Enhanced effect of limb remote ischemic postconditioning combined with paeoniflorin on alleviating cerebral ischemic injury via neutrophil NADPH pathway.

BACKGROUND: Limb remote ischemic postconditioning (LRIP) and paeoniflorin (PF) both can ameliorate cerebral ischemia reperfusion (I/R) injury. At present, whether LRIP combined with PF can achieve better therapeutic effect is unknown. PURPOSE: This study explored the alleviating effect and mechanism of LRIP in combination with PF on cerebral I/R injury in rats. METHODS: Middle cerebral artery occlusion (MCAO) surgery was performed on rats except Sham group. Then PF (2.5 mg/kg, 5 mg/kg, 10 mg/kg) was administrated by intraperitoneal injection 10 min before the start of reperfusion. LRIP was operated on the left femoral artery at 0 h of reperfusion. Behavioral testing was used to assess neurological impairment, while TTC staining was used to examine infarct volume. Protein expression of MyD88, TRAF6, p38-MAPK and phosphorylation of p47phox in neutrophils from rat peripheral blood were tested by Western blot. Rat bone marrow neutrophils were extracted and incubated for 24 h with serum from rats after LRIP combined with PF. p38 MAPK inhibitor group was administrated SB203580 while the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor group was administrated Apocynin. Neutrophils were stimulated by fMLP (10 µM). Reactive oxygen species (ROS) production and protein expression of MyD88, TRAF6, p38 MAPK, and p47phox (ser 304 and ser 345) were detected. RESULTS: LRIP combined with PF (5 mg/kg) reduced cerebral infarct volume, ameliorated neurological deficit score (NDS), decreased fMLP-stimulated ROS release and downregulated the protein expression of MyD88, TRAF6, p38-MAPK and phosphorylation of p47phox (ser 304 and ser 345) in neutrophils. CONCLUSION: The protective effect of LRIP combined with PF on cerebral I/R injury was better than either alone. Taken together, we provided solid evidence to demonstrate that the combination of LRIP and PF had potential to alleviate cerebral I/R injury, which was regulated by MyD88-TRAF6-p38 MAPK pathway and neutrophil NADPH oxidase pathway.

Targeting dendritic cell activation: the therapeutic impact of paeoniflorin in cortosteroid-dependent dermatitis management.

This study investigates the mechanism through which paeoniflorin inhibits TSLP expression to regulate dendritic cell activation in corticosteroid-dependent dermatitis treatment. Utilizing databases like TCMSP, we identified paeoniflorin's components, targets, and constructed networks. Molecular docking and gene enrichment analysis helped pinpoint key targets and pathways affected by paeoniflorin. In vitro and in vivo models were used to study CD80, CD86, cytokines, T-cell activation, skin lesions, histopathological changes, TSLP, CD80, and CD86 expression. Our study revealed paeoniflorin's active constituent targeting IL-6 in corticosteroid-dependent dermatitis. In vitro experiments demonstrated reduced TSLP expression, CD80, CD86, and cytokine secretion post-paeoniflorin treatment. In vivo, paeoniflorin significantly decreased skin lesion severity, cytokine levels, TSLP, CD80, and CD86 expression. The study highlights paeoniflorin's efficacy in inhibiting TSLP expression and suppressing dendritic cell activation in corticosteroid-dependent dermatitis, suggesting its potential as a therapeutic intervention. Additionally, it offers insights into the complex molecular mechanisms underlying paeoniflorin's anti-inflammatory properties in treating corticosteroid-dependent dermatitis.

Paeoniflorin exerts anti-PTSD effects in adult rats by modulating hippocampus and amygdala histone acetylation modifications in response to early life stress.

