhance its therapeutic efficacy in neuro-HIV management. Objective This review aims to evaluate the potential of Supersaturated Self-Nanoemulsifying Drug Delivery Systems (S-SNEDDS) in improving the bioavailability and CNS delivery of Atazanavir. It also explores synergistic components such as rosemary oil and their role in neuroprotective effects within the context of NeuroAIDS. Methods A comprehensive literature survey was conducted using peer-reviewed articles from databases including PubMed, Scopus, and Web of Science. Studies related to SNEDDS, S-SNEDDS, Atazanavir delivery, CNS targeting, BBB modulation, and phytochemical-based neuroprotection were critically analyzed and synthesized. Results Evidence from literature suggests that S-SNEDDS can significantly enhance the solubility and oral absorption of Atazanavir. Specific excipients such as surfactants and co-solvents have been reported to modulate BBB permeability, potentially facilitating CNS drug delivery. Rosemary oil components like carnosic acid and rosmarinic acid exhibit promising antioxidant and anti-inflammatory properties, offering neuroprotective benefits. However, these findings are primarily based on in vitro and preclinical studies, indicating a need for further translational research. Conclusion Atazanavir-loaded S-SNEDDS represent a promising strategy for overcoming current limitations in NeuroAIDS therapy by enhancing CNS drug targeting. While current evidence is encouraging, further clinical and pharmacokinetic validation is essential. The integration of smart healthcare technologies may further optimize such delivery systems in the future.

Heterotopic ossification (HO) pathogenesis involves ROS-driven stem cell differentiation. Carnosic acid (CA), a natural antioxidant, remains unexplored for HO. In vitro, tendon-derived stem cells (TDSCs) were stimulated with IL-1β, and CA was used for intervention to assess its effects on differentiation and ROS production via real-time quantitative PCR (qPCR), western blotting (WB), and immunofluorescence. Additionally, a burn and Achilles tendon transection-induced mouse model of traumatic HO was established to evaluate the therapeutic potential of CA. In vitro, CA activated nuclear factor erythroid 2-related factor 2 (Nrf2) and inhibited nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1), leading to increased antioxidant enzyme activity and reduced intracellular ROS levels. CA also regulated the PTEN/AKT signaling pathway, suppressing osteogenic and chondrogenic differentiation of TDSCs. In vivo, micro-computed tomography (Micro-CT) and histological analyses demonstrated that CA activated Nrf2 and enhanced antioxidant enzyme expression, thereby inhibiting osteogenic and chondrogenic factor expression in Achilles tendon tissue and reducing HO formation. CA is a novel HO therapeutic by dual targeting of oxidative stress and differentiation pathways.

Obesity, type 2 diabetes (T2D), and insulin resistance are pervasive metabolic disorders marked by chronic low-grade inflammation and systemic metabolic disorders. The emerging field of immunometabolism highlights how interactions between immune processes and metabolic pathways in adipose tissue, liver, muscle, and pancreatic islets contribute to disease pathogenesis. Lipid dysregulation plays a central role in these processes, with distinct lipid molecules identified in obese patients as compared to lean patients that correlate with insulin resistance, inflammation, and vascular dysfunction. This Special Issue compiles a multidisciplinary body of research aimed at elucidating molecular mechanisms, identifying novel biomarkers, and exploring innovative therapeutic strategies. Key contributions include studies on omega-3 long-chain polyunsaturated fatty acids (LCPUFAs) and their differential associations with neurocognitive development; the potential of beta-defensin 2 as a biomarker linking gut-derived inflammation and metabolic dysfunction; and the promotion of adipocyte browning by Carnosic acid via AMPK activation and GSK3β inhibition. Additionally, reviews of phytochemicals underscore their multisystem therapeutic potential, while investigations into sodium–glucose cotransporter-2 (SGLT2) inhibitors suggest possible metabolic and neuroprotective benefits beyond glucose control. Maternal lipid metabolism during pregnancy and its impact on maternal fetal health further emphasize the clinical complexity of lipid dysregulation. Despite promising insights, significant gaps remain regarding causality versus correlation in lipid biomarkers, standardization of analytical methodologies, tissue heterogeneity, and unintended effects of metabolic interventions. Collectively, these studies underscore the necessity of integrative, mechanism-driven research to bridge fundamental biology with translational and clinical applications, ultimately advancing precision therapies for metabolic diseases.

