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Purpose: We aimed to evaluate the clinical efficacy of a combined treatment regimen involving terpinen-4-ol (T4O) and eyelid deep cleaning for managing Demodex blepharitis., Methods: In this randomized, open-label trial, 40 patients diagnosed with Demodex blepharitis at the Cornea Specialty Clinic of Hankou Aier Eye Hospital were enrolled. Participants were randomly assigned to either a T4O or a combination treatment group. The T4O group used T4O cleaning wipes exclusively for two months. The combination group used T4O cleaning wipes and underwent deep eyelid cleaning at three scheduled visits (initial, first-, and second-month time points). A final follow-up was conducted one month after completion of treatment (three months after the beginning of treatment). At each visit, we assessed the number of Demodex mites, the ocular surface disease index (OSDI), eyelid margin sign scores, and corneal fluorescein staining scores., Results: After two months of treatment, both the T4O and combination groups exhibited significant reductions in Demodex mite counts of 5.65 ± 6.03 and 7.75 ± 6.91, respectively. The T4O group, however, showed an increase in mite counts one month after ceasing treatment. Conversely, the combination group maintained and enhanced the reduction in mite counts post-treatment, with a significant difference at the third-month follow-up (8.70 ± 6.81 vs. 4.15 ± 6.91, P = 0.043). Although both groups demonstrated overall declines in OSDI scores post-treatment, only the combination group showed significant improvements at the second- and third-month follow-ups. No adverse events were reported in either group., Conclusions: Treatment with T4O wipes for two months significantly reduces Demodex mite counts, although there is a notable risk of mite rebound when treatment is ceased. Combining T4O wipes and eyelid deep cleaning offers a more effective reduction in Demodex mite counts and improvement in ocular symptoms compared to T4O treatment alone., Translational Relevance: The study finds that T4O combined with eyelid deep cleaning is more effective in treating Demodex blepharitis, highlighting the need for appropriate treatment duration and adjunctive therapies.

Abstract: Terpenes are small hydrocarbon compounds that impart aroma and taste to many plants, including Cannabis sativa . A number of studies have shown that terpenes can produce pain relief in various pain states in both humans and animals. However, these studies were methodologically limited and few established mechanisms of action. In our previous work, we showed that the terpenes geraniol, linalool, β-pinene, α-humulene, and β-caryophyllene produced cannabimimetic behavioral effects via multiple receptor targets. We thus expanded this work to explore the potential antinociception and mechanism of these Cannabis terpenes in a mouse model of chronic pain. We first tested for antinociception by injecting terpenes (200 mg/kg, IP) into male and female CD-1 mice with mouse models of chemotherapy-induced peripheral neuropathy (CIPN) or lipopolysaccharide-induced inflammatory pain, finding that the terpenes produced roughly equal antinociception to 10 mg/kg morphine or 3.2 mg/kg WIN55,212. We further found that none of the terpenes produced reward as measured by conditioned place preference, while low doses of terpene (100 mg/kg) combined with morphine (3.2 mg/kg) produced enhanced antinociception vs either alone. We then used the adenosine A 2A receptor (A 2A R) selective antagonist istradefylline (3.2 mg/kg, IP) and spinal cord-specific CRISPR knockdown of the A 2A R to identify this receptor as the mechanism for terpene antinociception in CIPN. In vitro cAMP and binding studies and in silico modeling studies further suggested that the terpenes act as A 2A R agonists. Together these studies identify Cannabis terpenes as potential therapeutics for chronic neuropathic pain and identify a receptor mechanism for this activity., (Copyright © 2024 International Association for the Study of Pain.)

Statement of Problem: Overcoming compromised oral hygiene and susceptibility to opportunistic oropharyngeal candidal infections in patients with a maxillectomy are critical challenges. Tissue conditioners incorporated with lemongrass essential oil has been shown to have promising antifungal properties, but the effects of this incorporation on the mechanical properties of tissue conditioners remain unexplored., Purpose: The purpose of this in vitro study was to assess the effects of lemongrass essential oil incorporation at various concentrations on the tensile bond strength (TBS) and Shore A hardness (SAH) of tissue conditioners. The presence of lemongrass essential oil in the tissue conditioner was evaluated by using Raman spectroscopy., Material and Methods: Unmodified tissue conditioner served as the control, whereas tissue conditioner incorporated with lemongrass essential oil (final concentrations of 1.77%, 3.56%, and 7.17% [w/w]) and tissue conditioner incorporated with Nystatin served as the experimental groups. The SAH of Coe-Comfort specimens was measured at 2 hours, 24 hours, 7 days, and 30 days for each testing group (n=3/group). The TBS of tissue conditioner to denture base acrylic resin was determined by using a universal testing machine at a crosshead speed of 10 mm/minute (n=10/group). Furthermore, Raman spectra for the control and experimental tissue conditioner groups were obtained at 24 hours and 14 days. The data were analyzed with 2-way repeated measures ANOVA followed by the post hoc Bonferroni multiple comparison test for SAH testing and the 1-way ANOVA followed by the post hoc Tukey HSD multiple comparison test for TBS testing (α=.05)., Results: The unmodified tissue conditioner, 1.77% (w/w) lemongrass essential oil incorporated tissue conditioner, and Nystatin incorporated tissue conditioner showed no significant difference in SAH at ≤7 days (P>.05). However, at 30 days, the 1.77% (w/w) lemongrass essential oil and Nystatin groups showed no significant difference in SAH (P=.136), but both groups had significantly lower SAH compared with the control group (P=.016 and P<.001, respectively). The incorporation of 1.77% (w/w) lemongrass essential oil in tissue conditioners had no significant effect on TBS compared with the control group (P=.184), although both possessed significantly higher TBS than all remaining groups. In contrast, tissue conditioner incorporated with lemongrass essential oil concentrations ≥3.56% (w/w) and Nystatin showed a statistically significant decrease in TBS (P<.001). Raman spectrum analysis confirmed the presence of citral bands in the lemongrass essential oil incorporated specimens at 2 hours and 14 days, verifying its long-lasting presence., Conclusions: Incorporation of lemongrass essential oil in tissue conditioners at 1.77% (w/w) concentration produced both long-lasting antifungal properties and acceptable mechanical properties (SAH and TBS)., (Copyright © 2024 Editorial Council for The Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.)

Ethnopharmacological Relevance: Saffron, a traditional Chinese medicine, is derived from Crocus sativus L. stigmas and has been reported to possess neuroprotective properties and potentially contribute to the inhibition of apoptosis and inflammation. Safranal, a potent monothyral aldehyde, is a main component of saffron that has been reported to have antiepileptic activity. However, the specific mechanism by which safranal suppresses epileptic seizures via its antiapoptotic and anti-inflammatory properties is unclear., Aim: To evaluate the effect of safranal on seizure severity, inflammation, and postictal neuronal apoptosis in a mouse model of pentetrazole (PTZ)-induced seizures and explore the underlying mechanism involved., Materials and Methods: The seizure stage and latency of stage 2 and 4 were quantified to assess the efficacy of safranal in mitigating PTZ-induced epileptic seizures in mice. Electroencephalography (EEG) was employed to monitor epileptiform afterdischarges in each experimental group. The cognitive abilities and motor functions of the mice were evaluated using the novel object recognition test and the open field test, respectively. Neurons were quantified using hematoxylin and eosin staining. Additionally, bioinformatics tools were utilized to predict the interactions between safranal and specific target proteins. Glycogen synthase kinase-3β (GSK-3β), mitochondrial apoptosis-related proteins, and inflammatory factor levels were analyzed through western blotting. Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) concentrations in brain tissue were assessed by ELISA., Results: Safranal decreased the average seizure stage and increased the lantency of stage 2 and 4 seizures in PTZ-induced epileptic mice. Additionally, safranal exhibited neuroprotective effects on hippocampal CA1 and CA3 neurons and reduced hyperactivity caused by postictal hyperexcitability. Bioinformatics analysis revealed that safranal can bind to five specific proteins, including GSK-3β. By promoting Ser9 phosphorylation and inhibiting GSK-3β activity, safranal effectively suppressed the NF-κB signaling pathway. Moreover, the findings indicate that safranal treatment can decrease TNF-α and IL-1β levels in the cerebral tissues of epileptic mice and downregulate mitochondrial apoptosis-related proteins, including Bcl-2, Bax, Bak, Caspase 9, and Caspase 3., Conclusion: Safranal can suppress the NF-κB signaling pathway and mitochondrial-dependent apoptosis through GSK-3β inactivation, suggesting that it is a promising therapeutic agent for epilepsy treatment., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Nephrotoxicity occurs when the body is exposed to certain drugs or toxins. When kidney damage occurs, the kidney fails to eliminate excess urine and waste. Solanesol (C45H74O) is a tri-sesquiterpenoid alcohol first isolated from tobacco, and it is widely distributed in plants of the Solanaceae family. Solanesol (SNL) is an intermediate in the synthesis of coenzyme Q10 (CoQ10), an antioxidant which protects nerve cells. This study investigated the protective effect of SNL at doses of 30 and 60 mg/kg in gentamicin-induced nephrotoxicity in Wistar albino rats. Animals were distributed into six groups and administered 100 mg/kg gentamicin-intraperitoneal injection for 14 days. Biochemical assessments were performed on kidney homogenate, blood, and serum. Treatment with SNL was shown as lower serum levels of creatinine, blood urea nitrogen (BUN), thiobarbituric acid reactive substances (TBARS), and Tumor necrosis factor alpha)TNF-α ((p < .001). It also restored reduced glutathione (GSH) and mitochondrial complex enzymatic activity as protective measures against gentamicin-induced nephrotoxicity. SNL were shown to reduce inflammation and oxidative stress markers (p < .001). Histological findings furtherly augmented the protective effects of SNL. Long-term SNL therapy also restored mitochondrial electron transport chain complex enzymes, such as complex-I (p < .001). In conclusion, these findings suggest that SNL can represent a protective therapeutic option for drug-induced nephrotoxicity, a long-term adverse effect of aminoglycoside antibiotics such as gentamicin., (© 2024 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

