Berry anthocyanins prevent α-dicarbonyls and advanced glycation end product formation in phosphate-buffered saline-based model systems, cookie and ground pork.

α-Dicarbonyls and advanced glycation end products (AGEs) are the heat-induced potential toxicants commonly found in thermally processed foods due to the Maillard reaction. Research has shown that both α-dicarbonyls and AGEs can cause oxidative stress and inflammation and have a positive link with several chronic diseases, such as diabetes. This study found that commonly consumed berry fruits exhibited excellent methylglyoxal (MGO)-trapping and antiglycative activities, positively associated with their total phenolic and flavonoid contents. Blackcurrant exhibited the strongest MGO-trapping and antiglycative activities among the tested berry fruits. In addition, we demonstrated that fortification with blackcurrant significantly reduced α-dicarbonyls and AGEs formation in the chocolate cookies and marinated ground pork. Delphinidin and cyanidin glycosides were identified as the primary bioactive compounds of blackcurrant that trapped MGO to form the corresponding mono- and di-MGO adducts. This study suggested that blackcurrant anthocyanins might serve as a novel additive to reduce the consumption of dietary reactive carbonyl species and AGEs from both animal- and plant-derived processed foods. PRACTICAL APPLICATION: The levels of α-dicarbonyls and advanced glycation end products in ground pork and cookies were significantly reduced when fortified with blackcurrant. The blackcurrant anthocyanins might be a novel agent inhibiting α-dicarbonyls and dietary advanced glycation end products formation in thermally processed foods.

Protective Effects of an Oligo-Fucoidan-Based Formula against Osteoarthritis Development via iNOS and COX-2 Suppression following Monosodium Iodoacetate Injection.

Osteoarthritis (OA) is a debilitating joint disorder characterized by cartilage degradation and chronic inflammation, accompanied by high oxidative stress. In this study, we utilized the monosodium iodoacetate (MIA)-induced OA model to investigate the efficacy of oligo-fucoidan-based formula (FF) intervention in mitigating OA progression. Through its capacity to alleviate joint bearing function and inflammation, improvements in cartilage integrity following oligo-fucoidan-based formula intervention were observed, highlighting its protective effects against cartilage degeneration and structural damage. Furthermore, the oligo-fucoidan-based formula modulated the p38 signaling pathway, along with downregulating cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, contributing to its beneficial effects. Our study provides valuable insights into targeted interventions for OA management and calls for further clinical investigations to validate these preclinical findings and to explore the translational potential of an oligo-fucoidan-based formula in human OA patients.

Hinokitiol Inhibits Breast Cancer Cells In Vitro Stemness-Progression and Self-Renewal with Apoptosis and Autophagy Modulation via the CD44/Nanog/SOX2/Oct4 Pathway.

Breast cancer (BC) represents one of the most prevalent malignant threats to women globally. Tumor relapse or metastasis is facilitated by BC stemness progression, contributing to tumorigenicity. Therefore, comprehending the characteristics of stemness progression and the underlying molecular mechanisms is pivotal for BC advancement. Hinokitiol (ß-thujaplicin), a tropolone-related compound abundant in the heartwood of cupressaceous plants, exhibits antimicrobial activity. In our study, we employed three BC cell lines (MDA-MB-231, MCF-7, and T47D) to assess the expression of stemness-, apoptosis-, and autophagy-related proteins. Hinokitiol significantly reduced the viability of cancer cells in a dose-dependent manner. Furthermore, we observed that hinokitiol enhances apoptosis by increasing the levels of cleaved poly-ADP-ribose polymerase (PARP) and phospho-p53. It also induces dysfunction in autophagy through the upregulation of LC3B and p62 protein expression. Additionally, hinokitiol significantly suppressed the number and diameter of cancer cell line spheres by reducing the expression of cluster of differentiation44 (CD44) and key transcription factors. These findings underscore hinokitiol's potential as a therapeutic agent for breast cancer, particularly as a stemness-progression inhibitor. Further research and clinical studies are warranted to explore the full therapeutic potential of hinokitiol in the treatment of breast cancer.

Combining microfluidic chip and low-attachment culture devices to isolate oral cancer stem cells.