Early life stress (ELS) can cause long-term changes by epigenetic factors, especially histone acetylation modification, playing a crucial role, affect normal cognition, mood, and behavior, and increase susceptibility to post-traumatic stress disorder (PTSD) in adulthood. It has been found that paeoniflorin (PF) can cross the blood-brain barrier to exert anti-PTSD effects on adult PTSD rats. However, whether PF can alleviate the harmful effects caused by ELS in adulthood has not yet been reported. Therefore, to explore the relationship between ELS and PTSD susceptibility in adulthood and its mechanism, in this study, SPS was used as a stressor of ELS, and the mathematical tool Z-normalization was employed as an evaluation criterion of behavioral resilience susceptibility. To investigate the regulatory mechanism of PF on histone acetylation in the hippocampus and amygdala of ELS rats in adulthood, using changes in HATs/HDACs as the entry point, meanwhile, the epigenetic marks (H3K9 and H4K12) in the key brain regions of ELS (hippocampus and amygdala) were evaluated, and the effects of PF on behavioral representation and PTSD susceptibility were observed. This study found that ELS lead to a series of PTSD-like behaviors in adulthood and caused imbalance of HATs/HDACs ratio in the hippocampus and amygdala, which confirms that ELS is an important risk factor for the development of PTSD in adulthood. In addition, paeoniflorin may improve ELS-induced PTSD-like behaviors and reduce the susceptibility of ELS rats to develop PTSD in adulthood by modulating the HATs/HDACs ratio in the hippocampus and amygdala.

Antioxidant effects of Paeoniflorin and relevant molecular mechanisms as related to a variety of diseases: A review.

Paeoniflorin (PF), which is the main component of the Paeonia lactiflora Pall extract, is one of the traditional Chinese medicines. The pharmacological effects associated with PF include antioxidant, immunomodulatory, anti-inflammatory, anticancer, antidepressant-like and neuroprotective effects. Our previous studies had revealed that PF protected melanocytes and inhibited photodamage through the suppression of oxidative stress (OS). As OS plays a vital role in the progression of a variety of diseases, the capacity for PF to suppress OS may exert important effects upon them. However, no review exists on these antioxidant effects of PF as related to various diseases. Therefore, in this review we summarized studies involved with examining the antioxidant effects and molecular mechanisms of PF. Through its capacity to inhibit OS, PF has been shown to exert beneficial effects upon several systems including nervous, cardiac/vascular, digestive, and respiratory as well as specific diseases such as diabetes, autoimmune, pregnancy related, ocular, kidney, dermatology, along with suppression of distal flap necrosis, postoperative adhesions, and hearing loss. Such findings provide new insights and directions for future research directed at the development of PF as a natural antioxidant for the treatment of clinical diseases.

Linalool acts as a chemical chaperone by inhibiting amyloid-ß aggregation.

Linalool is a neuroprotective monoterpene found in essential oils from aromatic plants. Linalool's effectiveness in AD animal models has been established previously, but its mechanisms of action remain unclear. Therefore, this study aims to investigate whether linalool binds directly to the amyloid beta (Aß) fibrils to understand it's role in preventing neurodegeneration. The anti-aggregation ability of Linalool was determined using Dithiothreitol (DTT), and thermal aggregation assays followed by Thioflavin T (ThT) binding assay. AD animals were treated with Linalool, and Thioflavin T staining was used to check the binding of linalool to Aß fibrils in rat brain tissue sections. Preliminary studies revealed the anti-aggregation potential of linalool under the thermal and chemical stimulus. Further, in ThT binding assay Linalool inhibited Aß aggregation, binding directly to Aß fibrils. The reduced fluorescence intensity of ThT in AD brain tissues following linalool administration, highlights its neuroprotective potential as a therapeutic agent for AD.

Activation of ASIC3/ERK pathway by paeoniflorin improves intestinal fluid metabolism and visceral sensitivity in slow transit constipated rats.

Slow transit constipation (STC) is one of the most common gastrointestinal disorders in children and adults worldwide. Paeoniflorin (PF), a monoterpene glycoside compound extracted from the dried root of Paeonia lactiflora, has been found to alleviate STC, but the mechanisms of its effect remain unclear. The present study aimed to investigate the effects and mechanisms of PF on intestinal fluid metabolism and visceral sensitization in rats with compound diphenoxylate-induced STC. Based on the evaluation of the laxative effect, the abdominal withdrawal reflex test, enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, western blot, and immunohistochemistry were used to detect the visceral sensitivity, fluid metabolism-related proteins, and acid-sensitive ion channel 3/extracellular signal-regulated kinase (ASIC3/ERK) pathway-related molecules. PF treatment not only attenuated compound diphenoxylate-induced constipation symptoms and colonic pathological damage in rats but also ameliorated colonic fluid metabolic disorders and visceral sensitization abnormalities, as manifested by increased colonic goblet cell counts and mucin2 protein expression, decreased aquaporin3 protein expression, improved abdominal withdrawal reflex scores, reduced visceral pain threshold, upregulated serum 5-hydroxytryptamine, and downregulated vasoactive intestinal peptide levels. Furthermore, PF activated the colonic ASIC3/ERK pathway in STC rats, and ASIC3 inhibition partially counteracted PF's modulatory effects on intestinal fluid and visceral sensation. In conclusion, PF alleviated impaired intestinal fluid metabolism and abnormal visceral sensitization in STC rats and thus relieved their symptoms through activation of the ASIC3/ERK pathway.