This review focus on the terpenoids as potential therapeutic agents for depression and anxiety disorders, which naturally found in a variety of plants and exhibit a wide range of biological activities. Among the terpenoids discussed in this review are α-pinene, β-caryophyllene, α-phellandrene, limonene, β-linalool, 1, 8-cineole, β-pinene, caryophyllene oxide, p-cymene, and eugenol. All of these compounds have been studied extensively regarding their pharmacological properties, such as neuroprotective effect, anti-inflammation, antibacterial, regulation of neurotransmitters and antioxidant effect. Preclinical evidence are reviewed to highlight their diverse mechanisms of action and therapeutic potential to support antidepressant and anxiolytic properties. Additionally, challenges and future directions are also discussed to emphasize therapeutic utility of terpenoids for mental health disorders. Overall, this review provides a promising role of terpenoids as novel therapeutic agents for depression and anxiety, with potential implications for the development of more effective and well-tolerated treatments in the field of psychopharmacology., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Background: In recent decades, natural compounds have been considered a significant source of new antitumor medicines due to their unique advantages. Several in vitro and in vivo studies have focused on the effect of terpenoids on apoptosis mediated by mitochondria in malignant cells., Recent Findings: In this review article, we focused on six extensively studied terpenoids, including sesquiterpenes (dihydroartemisinin and parthenolide), diterpenes (oridonin and triptolide), and triterpenes (betulinic acid and oleanolic acid), and their efficacy in targeting mitochondria to induce cell death. Terpenoid-induced mitochondria-related cell death includes apoptosis, pyroptosis, necroptosis, ferroptosis, autophagy, and necrosis caused by mitochondrial permeability transition. Apoptosis and autophagy interact in meaningful ways. In addition, in view of several disadvantages of terpenoids, such as low stability and bioavailability, advances in research on combination chemotherapy and chemical modification were surveyed., Conclusion: This article deepens our understanding of the association between terpenoids and mitochondrial cell death, presenting a hypothetical basis for the use of terpenoids in anticancer management., (© 2024 The Author(s). Cancer Reports published by Wiley Periodicals LLC.)

Background: Inflammatory bowel disease (IBD) represents a significant global health challenge, and there is an urgent need to explore novel therapeutic interventions. Natural products have demonstrated highly promising effectiveness in the treatment of IBD., Purpose: This study systematically reviews the latest research advancements in leveraging natural products for IBD treatment., Methods: This manuscript strictly adheres to the PRISMA guidelines. Relevant literature on the effects of natural products on IBD was retrieved from the PubMed, Web of Science and Cochrane Library databases using the search terms "natural product," "inflammatory bowel disease," "colitis," "metagenomics", "target identification", "drug delivery systems", "polyphenols," "alkaloids," "terpenoids," and so on. The retrieved data were then systematically summarized and reviewed., Results: This review assessed the different effects of various natural products, such as polyphenols, alkaloids, terpenoids, quinones, and others, in the treatment of IBD. While these natural products offer promising avenues for IBD management, they also face challenges in terms of clinical translation and drug discovery. The advent of metagenomics, single-cell sequencing, target identification techniques, drug delivery systems, and other cutting-edge technologies heralds a new era in overcoming these challenges., Conclusion: This paper provides an overview of current research progress in utilizing natural products for the treatment of IBD, exploring how contemporary technological innovations can aid in discovering and harnessing bioactive natural products for the treatment of IBD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Chronic kidney disease (CKD) is a chronic and progressive systemic condition that characterizes irreversible alterations in the kidneys' function and structure over an extended period, spanning months to years. CKD is the one of the major causes of mortality worldwide. However, very limited treatment options are available in the market for management of the CKD. Diabetes and hypertension are the key risk factors for the progression of CKD. It is majorly characterised by glomerulosclerosis, tubular atrophy, and interstitial fibrosis. Plants are considered safe and effective in treating various chronic conditions. A diverse group of phytoconstituents, including polyphenols, flavonoids, alkaloids, tannins, saponins, and terpenes, have found significant benefits in managing chronic ailments. Terpenes constitute a diverse group of plant compounds with various therapeutic benefits. Evidence-based pharmacological studies underscore the crucial role played by terpenes in preventing and managing CKD. These substances demonstrate the capacity to hinder detrimental pathways, such as oxidative stress, inflammation and fibrosis, thereby demonstrating benefit in renal dysfunction. This review offers a comprehensive overview of the roles and positive attributes of commonly occurring terpenes in managing the causes and risk factors of CKD and the associated conditions., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: The continuously increasing extracellular matrix stiffness during intervertebral disc degeneration promotes disease progression. In an attempt to obtain novel treatment methods, this study aims to investigate the changes in nucleus pulposus cells under the stimulation of a stiff microenvironment., Design: RNA sequencing and metabolomics experiments were combined to evaluate the primary nucleus pulposus and screen key targets under mechanical biological stimulation. Additionally, small molecules work in vitro were used to confirm the target regulatory effect and investigate the mechanism. In vivo, treatment effects were validated using a rat caudal vertebrae compression model., Results: Our research results revealed that by activating TRPC6, hyperforin, a herbaceous extract can rescue the inflammatory phenotype caused by the stiff microenvironment, hence reducing intervertebral disc degeneration (IDD). Mechanically, it activates mitochondrial fission to inhibit PFKFB3., Conclusion: In summary, this study reveals the important bridging role of TRPC6 between mechanical stiffness, metabolism, and inflammation in the context of nucleus pulposus degeneration. TRPC6 activation with hyperforin may become a promising treatment for IDD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Plantar fasciitis is the most common cause of heel pain in adults with an overall prevalence of 0.85% in the adult population of the US, affecting over 2 million adults annually. Most current treatment modalities are not supported by sufficient evidence to recommend one particular strategy over another. Topical application of analgesics for soft tissue pain is well established, however the plantar fascia presents challenges in this regard due to thick skin, fibrotic tissue, and an often thickened fat pad. Sixty-two patients with plantar fasciitis were randomized to a placebo controlled trial testing the efficacy of a topical solution of plant terpenes containing camphor, menthol, eugenol, eucalyptol, and vanillin. Skin permeation of the mixture was enhanced with 15% dimethylsulfoxide (DMSO), 1% limonene, and rosemary oil. One ml of solution was applied topically twice daily, and pain scores evaluated on Day 0, Day 1, Day 3, and Day 10. Using the validated foot function index 78.1% of patients reported an 85% or greater decrease in their total pain score by day 10 while placebo treatment was without effect (One Way ANOVA, P < 0.01). This study adapts the treatment modality of topical analgesia for soft tissue pain to a problematic area of the body and shows therapeutic promise.ClinicalTrials.gov Identifier: NCT05467631., (© 2024. The Author(s).)