Background/purpose: Cancer stem cells (CSCs) are widely recognized as key drivers of cancer initiation, progression, and therapeutic resistance. Microfluidic chip technology offers a promising approach for CSC isolation and study. This study investigated the efficacy of a microfluidic chip-based method for isolating single cells from oral cancer cell lines characterized by high stem-like phenotypes. Specifically, the study focused on examining the sphere-forming capability and the expression of CSC markers, including aldehyde dehydrogenase 1A1 (ALDH1A1), CD44, and CD133, in isolated cell clones from OECM-1 and SAS cell lines. Materials and methods: Oral cancer cell lines were subjected to isolation using a microfluidic chip. The captured single cells were cultured to assess their sphere-forming capacity in ultra-low binding culture. Furthermore, the protein expression levels of ALDH1A1, CD44, and CD133 in the isolated cell clones were analyzed using western blotting. Results: The microfluidic chip-assisted isolation method significantly enhanced the sphere-forming capability of both OECM-1 and SAS cell clones compared to their parent cell lines. Moreover, the expression levels of CSC markers ALDH1A1, CD44, and CD133 were upregulated in the microfluidic chip-assisted isolated cell clones, indicating a higher stem-like phenotype. Conclusion: This study demonstrates the effectiveness of the microfluidic chip-based approach in isolating oral cancer cell clones with elevated stem-like characteristics. This method offers a valuable tool for further investigation of CSCs and their role in cancer progression, as well as future therapy development for oral cancers.

Association of higher transient receptor potential melastatin 8 expression with higher tumor histologic grades, lymph node metastasis, risk factors, and worse survival in patients with head and neck squamous cell carcinoma.

Background/purpose: Transient receptor potential melastatin 8 (TRPM8), a thermosensitive ion channel known for its role in cold sensation and menthol response, has emerged as a potential regulator in various cancers. This study aimed to investigate expression trends of TRPM8 in head and neck squamous cell carcinoma (HNSCC) cases and oral squamous cell carcinoma (OSCC) cell lines and its association with clinicopathological features. Materials and methods: The noncancerous matched tissues and HNSCC paired tissue samples from 84 HNSCC patients were utilized to evaluate the association of TRPM8 with HNSCC clinicopathological features. TRPM8 expression was examined in HNSCC patient tissues and OSCC cell lines treated with arecoline. Results: Kaplan-Meier survival analysis of TCGA data revealed high TRPM8 expression correlated with unfavorable outcomes and higher tumor histologic grades. TRPM8 mRNA expression was upregulated in HNSCC cell lines and patients' tissue samples. Arecoline treatment led to significantly increased TRPM8 mRNA and protein expression in OSCC cell lines. Lymph node metastasis showed a significant association with upregulated TRPM8 expression in combined OSCC and oropharyngeal squamous cell carcinoma (OPSCC) cases. TRPM8 mRNA expression was upregulated in HNSCC and OSCC patients with alcohol drinking and cigarette smoking habits, but not in betel quid chewing. Conclusion: These findings reveal the involvement of TRPM8 in HNSCC's malignant development and metastasis, suggesting that high expression of TRMP8 may be mutually causal with addiction to tobacco, alcohol, and betel nut in HNSCC patients. Further investigations are needed to determine the underlying pathways of TRPM8 in HNSCC's development and progression.

Arecoline Induces ROS Accumulation, Transcription of Proinflammatory Factors, and Expression of KRT6 in Oral Epithelial Cells.

Areca nut is a major contributor to the high prevalence of oral cancer in Asia. The precise mechanisms by which areca nut stimulates mucosal cells and contributes to the progression of oral cancer urgently require clarification. The current study aimed to assess the effects of arecoline on the normal human gingival epithelium cell line S-G. Cell viability, levels of reactive oxygen species (ROS), protein expression, cellular morphology, and gene expression were evaluated using the MTT test, flow cytometry, Western blot analysis, optical or confocal microscopy, and RT-qPCR. Keratin (KRT6) analysis involved matched normal and cancer tissues from clinical head and neck specimens. The results demonstrated that 12.5 µg/mL of arecoline induced ROS production, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) mRNA expression in S-G cells. This activation of the MAPK/ERK pathway increased KRT6 expression while limiting cell migration. In head and neck cancer tissues, KRT6B gene expression exceeded that of normal tissues. This study confirms that arecoline induces ROS accumulation in normal cells, leading to the secretion of proinflammatory factors and KRT6 expression. This impedes oral mucosal healing, thereby promoting the progression of oral cancer.