Geraniol and citral: recent developments in their anticancer credentials opening new vistas in complementary cancer therapy.

About 10 million people are diagnosed with cancer each year. Globally, it is the second leading cause of death after heart disease, and by 2035, the death toll could reach 14.6 million. Several drugs and treatments are available to treat cancer, but survival rates remain low. Many studies in recent years have shown that plant-derived monoterpenes, particularly geraniol and citral, are effective against various cancers, including breast, liver, melanoma, endometrial, colon, prostate, and skin cancers. This trend has opened new possibilities for the development of new therapeutics or adjuvants in the field of cancer therapy. These monoterpenes can improve the efficacy of chemotherapy by modulating many signaling molecules and pathways within tumors. Analysis of reports on the anticancer effects published in the past 5 years provided an overview of the most important results of these and related properties. Also, the molecular mechanisms by which they exert their anticancer effects in cell and animal studies have been explained. Therefore, this review aims to highlight the scope of geraniol and citral as complementary or alternative treatment options in cancer therapy.

Paeoniflorin attenuates cuproptosis and ameliorates left ventricular remodeling after AMI in hypobaric hypoxia environments.

This study investigates the cardioprotective effects of Paeoniflorin (PF) on left ventricular remodeling following acute myocardial infarction (AMI) under conditions of hypobaric hypoxia. Left ventricular remodeling post-AMI plays a pivotal role in exacerbating heart failure, especially at high altitudes. Using a rat model of AMI, the study aimed to evaluate the cardioprotective potential of PF under hypobaric hypoxia. Ninety male rats were divided into four groups: sham-operated controls under normoxia/hypobaria, an AMI model group, and a PF treatment group. PF was administered for 4 weeks after AMI induction. Left ventricular function was assessed using cardiac magnetic resonance imaging. Biochemical assays of cuproptosis, oxidative stress, apoptosis, inflammation, and fibrosis were performed. Results demonstrated PF significantly improved left ventricular function and remodeling after AMI under hypobaric hypoxia. Mechanistically, PF decreased FDX1/DLAT expression and serum copper while increasing pyruvate. It also attenuated apoptosis, inflammation, and fibrosis by modulating Bcl-2, Bax, NLRP3, and oxidative stress markers. Thus, PF exhibits therapeutic potential for left ventricular remodeling post-AMI at high altitude by inhibiting cuproptosis, inflammation, apoptosis and fibrosis. Further studies are warranted to optimize dosage and duration and elucidate PF's mechanisms of action.

Hinokitiol protects gastric injury from ethanol exposure via its iron sequestration capacity.

Hinokitiol is a natural bioactive tropolone derivative isolated from Chamaecyparis obtusa and Thuja plicata, which exhibits promising potential in terms of antioxidant and anti-inflammatory properties and possesses potent iron-binding capacity. In this study, we aimed to investigate the potential role of hinokitiol in protecting against ethanol-induced gastric injury and elucidate the underlying mechanism. Our results demonstrated that hinokitiol effectively attenuated hemorrhagic gastric lesions, epithelial cell loss, and inflammatory response in mice with ethanol-induced gastric injury. Intriguingly, we found that ethanol exposure affects iron levels both in vivo and in vitro. Moreover, the disturbed iron homeostasis was involved in the development of ethanol-induced injury. Iron depletion was found to enhance defense against ethanol-induced damage, while iron repletion showed the opposite effect. To further explore the role of iron sequestration in the protective effects of hinokitiol, we synthesized methylhinokitiol, a compound that shields the iron binding capacity of hinokitiol with a methyl group. Interestingly, this compound significantly diminishes the protective effect against ethanol-induced injury. These findings collectively demonstrated that hinokitiol could potentially be used to prevent or improve gastric injury induced by ethanol through regulating cellular iron homeostasis.