Gastrointestinal cancers continue to pose a significant global health challenge, with millions of new cases diagnosed each year. Despite advancements in treatment, the prognosis for many patients remains poor. This article explores the potential of garcinol, a polyisoprenylated benzophenone found in various Garcinia species, as a therapeutic agent against gastrointestinal malignancies. The objective is to review recent research on garcinol's anticancer properties, its mechanisms of action, and safety aspects. Garcinol exhibits anticancer effects in esophageal, gastric, colorectal, pancreatic, and liver cancers by inhibiting metastasis, inducing apoptosis, and targeting key molecular pathways in cancer progression. Nanotechnology is explored as a means to enhance garcinol delivery and efficacy. Safety assessments suggest a promising toxicity profile. Garcinol shows significant potential as a natural therapeutic agent for gastrointestinal cancers, and future research is needed on optimizing its delivery, exploring synergistic combinations, and conducting clinical trials to validate its efficacy and safety for clinical applications., (© 2024. The Author(s).)

Background: Diabetes mellitus, a hyperglycemic condition associated with multitudinous organ dysfunction, is a hallmark of the metabolic disorder. This life-threatening condition affects millions of individuals globally, harming them financially, physically and psychologically in the course of therapy., Purposes: The course therapy for illnesses has undergone ground-breaking transformations due to recent technical advances and insights. Alternatively, the administration of hyperglycemia-reducing agents results in several complications, including severe cardiovascular disease, kidney failure, hepatic problems, and several dermatological conditions. Consideration of alternate diabetic therapy having minimal side effects or no adverse reactions has been driven by such problems., Study Design: An extensive literature study was conducted in authoritative scientific databases such as PubMed, Scopus, and Web of Science to identify the studies elucidating the bioactivities of terpenoids in diabetic conditions., Methods: Keywords including 'terpenoids', 'monoterpenes', 'diterpenes', 'sesquiterpenes', 'diabetes', 'diabetes mellitus', 'clinical trials', 'preclinical studies', and 'increased blood glucose' were used to identify the relevant research articles. The exclusion criteria, such as English language, duplication, open access, abstract only, and studies not involving preclinical and clinical research, were set. Based on these criteria, 937 relevant articles were selected for further evaluation., Results: Triterpenes can serve as therapeutic agents for diabetic retinopathy, peripheral neuropathy, and kidney dysfunction by inhibiting several pathways linked to hyperglycemia and its complications. Therefore, it is essential to draw special attention to these compounds' therapeutic effectiveness and provide scientific professionals with novel data., Conclusion: This study addressed recent progress in research focussing on mechanisms of terpenoid, its by-products, physiological actions, and therapeutic applications, particularly in diabetic and associated disorders., Competing Interests: Declaration of competing interest All authors declare no competing personal and financial interests., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Adaptation to psychosocial stress is psychologically distressing, initiating/promoting comorbidity with alcohol use disorders. Emerging evidence moreover showed that ethanol (EtOH) exacerbates social-defeat stress (SDS)-induced behavioral impairments, neurobiological sequelae, and poor therapeutic outcomes. Hence, this study investigated the effects of geraniol, an isoprenoid monoterpenoid alcohol with neuroprotective functions on EtOH escalated SDS-induced behavioral impairments, and neurobiological sequelae in mice. Male mice chronically exposed to SDS for 14 days were repeatedly fed with EtOH (2 g/kg, p. o.) from days 8-14. From days 1-14, SDS-EtOH co-exposed mice were concurrently treated with geraniol (25 and 50 mg/kg) or fluoxetine (10 mg/kg) orally. After SDS-EtOH translational interactions, arrays of behavioral tasks were examined, followed by investigations of oxido-inflammatory, neurochemicals levels, monoamine oxidase-B and acetylcholinesterase activities in the striatum, prefrontal-cortex, and hippocampus. The glial fibrillary acid protein (GFAP) expression was also quantified in the prefrontal-cortex immunohistochemically. Adrenal weights, serum glucose and corticosterone concentrations were measured. EtOH exacerbated SDS-induced low-stress resilience, social impairment characterized by anxiety, depression, and memory deficits were attenuated by geraniol (50 and 100 mg/kg) and fluoxetine. In line with this, geraniol increased the levels of dopamine, serotonin, and glutamic-acid decarboxylase enzyme, accompanied by reduced monoamine oxidase-B and acetylcholinesterase activities in the prefrontal-cortex, hippocampus, and striatum. Geraniol inhibited SDS-EtOH-induced adrenal hypertrophy, corticosterone, TNF-α, IL-6 release, malondialdehyde and nitrite levels, with increased antioxidant activities. Immunohistochemical analyses revealed that geraniol enhanced GFAP immunoreactivity in the prefrontal-cortex relative to SDS-EtOH group. We concluded that geraniol ameliorates SDS-EtOH interaction-induced behavioral changes via normalization of neuroimmune-endocrine and neurochemical dysregulations in mice brains., Competing Interests: Declaration of competing interest Authors declare that they have no conflict of interest and all experiments were approved and performed under the guidelines of Faculty of Basic Medical Sciences, Delta State University Animals Ethic Committee (REC/FBMS/DELSU/22/148) and the National Institutes of Health Guide for Care and Use of Laboratory Animals (Publication number: 85–23, revised 1985)., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Hepatic ischemia/reperfusion (I/R) injury is a significant clinical condition that can arise during liver resections, trauma, and shock. Geraniol, an isoterpene molecule commonly found in nature, possesses antioxidant and hepatoprotective properties. This study investigates the impact of geraniol on hepatic damage by inducing experimental liver I/R injury in rats., Methods: Twenty-eight male Wistar Albino rats weighing 350-400 g were utilized for this study. The rats were divided into four groups: control group, I/R group, 50 mg/kg geraniol+I/R group, and 100 mg/kg geraniol+I/R group. Ischemia times were set at 15 minutes with reperfusion times at 20 minutes. Ischemia commenced 15 minutes after geraniol administration. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactic acid were measured, along with superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activity levels in liver tissues. Liver tissues were also examined histopathologically., Results: It was observed that intraperitoneal administration of 50 mg/kg and 100 mg/kg geraniol significantly reduced AST, lactic acid, and tumor necrosis factor-alpha (TNF-α) levels. The serum ALT level decreased significantly in the 50 mg/kg group, whereas no significant decrease was found in the 100 mg/kg group. SOD and GPx enzyme activities were shown to increase significantly in the 100 mg/kg group. Although there was an increase in these enzyme levels in the 50 mg/kg group, it was not statistically significant. Similarly, CAT enzyme activity increased in both the 50 mg/kg and 100 mg/kg groups, but the increase was not significant. The Suzuki score significantly decreased in both the 50 mg/kg and 100 mg/kg groups., Conclusion: The study demonstrates that geraniol reduced hepatic damage both biochemically and histopathologically and increased antioxidant defense enzymes. These findings suggest that geraniol could be used to prevent hepatic I/R injury, provided it is corroborated by large-scale and comprehensive studies.

Background: Translational microbiome research using next-generation DNA sequencing is challenging due to the semi-qualitative nature of relative abundance data. A novel method for quantitative analysis was applied in this 12-week clinical trial to understand the mechanical vs. chemotherapeutic actions of brushing, flossing, and mouthrinsing against the supragingival dental plaque microbiome. Enumeration of viable bacteria using vPCR was also applied on supragingival plaque for validation and on subgingival plaque to evaluate interventional effects below the gingival margin., Methods: Subjects with gingivitis were enrolled in a single center, examiner-blind, virtually supervised, parallel group controlled clinical trial. Subjects with gingivitis were randomized into brushing only (B); brushing and flossing (BF); brushing and rinsing with Listerine® Cool Mint® Antiseptic (BA); brushing and rinsing with Listerine® Cool Mint® Zero (BZ); or brushing, flossing, and rinsing with Listerine® Cool Mint® Zero (BFZ). All subjects brushed twice daily for 1 min with a sodium monofluorophosphate toothpaste and a soft-bristled toothbrush. Subjects who flossed used unflavored waxed dental floss once daily. Subjects assigned to mouthrinses rinsed twice daily. Plaque specimens were collected at the baseline visit and after 4 and 12 weeks of intervention. Bacterial cell number quantification was achieved by adding reference amounts of DNA controls to plaque samples prior to DNA extraction, followed by shallow shotgun metagenome sequencing., Results: 286 subjects completed the trial. The metagenomic data for supragingival plaque showed significant reductions in Shannon-Weaver diversity, species richness, and total and categorical bacterial abundances (commensal, gingivitis, and malodor) after 4 and 12 weeks for the BA, BZ, and BFZ groups compared to the B group, while no significant differences were observed between the B and BF groups. Supragingival plaque vPCR further validated these results, and subgingival plaque vPCR demonstrated significant efficacy for the BFZ intervention only., Conclusions: This publication reports on a successful application of a quantitative method of microbiome analysis in a clinical trial demonstrating the sustained and superior efficacy of essential oil mouthrinses at controlling dental plaque compared to mechanical methods. The quantitative microbiological data in this trial also reinforce the safety and mechanism of action of EO mouthrinses against plaque microbial ecology and highlights the importance of elevating EO mouthrinsing as an integral part of an oral hygiene regimen., Trial Registration: The trial was registered on ClinicalTrials.gov on 31/10/2022. The registration number is NCT05600231., (© 2024. The Author(s).)