BackgroundBisphenol A (BPA) is an endocrine‐disrupting chemical commonly used in polycarbonate plastic production (Mhaouty‐Kodja et al., 2024). Studies indicate that BPA activates microglial cells, leading to potential neuroinflammation (Ouyang et al., 2024). Carnosic acid (CA), a phenolic diterpene from rosemary (Rosmarinus officinalis L.), has potent antioxidant and neuroprotective properties (Hsu et al., 2024). This study investigated the protective effects of carnosic acid (CA) against BPA‐induced neuroinflammation and oxidative stress in human HMC3 microglia cellsand C57BL/6J male mice.MethodIn vitro experiments, cells were treated with 20 nM BPA and 1 μM CA for 3 h to investigate the effect of neuroinflammation and oxidative stress. Protein levels of inflammasome components, antioxidant enzymes, and transcription factors were assessed. We further used in vivo model to confirm the antioxidant capacity of CA. Mice were divided into four groups: control (olive oil 0.01 mL /g weight), BPA (50 μg/kg BPA), BLCA (50 μg/kg BPA + 5 mg/kg CA), BHCA (50 μg/kg BPA + 20 mg/kg CA). The antioxidant capacity of CA was assessed.ResultCA treatment improved the BPA‐induced inflammasome proteins, including NLRP3, cleaved caspase‐1, GSDMD‐N, and IL‐1β. Moreover, CA improved the BPA‐induced fluorescence expression of reactive oxygen species (ROS). CA also reversed the antioxidant enzymes, transcription factor Nrf2, and UDP glucuronosyltransferase (UGT) 1A1 protein reduced by BPA. In vivo experiments, CA treatment restored BPA‐induced the reduction of proteins in UGT1A1 and antioxidant enzymes in the striatum. The antioxidant capacity of CA was reduced in cells pretreated with L‐buthionine‐sulfoximine (BSO), a GSH synthesis inhibitor.ConclusionThese findings indicated that the neuroprotection of CA could reverse BPA‐induced oxidative stress and neuroinflammation by regulating inflammasome proteins and antioxidant enzymes in HMC3 microglial cells.

Carnosic acid (CA), a polyphenolic diterpene naturally found in Rosmarinus officinalis, has demonstrated a wide range of pharmacological activities according to scientific research, making it a key candidate for new therapeutic product development. The aim of this manuscript is to present an updated review of the literature on the latest research findings about carnosic acid, emphasizing its most relevant biological functions. Accordingly, this work highlights the main reported pharmacological activities, such as antioxidant, antidiabetic, anti-inflammatory, antimicrobial, antiobesity, anticancer, and neuroprotective properties. We conducted a systematic search of bibliographic databases for peer-reviewed literature based on a specific review question, utilizing scientific databases including PubMed, Scopus, Science Direct, and Google Scholar published since 1990. Numerous studies have highlighted the extensive therapeutic applications of carnosic acid. Among others, carnosic acid was found to have antioxidant, antidiabetic, anti-inflammatory, antimicrobial, antiobesity, anticancer, and neuroprotective activities. Further, carnosic acid displayed low toxicity levels and few side effects. CA shows great promise as a therapeutic agent in the prevention and treatment of many diseases, such as numerous cancers, infectious diseases, and newly emerging illnesses like Alzheimer’s and Parkinson’s diseases. In recent times, there has been a significant push to improve PBMs, proposing their application as natural drugs for several pathological conditions, with a focus on their anti-inflammatory and antioxidant capabilities. Carnosic acid exhibits antidiabetic, antimicrobial, antiobesity, and neuroprotective effects, as well as antitumor, anti-infectious, CNS, and endocrine system activities. However, further research on its precise pharmacological mechanisms is required before it can be reliably used to treat human diseases.