Perillaldehyde: A promising antibacterial agent for the treatment of pneumonia caused by Acinetobacter baumannii infection.

Perillaldehyde is a monoterpene compound mainly from the medicinal plant Perilla frutescens (L.) Britt., which has hypolipidemic, antioxidant, antibacterial and anti-inflammatory functions. In this investigation, we discovered that Perillaldehyde had powerful antimicrobial activity against Acinetobacter baumannii 5F1, and its minimum inhibitory concentration was 287.08 µg/mL. A. baumannii is a conditionally pathogenic bacterium with a high clinical resistance rate and is a major source of hospital infections, especially in intensive care units, which is one of the main causes of pneumonia. Inflammatory immune response is characteristic of pneumonia caused by A. baumannii infection. The results of our in vitro experiments indicate that Perillaldehyde disrupts the cell membrane of A. baumannii 5F1 and inhibits its quorum sensing to inhibit biofilm formation, among other effects. With an experimental model of murine pneumonia, we investigated that Perillaldehyde decreased NLRP3 inflammasome activation and TNF-α expression in lung tissues by inhibiting the NF-κB pathway, and also impacted MAPKs protein signaling pathway through the activation of TLR4. Notably, the use of high doses of Perillaldehyde for the treatment of pneumonia caused by A. baumannii 5F1 infection resulted in a survival rate of up to 80 % in mice. In summary, we demonstrated that Perillaldehyde is promising as a new drug for the treatment of pneumonia caused by A. baumannii 5F1 infection.

Monoterpenoids: An upcoming class of therapeutic agents for modulating cancer metastasis.

Monoterpenoids, a sub-class of terpenoids, are secondary metabolites frequently extracted from the essential oils of aromatic plants. Their antitumor properties including antiproliferative, apoptotic, antiangiogenic, and antimetastatic effects along with other biological activities have been the subject of extensive study due to their diverse characteristics. In recent years, numerous investigations have been conducted to understand its potential anticancer impacts, specifically focusing on antiproliferative and apoptotic mechanisms. Metastasis, a malignancy hallmark, can exert either protective or destructive influences on tumor cells. Despite this, the potential antimetastatic and antiangiogenic attributes of monoterpenoids need further exploration. This review focuses on specific monoterpenoids, examining their effects on metastasis and relevant signaling pathways. The monoterpenoids exhibit a high level of complexity as natural products that regulate metastatic proteins through various signaling pathways, including phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin, mitogen-activated protein kinase/extracellular signal-regulated kinase/jun N-terminal kinase, nuclear factor kappa B, vascular endothelial growth factor, and epithelial mesenchymal transition process. Additionally, this review delves into the biosynthesis and classification of monoterpenoids, their potential antitumor impacts on cell lines, the plant sources of monoterpenoids, and the current status of limited clinical trials investigating their efficacy against cancer. Moreover, monoterpenoids depict promising potential in preventing cancer metastasis, however, inadequate clinical trials limit their drug usage. State-of-the-art techniques and technologies are being employed to overcome the challenges of utilizing monoterpenoids as an anticancer agent.

Promoting reverse cholesterol transport contributes to the amelioration of atherosclerosis by paeoniflorin.

Reverse cholesterol transport (RCT) offers a practical approach to mitigating atherosclerosis. Paeoniflorin, a monoterpenoid glycoside found in plants of the Paeoniaceae family, has shown various effects on cardiovascular and liver diseases. Nevertheless, its impact on atherosclerosis in vivo remains poorly understood. The objective of this study is to examine the effect of paeoniflorin on atherosclerosis using apolipoprotein E-deficient (ApoE-/-) mice and explore the underlying mechanisms, with a specific focus on its modulation of RCT. ApoE-/- mice were continuously administered paeoniflorin by gavage for three months. We assessed lipid parameters in serum and examined pathological changes and gene expressions related to RCT pathways in the aorta, liver, and intestine. In an in vitro study, we utilized RAW264.7 macrophages to investigate the inhibitory effect of paeoniflorin on foam cell formation and its potential to promote RCT. The results revealed that paeoniflorin reduced atherosclerosis, alleviated hyperlipidemia, and mitigated hepatic steatosis. Paeoniflorin may promote RCT by stimulating cholesterol efflux from macrophages via the liver X receptor alpha pathway, enhancing serum high-density lipoprotein cholesterol and apolipoprotein A-I levels, and regulating key genes in hepatic and intestinal RCT. Additionally, treatment ApoE-/- mice with paeoniflorin suppressed the expression of inflammation-related genes, including CD68, tumor necrosis factor alpha, and monocyte chemoattractant protein-1, and mitigated oxidative stress in both the aorta and liver. Our results indicated that paeoniflorin has the potential to be a more effective and safer treatment for atherosclerosis, thanks to its promotion of RCT and its anti-inflammatory and anti-oxidative effects.