Context: Back pain is one of the most common problems experienced by patients after the cardiac electrophysiological study procedure. In addition, limitation of movement after the procedure negatively affects the comfort and satisfaction of patients., Objectives: The aim of this study was to determine the effect of back massage with frankincense and myrrh oil on back pain severity and comfort in patients who were to undergo cardiac electrophysiological study., Methods: This is a randomized controlled study with a pretest-posttest design. This study was conducted from October 2020 to March 2021, at the angio unit of a heart hospital at a university in Turkey. The study was completed with 30 patients in each group, a total of 90 people. Data were collected using a patient information form, a Visual Analogue Scale (VAS) and the General Comfort Questionnaire (GCQ). The intervention group and the placebo group received back massage with frankincense and myrrh essential oil and with jojoba fixed oil respectively. No intervention was applied to the control group., Results: There was no statistically significant difference between the post-procedure VAS values according to the groups. Except for sociocultural comfort, there were significant differences between the groups in terms of GCQ total scores and subscales at the first and last follow-up., Conclusions: Back massage with frankincense and myrrh oil increased overall comfort, physical comfort, the psychospiritual comfort. Additional research with a rigorous design is needed to determine its effect on pain., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

The prevalence of two major types of skin cancer, melanoma and non-melanoma skin cancer, has been increasing worldwide. Skin cancer incidence is estimated to rise continuously over the next 20 years due to ozone depletion and an increased life expectancy. Chemotherapeutic agents could affect healthy cells, and thus may be toxic to them and cause numerous side effects or drug resistance. Phytochemicals that are naturally occurring in fruits, plants, and herbs are known to possess various bioactive properties, including anticancer properties. Although the effects of phytochemicals are relatively milder than chemotherapeutic agents, the long-term intake of phytochemicals may be effective and safe in preventing tumor development in humans. Diverse phytochemicals have shown anti-tumorigenic activities for either melanoma or non-melanoma skin cancer. In this review, we focused on summarizing recent research findings of the natural and dietary terpenoids (eucalyptol, eugenol, geraniol, linalool, and ursolic acid) that have anticancer activities for both melanoma and non-melanoma skin cancers. These terpenoids may be helpful to protect skin collectively to prevent tumorigenesis of both melanoma and nonmelanoma skin cancers.

Hepatocellular carcinoma (HCC) is a challenging and very fatal liver cancer. The signal transducer and activator of transcription 3 (STAT3) pathway is a crucial regulator of tumor development and are ubiquitously active in HCC. Therefore, targeting STAT3 has emerged as a promising approach for preventing and treating HCC. Various natural bioactive compounds (NBCs) have been proven to target STAT3 and have the potential to prevent and treat HCC as STAT3 inhibitors. Numerous kinds of STAT3 inhibitors have been identified, including small molecule inhibitors, peptide inhibitors, and oligonucleotide inhibitors. Due to the undesirable side effects of the conventional therapeutic drugs against HCC, the focus is shifted to NBCs derived from plants and other natural sources. NBCs can be broadly classified into the categories of terpenes, alkaloids, carotenoids, and phenols. Most of the compounds belong to the family of terpenes, which prevent tumorigenesis by inhibiting STAT3 nuclear translocation. Further, through STAT3 inhibition, terpenes downregulate matrix metalloprotease 2 (MMP2), matrix metalloprotease 9 (MMP9) and vascular endothelial growth factor (VEGF), modulating metastasis. Terpenes also suppress the anti-apoptotic proteins and cell cycle markers. This review provides comprehensive information related to STAT3 abrogation by NBCs in HCC with in vitro and in vivo evidences., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Inflammatory bowel disease (IBD) refers to long-term medical conditions that involve inflammation of the digestive tract, and the global incidence and prevalence of IBD are on the rise. Gut microbes play an important role in maintaining the intestinal health of the host, and the occurrence, development, and therapeutic effects of IBD are closely related to the structural and functional changes of gut microbes. Published studies have shown that the natural products from traditional Chinese medicine have direct or indirect regulatory impacts on the composition and metabolism of the gut microbes. In this review, we summarize the research progress of several groups of natural products, i.e., flavonoids, alkaloids, saponins, polysaccharides, polyphenols, and terpenoids, for the therapeutic activities in relieving IBD symptoms. The role of gut microbes and their intestinal metabolites in managing the IBD is presented, with focusing on the mechanism of action of those natural products. Traditional Chinese medicine alleviated IBD symptoms by regulating gut microbes, providing important theoretical and practical basis for the treatment of variable inflammatory intestinal diseases.

Introduction: IDN5706 is a tetrahydro derivative of hyperforin. In this study, we aimed to explore the effect of IDN5706 on synovial macrophages in osteoarthritis (OA) rats and the underlying mechanisms., Methods: OA rats were employed for the in vivo experiments, and RAW264.7 cells were employed for the in vitro experiments. Histopathological changes in synovium were examined using hematoxylin-eosin staining. Cell apoptosis in synovium was assessed by TUNEL staining. Macrophage polarization was determined by immunohistochemical analysis and flow cytometry. The mRNA expression and protein level of genes were detected by qRT-PCR and Western blot. The efferocytosis of macrophages was assessed by flow cytometry., Results: IDN5706 reversed the increased CD86-positive cells (M1 macrophages) and decreased CD206-positive cells (M2 macrophages), both in synovium and synovial fluid of OA rats. The in vitro experiments further confirmed the promotion effect of IDN5706 on M2 macrophages, accompanied by the elevated Arg-1 and reduced iNOS. Also, the upregulated p-mTOR in synovium and synovial fluid of OA rats were reversed by IDN5706, and the decreased M1 macrophages and increased M2 macrophages induced by IDN5706 were reversed by the mTOR activator. IDN5706 enhanced the efferocytosis of IL-4-treated RAW264.7 cells, and the animal experiments further revealed the involvement of efferocytosis in the improvement of OA by IDN5706., Conclusions: IDN5706 enhanced the efferocytosis of synovial macrophages by inducing M2 polarization via inhibiting p-mTOR, thus suppressing synovial inflammation and OA development, providing a theoretical basis for IDN5706 as a clinical drug for inflammatory diseases., (© 2024 S. Karger AG, Basel.)

Diabetic nephropathy (DN) is the foremost ailment resulting in end-stage renal damage. Chronic hyperglycaemia and hyperlipidaemia are the foremost reason for disease progression. The disease is characterized by the severity of albuminuria and cardiovascular disorders. Approximately 20 to 40% of the global prevalence of DN is mostly reported to occur in individuals with diabetes, and nearly 28% of DN occurs in individuals with other renal disorders. The pathological mechanism is very complex, involving innumerable targets and leading to multiple pharmacological effects. Thus, the scientific community is forced to work in search of safe and potent therapeutics that can tackle the complex pathology of DN effectively. The secondary plant metabolites categorized as terpenoids gained attention as potential therapeutics contrary to others for the management of diabetic nephropathy and other associated syndromes by their strong antioxidant activity and inhibition of advanced glycation and its associated products. This review focused on herbal therapeutics for the management of diabetic nephropathy. Moreover, different types of terpenoids, their biological sources, and proposed mechanisms of action are explored for the development of a novel pharmacophore for diabetic nephropathy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Naegleria fowleri is one of the free-living amoebae and is a causative agent of a lethal and rare central nervous system infection called primary amoebic meningoencephalitis. Despite the advancement in antimicrobial chemotherapy, the fatality rate in the reported cases is more than 95%. Most of the treatment drugs used against N. fowleri infection are repurposed drugs. Therefore, a large number of compounds have been tested against N. fowleri in vitro , but most of the compounds showed high toxicity. To overcome this, we evaluated the effectiveness of naturally occurring terpene compounds against N. fowleri . In this study, we evaluated the antiamoebic potential of natural compounds including Thymol, Borneol, Andrographolide, and Forskolin against N. fowleri . Thymol showed the highest amoebicidal activity with IC 50 /24 h at 153.601 ± 19.6 μM. Two combinations of compounds Forskolin + Thymol and Forskolin + Borneol showed a higher effect on the viability of trophozoites as compared to compounds alone and hence showed a synergistic effect. The IC 50 reported for Forskolin + Thymol was 81.30 ± 6.86 μM. Borneol showed maximum cysticidal activity with IC 50 /24 h at 192.605 ± 3.01 μM. Importantly, lactate dehydrogenase release testing revealed that all compounds displayed minimal cytotoxicity to human HaCaT, HeLa, and SH-SY5Y cell lines. The cytopathogenicity assay showed that Thymol and Borneol also significantly reduced the host cell cytotoxicity of pretreated amoeba toward the human HaCaT cell line. So, these terpene compounds hold potential as therapeutic agents against infections caused by N. fowleri and are potentially a step forward in drug development against this deadly pathogen as these compounds have also been reported to cross the blood-brain barrier. Therefore, an in vivo study using animal models is necessary to assess the efficacy of these compounds and the need for further research into the intranasal route of delivery for the treatment of these life-threatening infections.