Due to the content of carnosic acid (CA), carnosol (C), and rosmarinic acid (RA), sage (Salvia officinalis L.) has antioxidant, anti-inflammatory, anticancer, antidiabetic, neuroprotective, antiaging, antimicrobial, and antiviral properties. However, current standardization and quality assessment procedures do not specify the content of these key substances in dried sage. The aim of this study was to analyze polyphenolic components, including CA, C, and RA, as well as basic nutrients, such as protein, fat, carbohydrates, and ash content in dried Salvia officinalis. Thirteen products available for sale in Poland were analyzed. HPLC studies have shown a very large variation in terms of CA, C, and RA (CA: 1.25-32.42 mg/g, C: 0-9.06 mg/g, and RA: 3.2-20.6 mg/g). Similarly, significant differences between samples were observed for the proximate composition. An appropriate system of standardization of herbs and spices could ensure the repeatability of the concentration of key, non-volatile active substances, which in adequate doses may have a beneficial effect on certain body functions, as well as on the shelf life and sensory characteristics of food.

The aim of this study was to compare the effectiveness of edible oil (as an extractant) for the extraction of CA (carnosic acid), C (carnosol), and RA (rosmarinic acid) from sage with popular solvents (methanol, ethanol, 70% methanol, 70% ethanol, and water), as well as to assess the stability and fit the kinetic reaction model to the course of CA and RA degradation in oil macerate and various extracts. The degradation rate constant and half-life of CA and RA were also estimated and compared. CA was most efficiently extracted from sage using ethanol and methanol (9.3–10.1 mg/g of sage), followed by oil (7.10 mg/g). For C and RA, the most suitable solvents were 70% ethanol and 70% methanol (C: 3.08–4.01 mg/g; RA: 19.16–20.24 mg/g). CA was most stable in oil, followed by ethanol > methanol > 70% ethanol > 70% methanol. CA degradation followed a first-order kinetic model. RA was very stable in all extracts, except water, where the kinetics of RA degradation most closely followed a second-order model. Although oil extracts smaller amounts of phytochemicals from sage than solvents, CA in oil was the most stable, and the maceration of sage in oil is safe and consistent with the concept of sustainable development.

Abstract: Thinning and hair loss, especially when linked to androgenetic alopecia (AGA), pose significant psychological and clinical challenges. Conventional treatments often have limitations, including side effects and inconsistent results. This paper focuses on the medicinal potential of rosemary (Rosmarinus officinalis) in preventing hair loss and promoting hair growth. It integrates the basic biology of hair, the dynamics of the hair growth cycle, and the underlying causes of hair loss. In addition to examining the plant's botanical origin, traditional uses, and chemical profile, the review highlights the bioactive components of rosemary, including 1,8-cineole, rosmarinic acid, and carnosic acid. These compounds possess multiple beneficial properties, such as en-hanced microcapillary circulation, inhibition of testosterone 5α-reductase, and antibacterial, anti-inflammatory, and antioxidant effects. Collectively, these characteristics support a healthier scalp and promote hair follicle renewal. Despite promising results from preclinical and clinical studies, challenges such as small sample sizes, inconsistent formulations, and a lack of long-term safety data remain. Future research should focus on standardizing extraction and formulation methods and conducting large-scale, long-term clinical trials to fully elucidate rosemary's therapeutic po-tential for hair restoration.

Effect of fatty acid composition on rosemary antioxidants in stabilizing woody edible oils: a kinetic and machine learning analysis of volatiles under accelerated oxidation.

Carnosic Acid as a Potent Ag85C Inhibitor Identified Through Integrated Pharmacokinetic Evaluation and Molecular Modeling in Mycobacterium Tuberculosis Drug Discovery

Mammalian skin wounds typically heal with a scar, characterized by fibrotic tissue that disrupts original tissue architecture and function. Therapies that limit fibrosis and promote regenerative healing remain a major unmet clinical need. Rosemary extract, particularly in the form of topical oils and creams, has gained widespread public attention for its purported wound-healing properties. However, its efficacy and mechanism of action remain poorly understood. We show in adult wound healing mouse models that an ethanol-based rosemary extract accelerates the speed of wound healing and mitigates fibrosis. Mechanistically, we identify that carnosic acid, a major bioactive component of rosemary leaves, activates the transient receptor potential ankyrin 1 (TRPA1) nociceptor on cutaneous sensory neurons to enhance tissue regeneration. Mice lacking TRPA1 in sensory neurons do not exhibit these pro-regenerative responses, confirming its role as a critical mediator. Together, these findings suggest that topical rosemary extract may represent an effective and accessible therapeutic approach to improve skin repair outcomes.