Current and Potential Applications of Monoterpenes and Their Derivatives in Oral Health Care.

Plant products have been employed in medicine for centuries. As the world becomes more health-conscious, there is a growing interest in natural and minimally processed products for oral health care. This has led to an increase in research into the bioactive compounds found in plant products, particularly monoterpenes. Monoterpenes are known to have beneficial biological properties, but the specific mechanisms by which they exert their effects are not yet fully understood. Despite this, some monoterpenes are already being used in oral health care. For example, thymol, which has antibacterial properties, is an ingredient in varnish used for caries prevention. In addition to this, monoterpenes have also demonstrated antifungal, antiviral, and anti-inflammatory properties, making them versatile for various applications. As research continues, there is potential for even more discoveries regarding the benefits of monoterpenes in oral health care. This narrative literature review gives an overview of the biological properties and current and potential applications of selected monoterpenes and their derivatives in oral health care. These compounds demonstrate promising potential for future medical development, and their applications in future research are expected to expand.

Inhibition of autophagy and induction of glioblastoma cell death by NEO214, a perillyl alcohol-rolipram conjugate.

Glioblastoma (GBM) is the most aggressive primary brain tumor, exhibiting a high rate of recurrence and poor prognosis. Surgery and chemoradiation with temozolomide (TMZ) represent the standard of care, but, in most cases, the tumor develops resistance to further treatment and the patients succumb to disease. Therefore, there is a great need for the development of well-tolerated, effective drugs that specifically target chemoresistant gliomas. NEO214 was generated by covalently conjugating rolipram, a PDE4 (phosphodiesterase 4) inhibitor, to perillyl alcohol, a naturally occurring monoterpene related to limonene. Our previous studies in preclinical models showed that NEO214 harbors anticancer activity, is able to cross the blood-brain barrier (BBB), and is remarkably well tolerated. In the present study, we investigated its mechanism of action and discovered inhibition of macroautophagy/autophagy as a key component of its anticancer effect in glioblastoma cells. We show that NEO214 prevents autophagy-lysosome fusion, thereby blocking autophagic flux and triggering glioma cell death. This process involves activation of MTOR (mechanistic target of rapamycin kinase) activity, which leads to cytoplasmic accumulation of TFEB (transcription factor EB), a critical regulator of genes involved in the autophagy-lysosomal pathway, and consequently reduced expression of autophagy-lysosome genes. When combined with chloroquine and TMZ, the anticancer impact of NEO214 is further potentiated and unfolds against TMZ-resistant cells as well. Taken together, our findings characterize NEO214 as a novel autophagy inhibitor that could become useful for overcoming chemoresistance in glioblastoma.Abbreviations: ATG: autophagy related; BAFA1: bafilomycin A1; BBB: blood brain barrier; CQ: chloroquine; GBM: glioblastoma; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MGMT: O-6-methylguanine-DNA methyltransferase; MTOR: mechanistic target of rapamycin kinase; MTORC: MTOR complex; POH: perillyl alcohol; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TMZ: temozolomide.

Anti-inflammatory and pro-regenerative effects of a monoterpene glycoside on experimental periodontitis in a rat model of diabetes.