Purpose: The resistance of parasite to readily affordable antimalarial drugs, the high cost of currently potent drugs, and the resistance of vector mosquitoes to insecticides threaten the possibility of malaria eradication in malaria endemic areas. Due to the fact that quinine and artemisinin were isolated from plants sources, researchers have been encouraged to search for new antimalarials from medicinal plants. This is especially the case in Africa where a large percentage of the population depends on medicinal plant to treat malaria and other ailments., Method: In this study, we evaluated previously characterized Plasmodium-cidal compounds obtained from the African flora to identify their likely biochemical targets, for an insight into their possible antimalarial chemotherapy. Molecular docking study was first conducted, after which remarkable compounds were submitted for molecular dynamic (MD) simulations studies., Results: From a total of 38 Plasmodium-cidal compounds docked with confirmed Plasmodium falciparum protein drug targets [plasmepsin II (PMII), histo-aspartic protein (HAP) and falcipain-2 (FP)], two pentacyclic triterpene, cucurbitacin B and 3 beta-O-acetyl oleanolic acid showed high binding affinity relative to artesunate. This implies their capacity to inhibit the three selected P. falciparum target proteins, and consequently, antimalarial potential. From the MD simulations studies and binding free energy outcomes, results confirmed that the two compounds are stable in complex with the selected antimalarial targets; they also showed excellent binding affinities during the 100 ns simulation., Conclusion: These results showed that cucurbitacin B and 3 beta-O-acetyl oleanolic acid are potent antimalarials and should be considered for further studies., (© 2023. The Author(s) under exclusive licence to Witold Stefański Institute of Parasitology, Polish Academy of Sciences.)

Human neutrophil elastase (HNE) is an enzyme that plays a key role in the body's inflammatory response. It has been linked to several diseases such as chronic obstructive pulmonary disease (COPD), emphysema, and cystic fibrosis. As potential treatments for these diseases, HNE inhibitors are of great interest. Metabolites derived from plants, particularly terpenoids such as β-caryophyllene found in black pepper and other plants, and geraniol present in several essential oils, are recognized as significant sources of inhibitors for HNE. Because of their ability to inhibit HNE, terpenoids are considered promising candidates for developing novel therapies to treat inflammatory conditions such as COPD and emphysema. Furthermore, nature can serve as an excellent designer, and it may offer a safer drug candidate for inhibiting HNE production and activity in the future. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses were searched to get relevant and up-to-date literature on terpenoids as human neutrophil elastase inhibitors. This review focuses on the isolation, chemical diversity, and inhibition of human neutrophil elastase (HNE) of various terpenoids reported from natural sources up to 2022. A total of 251 compounds from various terpenoids classes have been reported. Further, it also provides a summary of HNE inhibitors and includes a thorough discussion on the structure-activity relationship., (© 2023 Wiley-VCH GmbH.)

Neurological ailments, including stroke, Alzheimer's disease (AD), epilepsy, Parkinson's disease (PD), and other related diseases, have affected around 1 billion people globally to date. PD stands second among the common neurodegenerative diseases caused as a result of dopaminergic neuron loss in the midbrain's substantia nigra regions. It affects cognitive and motor activities, resulting in tremors during rest, slow movement, and muscle stiffness. There are various traditional approaches for the management of PD, but they provide only symptomatic relief. Thus, a survey for finding new biomolecules or substances exhibiting the therapeutic potential to patients with PD is the main focus of present-day research. Medicinal plants, herbal formulations, and natural bioactive molecules have been gaining much more attention in recent years as synthetic molecules orchestrate a number of undesired effects. Several in vitro, in vivo, and in silico studies in the recent past have demonstrated the therapeutic potential of medicinal plants, herbal formulations, and plant-based bioactives. Among the plant-based bioactives, polyphenols, terpenes, and alkaloids are of particular interest due to their potent anti-inflammatory, antioxidant, and brain-health-promoting properties. Further, there are no concise, elaborated articles comprising updated mechanism-of-action-based reviews of the published literature on potent, recently investigated (2019-2023) medicinal plants, herbal formulations, and plant based-bioactive molecules, including polyphenols, terpenes, and alkaloids, as a method for the management of PD. Therefore, we designed the current review to provide an illustration of the efficacious role of various medicinal plants, herbal formulations, and bioactives (polyphenols, terpenes, and alkaloids) that can become potential therapeutics against PD with greater specificity, target approachability, bioavailability, and safety to the host. This information can be further utilized in the future to develop several value-added formulations and nutraceutical products to achieve the desired safety and efficacy for the management of PD.

Background: Cutaneous T cell lymphoma (CTCL) is a T cell-derived non-Hodgkin lymphoma primarily affecting the skin, with treatment posing a significant challenge and low survival rates., Objective: In this study, we investigated the anti-cancer potential of Neosetophomone B (NSP-B), a fungal-derived secondary metabolite, on CTCL cell lines H9 and HH., Methods: Cell viability was measured using Cell counting Kit-8 (CCK8) assays. Apoptosis was measured by annexin V/PI dual staining. Immunoblotting was performed to examine the expression of proteins. Applied Biosystems' high-resolution Human Transcriptome Array 2.0 was used to examine gene expression., Results: NSP-B induced apoptosis in CTCL cells by activating mitochondrial signaling pathways and caspases. We observed downregulated expression of BUB1B, Aurora Kinases A and B, cyclin-dependent kinases (CDKs) 4 and 6, and polo-like kinase 1 (PLK1) in NSP-B treated cells, which was further corroborated by Western blot analysis. Notably, higher expression levels of these genes showed reduced overall and progression-free survival in the CTCL patient cohort. FOXM1 and BUB1B expression exhibited a dose-dependent reduction in NSP-B-treated CTCL cells.FOXM1 silencing decreased cell viability and increased apoptosis via BUB1B downregulation. Moreover, NSP-B suppressed FOXM1-regulated genes, such as Aurora Kinases A and B, CDKs 4 and 6, and PLK1. The combined treatment of Bortezomib and NSP-B showed greater efficacy in reducing CTCL cell viability and promoting apoptosis compared to either treatment alone., Conclusion: Our findings suggest that targeting the FOXM1 pathway may provide a promising therapeutic strategy for CTCL management, with NSP-B offering significant potential as a novel treatment option., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2023 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Common carp (Cyprinus carpio), a valuable aquaculture species susceptible to various infections, requires effective immune enhancement strategies. This study investigates the immunomodulatory effects of orally administered terpenoids and phenol fraction (TPF) from Padina gymnospora in C. carpio, focusing on stimulation of nonspecific immune response, immune gene expression, and protection against experimental infection. P. gymnospora is a brown seaweed species known for its bioactive compounds and medicinal properties. TPF was extracted using the Harborne fractionation method, and the presence of terpenoids and phenol compounds was confirmed by qualitative analysis and high-performance thin layer chromatography (HPTLC). TPF was administered orally in different doses to carp. Nonspecific immune responses were evaluated by measuring cellular ROS, RNI, and peroxidase production. The expression of immune genes (lysozyme and interleukin-1β) was assessed by reverse transcriptase PCR. Furthermore, the protective efficacy of TPF was determined by infecting carp with a virulent pathogen, Aeromonas hydrophila, and monitoring mortality rates and disease symptoms. The results demonstrate that oral TPF administration significantly enhances nonspecific immune responses, with increased ROS, RNI, and peroxidase production, indicating improved immune function. Expression levels of lysozyme and interleukin-1β were upregulated, suggesting immune system activation. Moreover, TPF exhibited significant protection against experimental infection, with lower mortality rates compared to the control group. These findings highlight TPF's potential as an effective immunostimulatory agent, enhancing immune responses and providing infection protection in carp. In conclusion, oral TPF administration stimulates nonspecific immune responses, modulates immune gene expression, and confers protection against experimental infection in carp, displaying its potential for enhancing immune responses and disease resistance in aquaculture species, and contributing to sustainable fish health management., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Melanoma is a highly aggressive and life-threatening form of skin cancer that accounts for a significant proportion of cancer-related deaths worldwide. Although conventional cancer therapies, such as surgical excision, chemotherapy, and radiation, have been used to treat malignant melanoma, their efficacy is often limited due to the development of resistance and adverse side effects. Therefore, there is a growing interest in developing alternative treatment options for melanoma that are more effective and less toxic. Terpenes, a diverse group of naturally occurring compounds of plant origin, have emerged as potential anticancer agents due to their ability to inhibit tumor growth and induce apoptosis in cancer cells. In this review, the current understanding of the anticancer effects of terpenes (including, thymoquinone, β-elemene, carvacrol, limonene, α-pinene, β-caryophyllene, perillyl alcohol, taxol, betulinic acid, α-bisabolol, ursolic acid, linalool, lupeol, and artesunate) was summarized, with a special focus on their potential as therapeutic agents for malignant melanoma., (© 2023. The Author(s).)