BackgroundFerroptosis, caused by abnormal iron metabolism and lipid peroxidation, has been linked to pathogenic processes in several disorders. Its function and regulating mechanisms in periodontitis are still unclear, nevertheless. As a naturally derived phenolic diterpenoid molecule, carnosic acid (CA) serves multiple biological roles, including antioxidant, anti-inflammatory, and cytoprotective properties. Its potential for intervention in periodontitis and ferroptosis warrants further exploration.MethodsIn this investigation, we combined network pharmacology analysis with in vitro and in vivo experimental validation to systematically evaluate the mechanism of action of CA intervention in periodontitis. Through an intersectional analysis of drug targets, ferroptosis-related genes, and periodontitis-related genes, potential core targets were identified, and GO/KEGG enrichment analysis was performed. The results suggest that Nrf2 is at the core of the protein interaction network and is significantly enriched in antioxidant response and iron homeostasis regulation pathways. Subsequently, changes in ROS, MDA, GSH, SOD, Fe²⁺, and other indicators, as well as the expression of ferroptosis-related indicators (GPX4, SLC7A11, FTH1), were detected in LPS-induced RAW264.7 cell models and rat periodontal ligation models. The key role of Nrf2 was verified using the Nrf2-specific inhibitor ML385.ResultsNetwork pharmacology results indicate that ferroptosis is crucial in the potential mechanism of CA action on periodontitis. Nrf2 is the core regulatory molecule connecting CA, periodontitis, and ferroptosis. The experimental results revealed that CA dramatically lowered ROS and MDA levels in cells and periodontal tissues, inhibited the accumulation of Fe²⁺, elevated the contents of GSH and SOD, and GPX4, SLC7A11, and FTH1 expression. Mechanistic studies have found that CA restores the antioxidant and iron homeostasis regulatory system by activating the Nrf2/GPX4 signaling axis, thereby inhibiting the vicious cycle of ferroptosis. After Nrf2 was blocked by ML385, the anti-ferroptosis and anti-inflammatory effects of CA were significantly weakened.ConclusionThe current research is the first to elucidate that CA can alleviate periodontitis pathological damage by suppressing ferroptosis via activating the Nrf2/GPX4 signaling axis. This enriches the pharmacological action spectrum of CA and provides new targets and a theoretical basis for periodontitis intervention strategies based on ferroptosis regulation.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12903-025-07048-1.

Carnosic acid (CA) is a phenolic diterpene with high antioxidant activity that supports its radioprotective capacity. This study aims to determine whether the radiosensitizing effect of CA established in B16F10 melanoma cells also occurs in other melanin-producing cells. Cell survival analysis, apoptosis, intracellular glutathione levels, and cell cycle progression were evaluated by comparing radiosensitive cells (PNT2) with radioresistant melanin-producing cells (MELAN A, SK-MEL-1, and B16F10). In PNT2 cells, CA exhibited radioprotective capacity, with 100% cell survival after exposure to 20 Gy of X-rays (p < 0.001), decreasing apoptosis (p < 0.001) and increasing the GSH/GSSG ratio (p < 0.01), without significant modification in cell cycle progression. However, CA administration to irradiated cells failed to exert radioprotection in MELAN A and SK-MEL-1 cells, and even doubled cell death in B16F10 cells (p < 0.001). Specifically, CA did not alter apoptosis or prevent the decrease in GSH/GSSG ratio in MELAN A and SK-MEL-1 cells, while it intensified radiation-induced cell cycle disruptions in all melanin-producing cells. All of these led to a loss of radioprotective capacity in the melanin-producing cells (MELAN A and SK-MEL-1) and even induced a radiosensitizing effect in B16F10 cells. Understanding the mechanisms of action of substances such as CA could promote new applications that protect healthy cells and exclusively damage neoplastic cells when both are present within the same irradiated volume in cancer patients requiring radiotherapy.