OBJECTIVE: Paeoniflorin (Pae) is a monoterpene glycoside with immune-regulatory effects. Several studies have already demonstrated the impact of Pae on periodontitis, but its effect on diabetic periodontitis is unclear. In this study, our aim was to test the hypothesis that Pae had a strong anti-inflammatory effect that prevented bone loss in diabetic periodontitis. METHODS: Thirty male Wistar albino rats were randomly divided into control (healthy, n = 10), periodontitis (PD) + diabetes (DM; n = 10), and PD + DM + Pae (n = 10) groups. Ligature-induced periodontitis was created by placing 4-0 silk ligatures around the lower first molars on both sides of the mandibulae. Experimental DM was created via an injection of 50 mg/kg and streptozotocin (STZ). Hyperglycemia was confirmed by the blood glucose levels of rats (>300 mg/dL). The bone mineral density (BMD), trabecular number, trabecular thickness, and bone loss were measured by micro-CT. The expression levels of IL-1ß, IL-6, and TNF-α were measured in tissue homogenates by ELISA. RESULTS: The PD + DM + Pae group had significantly less alveolar crest resorption when compared to the PD + DM group. There was also a significant difference between the PD + DM + Pae group compared to PD + DM group in trabecular thickness, BMD, and the number of trabeculae. Pae application led to a statistically significant decrease in IL-1ß, IL-6, and TNF-α levels in diabetic periodontitis. CONCLUSION: Systemic application of Pae suppressed inflammation caused by PD and DM, leading to reduced bone loss and enhanced bone quality.

Linalool: Monoterpene alcohol effectiveness in chronic synovitis through lowering Interleukin-17, spleen and thymus indices.

Interleukin-17 has a positive role in the initial induction and late chronic phases of many inflammatory disorders like arthritis. This cytokine has a strong option for therapeutic targeting due to the fact that it was found in the inflamed joints of individual with rheumatoid arthritis (RA) and persuasive evidence from experimental arthritis models indicating its pro-inflammatory actions. IL-17 suppression lessened the asperity of arthritis. The present study aimed to assess the anti-arthritic potential of linalool in a model of chronic joint inflammation (CFA-mediated rheumatoid arthritis) in rats. Linalool markedly lowered spleen and thymus indices as opposed to arthritic control. The over-formation of IL-17, COX-2, TNF-α IL-1ß, iNOS and IL-6 were markedly impaired in all linalool treated rats, but IL-10 was raised as compared to arthritic animals in Real time-PCR. There was reduction in associated parameters like paw volume, arthritic index, mobility score, and flexion pain score and a marked increase in stance score in CFA model as compared to the arthritic control group. Furthermore, there was improvement in body weight, hematological, tissue, and radiological parameters in the CFA-model. Molecular docking study exhibited strong binding interaction of linalool with IL-17, PGE-2, iNOS and COX-2, thus providing a good correlation among experimental and theoretical results. The current findings show that linalool reduces adjuvant arthritis by suppressing pro-inflammatory mediators, arthritic development, and spleen and thymus indices. Thus, linalool may be employed therapeutically to alleviate arthritis in humans.

Evaluation of the antinociceptive effect generated by citronellal monoterpene isomers.

Due to the complex nature of pain and the participation of physical, cognitive, psychological and behavioral aspects, pain management has several approaches. The use of medicinal plants in developing countries is quite expressive. Seeking new options for the treatment of emerging or debilitating diseases. Therefore, the present study seeks to elucidate the effects of the monoterpene, citronellal, differentiating its activity by isomers (R)-(+) and (S)-(-) citronellal. The study used several methods to evaluate the effects of citronellal isomers on motor coordination, nociceptive response, and the involvement of opioid, glutamatergic, and transient receptor pathways. The methods included rota-rod, hot-plate, and formalin tests, as well as the use of specific inhibitors and agonists. Data were analyzed using inferential statistics with a 95% confidence level. Both isomers did not significantly affect the motor coordination of the studied animals. The isomer (S)-(-) citronellal showed better results in relation to its structural counterpart, managing to have an antinociceptive effect in the formalin and hot plate tests with a lower concentration (100 mg/kg) and presenting fewer side effects, however, the this study was not able to elucidate the mechanism of action of this isomer despite having activity in studies with substances that act on specific targets such as glutamate and capsaicin, its activity was not reversed with the use of antagonists for pathways related to nociception. While the (R)-(+) citronellal isomer, despite showing total activity only at a concentration of 150 mg/kg, was able to determine its mechanism of action related to the opioid pathway by reversing its activity by the antagonist naloxone, being this is a pathway already correlated with nociception control treatments, however, it is also related to some unwanted side effects. In this way, new studies are sought to elucidate the mechanism related to the isomer (S)-(-) citronellal and a possibility of use in other areas related to the treatment of pain or inflammation.