Leishmaniasis is a neglected tropical disease with a wide spectrum of clinical manifestations, ranging from visceral to cutaneous, with millions of new cases and thousands of deaths reported each year. The species of Leishmania and the immune response of the host determine the severity of the disease. Leishmaniasis remains challenging to diagnose and treat, and there is no vaccine available. Several studies have been conducted on the use of herbal medicines for the treatment of leishmaniasis. Natural products can provide an inexhaustible source of chemical diversity with therapeutic potential. Terpenes are a class of natural products derived from a single isoprene unit, a five-carbon compound that forms the basic structure of isoprenoids. This review focuses on the most important and recent advances in the treatment of parasites of the genus Leishmania with different subclasses of terpenes. Several mechanisms have been proposed in the literature, including increased oxidative stress, immunomodulatory role, and induction of different types of parasite cell death. However, this information needs to be brought together to provide an overview of how these compounds can be used as therapeutic tools for drug development and as a successful adjuvant strategy against Leishmania sp., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rodrigues, Carloto, Gonçalves, Concato, Detoni, Santos, Cruz, Madureira, Nunes, Pires, Santos, Marques, Bidoia, Borges Figueiredo and Pavanelli.)

Inflammatory Bowel Disease (IBD) are autoimmune diseases characterized by chronic intestinal inflammation. Considered a western disease, IBD incidence in newly developed countries is skyrocketing. Accordingly, global prevalence is steadily increasing. There are two major IBD phenotypes, ulcerative colitis (UC) and Crohn's disease (CD). UC manifests as uninterrupted inflammation localized in the colon and rectum. Meanwhile, CD presents as interrupted inflammation that can occur throughout the digestive tract. As a result, therapeutics have focused on anti-inflammatory approaches for its treatment. Unfortunately, only 50% of patients benefit from current Food and Drug Administration approved treatments, and all are associated with serious adverse effects. Thus, there is a need for safer and novel therapeutics to increase the efficacy in this population. One aspect that is critical in understanding IBD is how food and phytochemicals therein may be associated with modifying the pathogenesis of IBD. A variety of retrospective and prospective studies, and clinical trials have shown benefits of plant-rich diets on the prevention and symptomatic improvement of IBD. The Mediterranean diet is rich in vegetables, fruits, legumes, and herbs; and characterized by the abundance of anti-inflammatory phytochemicals. An understudied phytochemical class enriched in this diet is terpenes; isoprene-based molecules are widely available in Mediterranean herbs and citrus fruits. Various terpenes have been evaluated in different IBD models. However, some present contradictory or inconclusive results. Therefore, in this review we evaluated preclinical studies of terpenes modulating basic inflammatory signaling related to IBD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Cannabis sativa is a multipurpose plant that has been used in medicine for centuries. Recently, considerable research has focused on the bioactive compounds of this plant, particularly cannabinoids and terpenes. Among other properties, these compounds exhibit antitumor effects in several cancer types, including colorectal cancer (CRC). Cannabinoids show positive effects in the treatment of CRC by inducing apoptosis, proliferation, metastasis, inflammation, angiogenesis, oxidative stress, and autophagy. Terpenes, such as β-caryophyllene, limonene, and myrcene, have also been reported to have potential antitumor effects on CRC through the induction of apoptosis, the inhibition of cell proliferation, and angiogenesis. In addition, synergy effects between cannabinoids and terpenes are believed to be important factors in the treatment of CRC. This review focuses on the current knowledge about the potential of cannabinoids and terpenoids from C. sativa to serve as bioactive agents for the treatment of CRC while evidencing the need for further research to fully elucidate the mechanisms of action and the safety of these compounds.

Traumatic brain injury is common, and often results in debilitating consequences. Even mild traumatic brain injury leaves approximately 20% of patients with symptoms that persist for months. Despite great clinical need there are currently no approved pharmaceutical interventions that improve outcomes after traumatic brain injury. Increased understanding of the endocannabinoid system in health and disease has accompanied growing evidence for therapeutic benefits of Cannabis sativa. This has driven research of Cannabis' active chemical constituents (phytocannabinoids), alongside endogenous and synthetic counterparts, collectively known as cannabinoids. Also of therapeutic interest are other Cannabis constituents, such as terpenes. Cannabinoids interact with neurons, microglia, and astrocytes, and exert anti-inflammatory and neuroprotective effects which are highly desirable for the management of traumatic brain injury. In this review, we comprehensively appraised the relevant scientific literature, where major and minor phytocannabinoids, terpenes, synthetic cannabinoids, and endogenous cannabinoids were assessed in TBI, or other neurological conditions with pathology and symptomology relevant to TBI, as well as recent studies in preclinical TBI models and clinical TBI populations., (© 2023. The Author(s).)

Objectives: Solanum lyratum Thunb (SLT) is a perennial plant of the Solanaceae family, and is extensively used in the clinical practice of traditional Chinese medicine. Malaria, oedema, gonorrhoea, cancer, wind and fever, jaundiced hepatitis, cholecystitis and rheumatoid arthritis are among the diseases that it is used to treat. To offer a foundation for further development and usage of SLT, the pieces of literature about the chemical composition and pharmacological action of SLT were reviewed and analysed., Key Findings: The chemical constituents of SLT mainly included steroids, alkaloids, flavonoids, terpenoids, anthraquinones, phenylpropanoids and others. Pharmacological action mainly contains anti-tumour, antibacterial, anti-inflammatory, anti-oxidation and other pharmacological actions, among them, the anti-tumour effect is particularly outstanding., Summary: At present, studies on the pharmacological effects of SLT mainly focus on alkaloids and steroidal saponins. In the follow-up studies, studies on the pharmacological activities of other chemical components in SLT, such as flavonoids and terpenoids, should be strengthened. It has the potential to pave the way for more research and development of novel SLT medicines., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Gynecological cancers encompass all uncontrolled and aberrant cell growth in the female reproductive system, therapeutic interventions are constantly evolving, but there is still a high death rate, significant side effects and medication resistance, making the task of treatment challenging and complex. The essential oil extracted from the rhizome of Curcuma longa is a promising natural drug, which has excellent biological activity on cancer cells and is to be developed as a new type of anti-gynecological tumor therapeutic agent., Purpose: To systematically summarize the available evidence for the efficacy of Curcuma oil and its terpenoids (β-elemene, curcumol, furanodiene, and germacrone) in gynecological cancers, primarily malignancies of the reproductive system, involving ovarian, cervical, and endometrial cancers, explain the underlying mechanisms of preventing and treating gynecological cancers, and assess the shortcomings of existing work., Results: Through several signaling channels, Curcuma oil and its terpenoids can not only stop the growth of ovarian cancer, cervical cancer, and endometrial cancer cells, limit the formation of tumors, but also raise the effectiveness of chemotherapy drugs and improve the quality of life for patients., Conclusion: It provides a preclinical basis for the efficacy of Curcuma oil as a broad-spectrum anti-tumor agent for the prevention and treatment of gynecological cancers. Even so, further efforts are still needed to improve the bioavailability of Curcuma oil and upgrade related experiments., Competing Interests: Conflict of Interest Statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

A great number of research has been focused on plants as a source of medicine against many diseases to overcome the many side effects of chemical drugs. Safranal, one of the main constituents of saffron [Crocus sativus], has a broad spectrum of pharmacological effects, including anti-inflammatory, antioxidant, and antiapoptotic effects. The present review elaborates on the current understanding of the neuroprotective effects of safranal. According to data published so far, safranal has the potential to exert neuroprotective effects in neurological disorders such as epilepsy, stroke, multiple sclerosis, Parkinson, and Alzheimer's disease. Safranal could be considered a promising therapeutic agent in the future, although there is a great need for clinical trial studies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Natural products have been the most productive source for the development of drugs. Terpenoids are a class of natural active products with a wide range of pharmacological activities and therapeutic effects, which can be used to treat a variety of diseases. Non-alcoholic fatty liver disease (NAFLD), a common metabolic disorder worldwide, results in a health burden and economic problems. A literature search was conducted to obtain information relevant to the treatment of NAFLD with terpenoids using electronic databases, namely PubMed, Web of Science, Science Direct, and Springer, for the period 2011-2021. In total, we found 43 terpenoids used in the treatment of NAFLD. Over a dozen terpenoid compounds of natural origin were classified into five categories according to their structure: monoterpenoids, sesquiterpenoids, diterpenoids, triterpenoids, and tetraterpenoids. We found that terpenoids play a therapeutic role in NAFLD, mainly by regulating lipid metabolism disorder, insulin resistance, oxidative stress, and inflammation. The AMPK, PPARs, Nrf-2, and SIRT 1 pathways are the main targets for terpenoid treatment. Terpenoids are promising drugs and will potentially create more opportunities for the treatment of NAFLD. However, current studies are restricted to animal and cell experiments, with a lack of clinical research and systematic structure-activity relationship (SAR) studies. In the future, we should further enrich the research on the mechanism of terpenoids, and carry out SAR studies and clinical research, which will increase the likelihood of breakthrough insights in the field.