Rosmarinus officinalis L. (rosemary), a well-known aromatic herb of the Lamiaceae family, has long been valued for its culinary, medicinal, and industrial applications. Unlike previous reviews, this study integrates updated evidence (1998–2025) on rosemary’s phytochemical composition, highlighting how geographical origin, environmental conditions, and extraction methods influence its bioactive profile. Rich in rosmarinic acid, carnosic acid, carnosol, and essential oils, rosemary exhibits diverse biological activities, including antioxidant, anti-inflammatory, antitumor, neuroprotective, cardioprotective, hepatoprotective, and antidiabetic effects. The graphical abstract 1 illustrates the major bioactive constituents of Rosmarinus officinalis L. and highlights their therapeutic potentials, emphasizing its role as a promising functional food and medicinal plant.This review uniquely emphasizes rosemary’s functional food potential, including applications in food preservation, active packaging, and health-promoting dietary interventions. Mechanistic insights reveal that rosemary bioactives act through enhancement of antioxidant defenses, modulation of inflammatory pathways, regulation of apoptosis, and restoration of metabolic balance. By synthesizing mechanistic, pharmacological, and functional food perspectives, this review provides a novel, comprehensive resource for future research and practical applications in nutrition and therapeutics. Keywords: rosemary, rosmarinic acid, carnosic acid, carnosol, antioxidant, functional food

The escalating threat of drug-resistant superbugs has urgently necessitated the development of antibiotics with novel scaffolds and mechanisms. Herein, we rationally designed and synthesized novel abietane diterpenoid derivatives from carnosic acid (CA) inspired by the "amine/guanidine" modification strategy. Most derivatives designed exhibited greater activities than CA and even vancomycin (∼2-64-fold). The optimized 4c demonstrated ultrabroad-spectrum activity against MRSA, VRE, CRAB, and mycobacteria, coupled with desirable properties of rapid bactericidal ability, low resistance development propensity, and good safety profile. Mechanistic studies first revealed a novel independent and synergistic "cell wall-membrane" dual inhibitory mechanism, respectively, via interfering with bacterial lipid II cycle and inducing membrane permeabilization and depolarization. Subsequent in vivo studies elucidated that 4c demonstrated favorable efficacy in zebrafish and mouse infection models. Collectively, these findings highlight the antimicrobial potential of abietane diterpenoids derived from CA and identify 4c as a promising drug candidate against drug-resistant bacterial infections.

Exploring the therapeutic potential of rosemary in metabolic syndrome: From traditional use to modern research.

Carnosol modulates mPGES-1/PPAR-γ biological axis: from in silico to in vivo clinical imaging and investigations.

Perovskia atriplicifolia Benth., a perennial aromatic plant widespread in Iran’s Sistan and Baluchestan region, is known for its essential oil composition, rich in aromatic and non-aromatic sesquiterpenes. To the best of our knowledge, limited information exists on the composition of its non-volatile extracts. Herein, the phytochemical investigation of the EtOH extract of P. atriplicifolia aerial parts was performed, guided by an analytical approach based on LC-(-)ESI/QExactive/MS/MS. This led to the identification of phenolics, flavonoids, diterpenes (mainly carnosic acid derivatives), and triterpenes. Structural elucidation was performed via NMR and HRMSMS analysis. Furthermore, considering the occurrence of diterpenes closely related to carnosic acid and carnosol, known for their antioxidant properties, the antioxidant activity of the extract (0.5–5.0 μg/mL) and selected pure compounds (0.5–25 μM; compounds 5, 7, 9, 10, 12, 16) was evaluated in Caco-2 intestinal cells, showing significant reduction in free radical levels. The quantitative results highlighted that the above cited compounds occurred in concentrations ranging from 1.73 to 520.21 mg/100 g aerial parts, with carnosol (12) exhibiting the highest concentration (520.21 mg/100 g aerial parts), followed by 1α-hydroxydemethylsalvicanol (9) (91.73 mg/100 g aerial parts) and carnosic acid (16) (88.16 mg/100 g aerial parts).