Licochalcone A induces endoplasmic reticulum stress-mediated apoptosis of endometrial cancer cells via upregulation of GRP78 expression.

Licochalcone A (LicA), a natural compound extracted from licorice root, has been shown to exert a variety of anticancer activities. Whether LicA has such effects on endometrial cancer (EMC) is unclear. This study aims to investigate the antitumor effects of LicA on EMC. Our results show that LicA significantly reduced the viability and induced apoptosis of EMC cells and EMC-7 cells from EMC patients. LicA was also found to induce endoplasmic reticulum (ER) stress, leading to increased expression of ER-related proteins (GRP78/PERK/IRE1α/CHOP) in EMC cell lines. Suppression of GRP78 expression in human EMC cells treated with LicA significantly attenuated the effects of LicA, resulting in reduced ER-stress mediated cell apoptosis and decreased expression of ER- and apoptosis-related proteins. Our findings demonstrate that LicA induces apoptosis in EMC cells through the GRP78-mediated ER-stress pathway, emphasizing the potential of LicA as an anticancer therapy for EMC.

Alleviating 3-MCPD-induced male reproductive toxicity: Mechanistic insights and resveratrol intervention.

3-Monochloropropane-1, 2-diol (3-MCPD), a food-borne contaminant, is widely regarded as the primary cause of male infertility. At present, identifying a method to improve/reduce the male reproductive toxicity caused by 3-MCPD is important. In our study, we explored the potential application of resveratrol (RSV) in mitigating the adverse effects of 3-MCPD. Using 7-week-old Sprague-Dawley (SD) rats as animal models, we investigated the impacts and underlying mechanisms of 3-MCPD and RSV on reproductive function. The administration of 3-MCPD led to significant reductions in testicular and epididymal weights, as well as disruptions in spermatogenesis and histological abnormalities. However, co-treatment with RSV and 3-MCPD mitigated these adverse effects. In vitro study, RSV exhibited the ability to reverse the decline in Leydig and Sertoli cell populations inflicted by 3-MCPD treatment. Mechanistically, RSV reduced endoplasmic reticulum stress (PARP), inflammasome activation (NLRP3), and autophagy-mediated lysosome dysfunction (p62 and LC3BII) induced by 3-MCPD. In addition, 3-MCPD treatment increased the expression level of steroidogenesis-related proteins, steroidogenic acute regulatory (StAR) and CYP11A1, but RSV normalized StAR expression. Moreover, 3-MCPD-induced pro-inflammatory responses were counteracted by RSV treatment, with the cytokine reduction and modulation of CD206 expression, a marker of macrophage activation. These findings indicate that RSV attenuates 3-MCPD-induced reproductive toxicity, highlighting its application potential as an adjuvant agent for male reproductive health.

Hinokitiol as a modulator of TLR4 signaling and apoptotic pathways in atopic dermatitis.

Atopic dermatitis (AD) poses a significant global health challenge, characterized by dysregulated inflammation and apoptotic processes. This study explores the therapeutic efficacy of hinokitiol, employing a comprehensive in vivo and in vitro approach. Assessment of inflammation-related markers in the animal model included observation of physical appearance, Western blotting, ELISA, and H&E staining. Additionally, the cell culture model enabled the evaluation of apoptosis and ROS levels using MTT assay, crystal violet staining, Western blot, and DCFDA assays. The results revealed hinokitiol's proficiency in ameliorating ear and skin morphology in the DNCB-induced AD model, mediated through the TLR4/MyD88 pathway. Notably, hinokitiol intervention led to a reduction in both M1 and M2 macrophage phenotypes. In vitro investigations demonstrated hinokitiol's ability to enhance cell viability and morphology under TNF-α and IFN-γ induction. Mechanistically, hinokitiol exhibited regulatory effects on apoptosis-related proteins, including Bax, Cytochrome c, Caspase-3, and PARP, thereby averting cellular damage. These findings suggest that hinokitiol is a promising natural compound with significant potential for alleviating inflammation and apoptosis in AD, indicating potential avenues for future therapeutic developments.

Current and Emerging Treatment Options for Uterine Fibroids.