Cancer is characterized by alterations that cause the over-proliferation of cells and hyperactivation of signaling pathways. Alterations of signaling molecules dysregulate physiological functions like cell growth, proliferation, metastasis, and cell death. Hence, the potential anticancer compounds primarily target signaling networks for therapeutic interventions in cancer. In the past few years, cancer therapy directed its focus on bioactive compounds that originated from marine sources considering their diverse and untapped nature. These Marine Bioactive Compounds (MBCs) are broadly classified into distinct categories such as alkaloids, carbohydrates, fatty acids, peptides, phenols, quinones, terpenes, and saponins. Bioactive compounds from each class initiate cell death via different signaling pathways. The primary objective of this review is to provide comprehensive information about the pathways that are predominantly targeted by every class of MBCs and integrating data from several marine anticancer research. Here, we studied the role of MBCs in signaling networks that inhibit various cancer types. As a result, we concluded that PI3K/AKT, ROS, and p53 are the three prime signaling pathways targeted by the MBCs to induce apoptosis in cancer cells. Carbohydrates, peptides, and terpenes are the major MBCs classes that regulate signaling pathways in cancer. Hence it is concluded that future anticancer research can be primarily focused on the MBCs derived from the scrutinized classes that adhere to pathways like PI3K/AKT, ROS, and p53 to achieve par excellence results., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The number of people diagnosed with diabetes mellitus and its complications is markedly increasing worldwide, leading to a worldwide epidemic across all age groups, from children to older adults. Diabetes is associated with premature aging. In recent years, it has been found that peripheral overactivation of the endocannabinoid system (ECS), and in particular cannabinoid receptor 1 (CB1R) signaling, plays a crucial role in the progression of insulin resistance, diabetes (especially type 2), and its aging-related comorbidities such as atherosclerosis, nephropathy, neuropathy, and retinopathy. Therefore, it is suggested that peripheral blockade of CB1R may ameliorate diabetes and diabetes-related comorbidities. The use of synthetic CB1R antagonists such as rimonabant has been prohibited because of their psychiatric side effects. In contrast, phytocannabinoids such as cannabidiol (CBD) and tetrahydrocannabivarin (THCV), produced by cannabis, exhibit antagonistic activity on CB1R signaling and do not show any adverse side effects such as psychoactive effects, depression, or anxiety, thereby serving as potential candidates for the treatment of diabetes and its complications. In addition to these phytocannabinoids, cannabis also produces a substantial number of other phytocannabinoids, terpenes, and flavonoids with therapeutic potential against insulin resistance, diabetes, and its complications. In this review, the pathogenesis of diabetes, its complications, and the potential to use cannabinoids, terpenes, and flavonoids for its treatment are discussed., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Onychomycosis, the most prevailing affliction of the nail, accounts for approximately 90% of the toenail infection worldwide. Owing to this infection, the affected patients experience reduced quality of their life as its awful appearance undermines their daily activities and social interactions. Onychomycosis is notoriously strenuous to cure. Systemic therapy, though effective, possess severe complication of toxicities, contra-indication, and drug-drug interaction. Albeit topical therapy is favorable to its localized effect, its potency relates to the effective concentration of the antifungal drugs achieved at the infection site. An approach to accomplish this goal would be acquiring benefits from the terpenes as penetration enhancers from natural sources. This investigation aimed to study the effectiveness of six terpenes, namely safranal, lavandulol, rose oxide, 3-methyl-2-butene-1-ol, linalool, and limonene, as potential penetration enhancers for improved nail permeation of fluconazole through the human nail., Methods: Ex vivo permeation experiments were carried out by soaking the nail clippings of human volunteers in control and working solutions containing fluconazole (5 mg/ml) per se and fluconazole (5 mg/ml) with 6% of each terpene, including safranal, lavandulol, rose oxide, 3-methyl-2-butene-1-ol, linalool, and limonene, respectively, for 48 h. The amount of fluconazole in nail clippings was quantified using an HPLC method., Results: Statistical analysis showed that fluconazole transungual permeation was influenced by the studied terpenes in the following order: safranal >lavandulol acetate >limonene > rose oxide (p-value >0.05) while the other terpenes showed no significant difference with the control group and safranal represents as the most effective permeation enhancer for the transungual delivery of fluconazole., Conclusion: It is concluded that the safranal can be successfully used as a safe and potential permeation enhancer to enhance the transungual delivery of fluconazole for the treatment of onychomycosis., (© 2022 Wiley Periodicals LLC.)

Background: Curing refractory Helicobacter pylori infection is difficult. In addition, there is currently no research on the gastric microbiota of refractory H. pylori infection., Methods: We designed a clinical retrospective study involving 32 subjects divided into three groups: 1. nAGHp.a, treatment-naïve patients with H. pylori infection; 2. nAGHp.b, H. pylori -negative patients; and 3. EFHp.a, patients with refractory H. pylori infection. Gastric mucosal samples from the biobank of our research center were collected for 16S rRNA sequencing analysis and bacterial functions were predicted via PICRUSt., Results: There were significant differences between the H. pylori- positive group and the H. pylori- negative group in species diversity, gastric microbiota structure, and bacterial function. The beneficial Lactobacillus in the H. pylori -positive group were significantly enriched compared with those in the refractory H. pylori infection group. The bacterial interaction network diagram suggested that the microbiota interactions in the refractory H. pylori infection group decreased. The gastric microbiota of the refractory H. pylori infection group was enriched in the pathways of metabolism and infectious diseases (energy metabolism, bacterial secretion system, glutathione metabolism, protein folding and associated processing, sulphur metabolism, membrane and intracellular structural molecules, lipopolysaccharide biosynthesis, ubiquinone and other terpenoid-quinone biosynthesis, inorganic ion transport and metabolism, and metabolism of cofactors and vitamins) when compared with the H. pylori -positive group without treatment based on PICRUSt analysis., Conclusion: Significant alterations occurred in the gastric microbiota when eradication of H. pylori failed multiple times. A history of eradication of multiple H. pylori infections leads to an imbalance in the gastric mucosal microbiota to a certain extent, which was mainly reflected in the inhibition of the growth of beneficial Lactobacillus in the stomach. Patients with refractory H. pylori infection may be at a higher risk of developing gastric cancer than other H. pylori -positive patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Wang and Xie.)