Paeoniflorin Attenuates Lipopolysaccharide-Induced Cognitive Dysfunction by Inhibition of Amyloidogenesis in Mice.

Alzheimer's disease (AD) is a neurodegenerative disease, associated with progressive cognitive impairment and memory loss. In the present study, we examined the protective effects of paeoniflorin against memory loss and cognitive decline in lipopolysaccharide (LPS)-induced mice. Treatment with paeoniflorin alleviated LPS-induced neurobehavioral dysfunction, as confirmed by behavioral tests, including the T-maze test, novel-object recognition test, and Morris water maze test. LPS stimulated the amyloidogenic pathway-related proteins (amyloid precursor protein, APP; ß-site APP cleavage enzyme, BACE; presenilin1, PS1; presenilin2, PS2) expression in the brain. However, paeoniflorin decreased APP, BACE, PS1, and PS2 protein levels. Therefore, paeoniflorin reverses LPS-induced cognitive impairment via inhibition of the amyloidogenic pathway in mice, which suggests that paeoniflorin may be useful in the prevention of neuroinflammation related to AD.

Regenerative marine waste towards CaCO3 nanoformulation for Alzheimer's therapy.

Alzheimer's disorder (AD) is associated with behavioural and cognitive destruction with due respect to the neurological degeneration. Conventional therapeutic approach for treatment of AD using neuroprotective drugs suffered certain limitations such as poor solubility, insufficient bioavailability, adverse side effects at higher dose and ineffective permeability on blood brain barrier (BBB). Development of nanomaterial based drug delivery system helped to overcome these barriers. Hence the present work focused on encapsulating neuroprotective drug citronellyl acetate within CaCO3 nanoparticles to develop neuroprotective CaCO3 nanoformulation (CA@CaCO3 NFs). CaCO3 was derived from marine conch shell waste, while the neuroprotective drug citronellyl acetate was scrutinized by in-silico high throughput screening. In-vitro findings revealed that CA@CaCO3 nanoformulation exhibited enhanced free radical scavenging activity of 92% (IC50 value - 29.27 ± 2.6 µg/ml), AChE inhibition of 95% (IC50 value - 25.6292 ± 1.5 µg/ml) at its maximum dose (100 µg/ml). CA@CaCO3 NFs attenuated the aggregation of ß-amyloid peptide (Aß) and also disaggregated the preformed mature plaques the major risk factor for AD. Overall, the present study reveals that CaCO3 nanoformulations exhibits potent neuroprotective potential when compared to the CaCO3 nanoparticles alone and citronellyl acetate alone due to the sustained drug release and synergistic effect of CaCO3 nanoparticles and citronellyl acetate depicting the fact that CaCO3 can act as promising drug delivery system for treatment of neurodegenerative and CNS related disorders.

Natural Monoterpenes as Potential Therapeutic Agents against Atherosclerosis.

Traditional herbal medicines based on natural products play a pivotal role in preventing and managing atherosclerotic diseases, which are among the leading causes of death globally. Monoterpenes are a large class of naturally occurring compounds commonly found in many aromatic and medicinal plants. Emerging evidence has shown that monoterpenes have many biological properties, including cardioprotective effects. Remarkably, an increasing number of studies have demonstrated the therapeutic potential of natural monoterpenes to protect against the pathogenesis of atherosclerosis. These findings shed light on developing novel effective antiatherogenic drugs from these compounds. Herein, we provide an overview of natural monoterpenes' effects on atherogenesis and the underlying mechanisms. Monoterpenes have pleiotropic and multitargeted pharmacological properties by interacting with various cell types and intracellular molecular pathways involved in atherogenesis. These properties confer remarkable advantages in managing atherosclerosis, which has been recognized as a multifaceted vascular disease. We also discuss limitations in the potential clinical application of monoterpenes as therapeutic agents against atherosclerosis. We propose perspectives to give new insights into future preclinical research and clinical practice regarding natural monoterpenes.