Uterine fibroids are the most common benign neoplasm of the female reproductive tract in reproductive age women. Their prevalence is age dependent and can be detected in up to 80% of women by the age of 50 years. Patients affected by uterine fibroids may experience a significant physical, emotional, social, and financial toll as well as losses in their quality of life. Unfortunately, curative hysterectomy abolishes future pregnancy potential, while uterine-sparing surgical and radiologic alternatives are variously associated with reduced long-term reproductive function and/or high tumor recurrence rates. Recently, pharmacological treatment against uterine fibroids have been widely considered by patients to limit uterine fibroid-associated symptoms such as heavy menstrual bleeding. This hormonal therapy seemed effective through blocking the stimulatory effects of gonadal steroid hormones on uterine fibroid growth. However, they are contraindicated in women actively pursuing pregnancy and otherwise effective only during use, which is limited because of long-term safety and other concerns. Accordingly, there is an urgent unmet need for safe, durable, and fertility-compatible non-surgical treatment options for uterine fibroids. In this review article, we cover the current pharmacological treatments for uterine fibroids including their comparable efficacy and side effects as well as emerging safe natural compounds with promising anti-uterine fibroid effects.

Oxidative stress mediates the inhibitory effects of Manzamine A on uterine leiomyoma cell proliferation and extracellular matrix deposition via SOAT inhibition.

Uterine fibroids, the most common benign tumors of the myometrium in women, are characterized by abnormal extracellular matrix deposition and uterine smooth muscle cell neoplasia, with high recurrence rates. Here, we investigated the potential of the marine natural product manzamine A (Manz A), which has potent anti-cancer effects, as a treatment for uterine fibroids. Manz A inhibited leiomyoma cell proliferation in vitro and in vivo by arresting cell cycle progression and inducing caspase-mediated apoptosis. We performed target prediction analysis and identified sterol o-acyltransferases (SOATs) as potential targets of Manz A. Cholesterol esterification and lipid droplet formation were reduced by Manz A, in line with reduced SOAT expression. As a downstream target of SOAT, Manz A also prevented extracellular matrix deposition by inhibiting the ß-catenin/fibronectin/metalloproteinases axis and enhanced autophagy turnover. Excessive free fatty acid accumulation by SOAT inhibition led to reactive oxygen species to impair mitochondrial oxidative phosphorylation and trigger endoplasmic reticulum stress via PERK/eIF2α/CHOP signaling. The inhibitory effect of ManzA on cell proliferation was partially restored by PERK knockdown and eliminated by tauroursodeoxycholic acid, suggesting oxidative stress plays a critical role in the mechanism of action of Manz A. These findings suggest that targeting SOATs by Manz A may be a promising therapeutic approach for uterine fibroids.

Para-toluenesulfonamide, a novel potent carbonic anhydrase inhibitor, improves hypoxia-induced metastatic breast cancer cell viability and prevents resistance to αPD-1 therapy in triple-negative breast cancer.

Overexpression of the hypoxia-induced transmembrane enzyme carbonic anhydrase IX (CA9) has been associated with poor prognosis and chemoresistance in aggressive breast cancer. This study aimed to investigate the involvement of CA9 in the anti-tumor activity of para-toluenesulfonamide (PTS) and elucidate its mechanism of action against breast cancer both in vitro and in vivo. MCF-7 and MDA-MB-231 breast cancer cells were treated with PTS or subjected to hypoxic conditions using cobalt chloride (CoCl2), with acetazolamide serving as a positive control. Additionally, 4T1 breast cancer cell allograft mice were co-treated with PTS and α-programmed cell death 1 (αPD-1) monoclonal antibody for one month. The results demonstrated that PTS effectively reduced cell viability and reversed migration ability in MCF-7 and MDA-MB-231 cells under CoCl2-induced hypoxia. Furthermore, PTS upregulated the expression of apoptosis-related proteins and downregulated CA9, hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF) proteins, possibly through modulation of p38 MAPK and ERK1/2 phosphorylated proteins. In the animal model, PTS100 inhibited tumor growth and lung metastasis in mammary tumor allograft mice, exhibiting synergistic effects when combined with αPD-1 therapy. Collectively, our findings suggest that PTS inhibits breast cancer growth and metastasis through the p38 MAPK/ERK1/2 pathway. Moreover, PTS may have the potential to prevent the development of resistance to αPD-1 therapy in breast cancer.

Caffeic acid's role in mitigating polycystic ovary syndrome by countering apoptosis and ER stress triggered by oxidative stress.