Ethnopharmacological Relevance: Ziziphus mauritiana Lam leaves were utilized in treating asthma, diabetes, inflammation, and hepatic diseases in Indian traditional medicine. The leaves were used as an edible vegetables in rural parts of India., Aim of the Study: The aim is to prove the anti-inflammatory activity of Ziziphus mauritiana Lam leaves against LPS-stimulated RAW 264.7 macrophages and OVA-induced airway inflammation in mice through its attenuation mechanism in the NFκB signalling pathway., Materials and Methods: Terpenoids present in MEZ were quantified using U(H)PLC analysis. MEZ at 50 and 100 μg/mL were tested against LPS stimulated RAW 264.7 macrophages. The concentration of NO, ROS, and cytokines was quantified from the cell culture supernatants. OVA-induced asthma in mice was adopted for screening airway inflammation. MEZ at 250 and 500 mg/kg was tested for airway hyperresponsiveness, leukocyte counting, pro-inflammatory cytokines (IL-4, IL-5, IL-13 and TNF-α), lung histopathology, and various inflammatory gene expressions in lungs for NFκB signalling pathway in asthma., Results: Terpenoids like betulin, betulinic acid, oleanolic acid, and ursolic acid were quantified from U(H)PLC analysis. MEZ at higher doses reduced the NO, ROS, and pro-inflammatory cytokines in LPS stimulated RAW 264.7 macrophages. MEZ at 500 mg/kg significantly reduced AHR and also decreased total and differential leukocytes. MEZ also reduced the expressions of ICAM, VCAM, and Muc5C genes. Histopathological analysis revealed MEZ significantly reduced the leukocyte infiltration and mucus hypersecretion in the lungs. MEZ suppressed lung inflammation by inhibition of p65 mediated IκB-α translocation in the NFκB signalling pathway., Conclusion: From these findings, MEZ significantly reduced airway inflammation by inhibiting NFκB mediated inflammatory pathway. Hence, this study proved that Ziziphus mauritiana Lam has anti-asthmatic potential in Indian traditional medicine., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Epidemic obesity is contributing to increases in the prevalence of obesity-related metabolic diseases and has, therefore, become an important public health problem. Adipose tissue is a vital energy storage organ that regulates whole-body energy metabolism. Triglyceride degradation in adipocytes is called lipolysis. It is closely tied to obesity and the metabolic disorders associated with it. Various natural products such as flavonoids, alkaloids, and terpenoids regulate lipolysis and can promote weight loss or improve obesity-related metabolic conditions. It is important to identify the specific secondary metabolites that are most effective at reducing weight and the health risks associated with obesity and lipolysis regulation. The aims of this review were to identify, categorize, and clarify the modes of action of a wide diversity of plant secondary metabolites that have demonstrated prophylactic and therapeutic efficacy against obesity by regulating lipolysis. The present review explores the regulatory mechanisms of lipolysis and summarizes the effects and modes of action of various natural products on this process. We propose that the discovery and development of natural product-based lipolysis regulators could diminish the risks associated with obesity and certain metabolic conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Ge, Jiang and Yang.)

Toona sinensis (A. Juss.) Roem is an edible medicinal plant that belongs to the genus Toona within the Meliaceae family. It has been confirmed to display a wide variety of biological activities. During our continuous search for active constituents from the seeds of T. sinensis , two new acyclic diterpenoids ( 1 - 2 ), together with five known limonoid-type triterpenoids ( 3 - 7 ), five known apotirucallane-type triterpenoids ( 8 - 12 ), and three known cycloartane-type triterpenoids ( 13 - 15 ), were isolated and characterized. Their structures were identified based on extensive spectroscopic experiments, including nuclear magnetic resonance (NMR), high-resolution electrospray ionization mass spectra (HR-ESI-MS), and electronic circular dichroism (ECD), as well as the comparison with those reported in the literature. We compared these findings to those reported in the literature. Compounds 5 , 8 , and 13 - 14 were isolated from the genus Toona , and compounds 11 and 15 were obtained from T. sinensis for the first time. The antidiabetic nephropathy effects of isolated compounds against high glucose-induced oxidative stress and inflammation in rat glomerular mesangial cells (GMCs) were assessed in vitro. The results showed that new compounds 1 and 2 could significantly increase the levels of Nrf-2/HO-1 and reduce the levels of NF-κB, TNF- α , and IL-6 at concentrations of 30 μM. These results suggest that compounds 1 and 2 might prevent the occurrence and development of diabetic nephropathy (DN) and facilitate the research and development of new antioxidant and anti-inflammatory drugs suitable for the prevention and treatment of DN.

Chemotherapeutic resistance can limit breast cancer outcomes; therefore, the exploration of novel therapeutic options is warranted. Isolated compounds found in cannabis have previously been shown to exhibit anti-cancer effects, but little is known about their effects in resistant breast cancer. Our study aimed to evaluate the effects of terpenes found in cannabis in in vitro chemotherapy-resistant model of breast cancer. We aimed to identify whether five terpenes found in cannabis produced anti-cancer effects, and whether their effects were improved upon co-treatment with cannabinoids and flavonoids also found in cannabis. Nerolidol and β-caryophyllene produced the greatest cytotoxic effects, activated the apoptotic cascade, and reduced cellular invasion. Combinations with the flavonoid kaempferol potentiated the cytotoxic effects of ocimene, terpinolene, and β-myrcene. Combinations of nerolidol and Δ9-tetrahydrocannabinol or cannabidiol produced variable responses ranging from antagonism and additivity to synergy, depending on concentrations used. Our results indicate that cannabis terpenes, alone or combined with cannabinoids and flavonoids, produced anti-cancer effects in chemotherapy-resistant breast cancer cell lines. This study is a first step in the identification of compounds that could have therapeutic potential in the treatment of resistant breast cancer.

Cannabis -based terpenes are believed to modulate physiological responses to disease and alter the efficacy of cannabinoids in the so-called "entourage effect". The monoterpene myrcene can reduce nociception produced by noxious thermal and mechanical stimuli as well as reducing acute inflammation. The current study examined the role of myrcene and cannabidiol (CBD) in controlling chronic joint inflammation and pain. Chronic arthritis was induced in male Wistar rats by intra-articular injection of Freund's complete adjuvant into the right knee. On days 7 and 21 after arthritis induction, joint pain (von Frey hair algesiometry), inflammation (intravital microscopy, laser speckle contrast analysis) and joint histopathology were assessed. Local application of myrcene (1 and 5 mg/kg s.c.) reduced joint pain and inflammation via a cannabinoid receptor mechanism. The combination of myrcene and CBD (200 μg) was not significantly different from myrcene alone. Repeated myrcene treatment had no effect on joint damage or inflammatory cytokine production. These data suggest that topical myrcene has the potential to reduce chronic arthritis pain and inflammation; however, it has no synergistic effect with CBD.

Fungal infections are one of the main public health problems, especially in immunocompromised patients, nosocomial environments, patients with chronic diseases, and transplant recipients. These diseases are increasingly frequent and lethal because the microorganism has a high capacity to acquire resistance to available therapy. The main resistance factors are the emergence of new strains and the uncontrolled use of antifungals. It is, therefore, important to develop new methods that contribute to combating fungal diseases in the clinical area. Natural products have considerable potential for the development of new drugs with antifungal activity, mainly due to their biocompatibility and low toxic effect. This promising antimicrobial activity of natural products is mainly due to the presence of flavonoids, terpenes, and quinones, which explains their antifungal potential. Pharmaceutical nanotechnology has been explored to enhance the delivery, selectivity, and clinical efficacy of these products. Nanotechnological systems provide a safe and selective environment for various substances, such as natural products, improving antifungal activity. However, further safety experiments (in vivo or clinical trials) need to be carried out to prove the therapeutic action of natural products, since they may have undesirable, toxic, and mutagenic effects. Therefore, this review article addresses the main nanotechnological methods using natural products for effective future treatment against the main fungal diseases., (© 2022 John Wiley & Sons Ltd.)

Tuberculosis is considered as a leading health issue globally. Even though, the todays first line anti-mycobacterial treatments used in the hospital have low deaths, multidrug-resistance forms of the ailment have now spread globally and become a major issue. The wide-ranging biodiversity of medicinal plants, ocean animals have gained considerable attention for drug discovery in previous spans, and the emergence of TB drug resistance has inspired interest in judging natural products (NPs) to cure this disease. Till now, several compounds have been isolated from natural sources with anti-mycobacterial activity, few of which demonstrate significant activity and have the potential for further development. Worldwide huge natural flora and fauna are existing, this flora and fauna must be investigated for new potent lead against infectious TB. This review systematically surveys various classes of terpenoid molecules obtained from different medicinal plants, fungi, sponges, and sea plumes with anti-TB activity, which could be useful for further optimization and development in this field., Competing Interests: Conflicts of interest The authors have none to declare., (Copyright © 2021 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.)

Osteoporosis (OP) is a systemic metabolic skeletal disease which can lead to reduction in bone mass and increased risk of bone fracture due to the microstructural degradation. Traditional Chinese medicine (TCM) has been applied in the prevention and treatment of osteoporosis for a long time. Terpenoids, a class of natural products that are rich in TCM, have been widely studied for their therapeutic efficacy on bone resorption, osteogenesis, and concomitant inflammation. Terpenoids can be classified in four categories by structures, monoterpenoids, sesquiterpenoids, diterpenoids, and triterpenoids. In this review, we comprehensively summarize all the currently known TCM-derived terpenoids in the treatment of OP. In addition, we discuss the possible mechanistic-of-actions of all four category terpenoids in anti-OP and assess their therapeutic potential for OP treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhuo, Li, Jiang, Ke, Liang, Zeng and Fang.)