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder that affects women of reproductive age, characterized by androgen-induced oxidative stress leading to several metabolic disorders. In this study, we investigated the potential therapeutic effect of caffeic acid on PCOS and its underlying molecular mechanism. We used a human ovarian granulosa cell line (KGN cells) induced by hydrogen peroxide (H2O2) to examine how caffeic acid influences the protein expression of oxidative stress-induced apoptosis-related markers. Our results indicate that caffeic acid significantly inhibits intracellular reactive oxygen species (ROS) generation and safeguards KGN cells against oxidative stress. For the in vivo aspect of our study, female Sprague-Dawley (SD) rats were utilized to induce the PCOS model using dehydroepiandrosterone (DHEA). Caffeic acid was then administered to the rats for a duration of 6 weeks. The outcomes revealed that caffeic acid effectively improved irregular estrous cycles, fasting blood glucose levels, liver function, and lipid profiles in DHEA-induced PCOS rats. Additionally, it mitigated hyperandrogenism, enhanced steroidogenesis enzyme expression, and modulated apoptosis-related protein expression. Our findings strongly suggest that caffeic acid holds promising potential in reducing oxidative stress-induced damage and ameliorating PCOS-related complications by modulating ER stress.

Allyl isothiocyanate mitigates airway inflammation and constriction in a house dust mite-induced allergic asthma model via upregulation of tight junction proteins and the TRPA1 modulation.

Asthma is a chronic inflammatory disease that has been associated with insufficient vegetable intake. Allyl Isothiocyanate (AITC) is a natural isothiocyanate found in cruciferous plants with anti-inflammatory and antioxidant abilities. Our study aimed to investigate the potential effect of AITC on tracheal constriction in a house dust mite (HDM)-induced asthma animal model, and explore the underlying mechanisms. To investigate the effects of AITC on HDM-induced allergic asthma model, established by intranasally administering extracts of HDM and AITC or DEX was given orally for four weeks. Flexivent SCIREQ, H&E staining, ELISA were employed to evaluate the lung function and the cytokine secretion. Possible mechanisms were determined by Western blot. Rat tracheae contraction was measured by Labscribe. We utilized lung epithelial cells (BEAS-2B) to assess the adhesion response to the combination of inflammatory factors TNF-α and IL-4. The results of the study showed that AITC significantly reduced tracheal constriction in ex vivo experiments and improved lung function in in vivo experiments compared to HDM-induced mice. Additionally, AITC decreased cytokine secretion, inflammatory cell infiltration in the lung, and constriction-related proteins expression in both lung and tracheae. Moreover, AITC increased tight junction-related protein expression in lung tissues. In vitro experiments showed that AITC had a protective effect through TRPA1 channel without affecting cell viability. Our results demonstrate that AITC has potential anti-asthma effects in HDM-induced asthma models by alleviating airway inflammation and airway constriction through increasing tight junction-related protein expression and suppressing Ca2+ signaling. These findings suggest that AITC may be a beneficial adjuvant therapy in asthma treatment.

Effect of Vitamin D Supplementation on Primary Dysmenorrhea: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

Dysmenorrhea causes pain and inconvenience during menstruation. In addition to medication, natural compounds are widely used to relieve various types of pain. In this study, we aimed to assess the effects of vitamin D (vit. D) supplementation in relieving the symptoms of primary dysmenorrhea. A comprehensive systematic database search of randomized controlled trials (RCTs) was performed. Oral forms of vit. D supplementation were included and compared with a placebo or standard care. The degree of dysmenorrhea pain was measured with a visual analogue scale or numerical rating scale. Outcomes were compared using the standardized mean difference (SMD) and 95% confidence intervals (CIs) in a meta-analysis. RCTs were assessed using the Cochrane risk-of-bias v2 (RoB 2) tool. The meta-analysis included 8 randomized controlled trials involving 695 participants. The results of the quantitative analysis showed a significantly lower degree of pain in the vit. D versus placebo in those with dysmenorrhea (SMD: -1.404, 95% CI: -2.078 to -0.731). The results of subgroup analysis revealed that pain lessened when the average weekly dose of vit. D was over 50,000 IU, in which dysmenorrhea was relieved regardless of whether vit. D was administered for more or less than 70 days and in any dose interval. The results revealed that vit. D treatment substantially reduced the pain level in the primary dysmenorrhea population. We concluded that vit. D supplementation is an alternative treatment for relieving the pain symptoms of dysmenorrhea.

Protective Effect of Electroacupuncture on Chemotherapy-Induced Salivary Gland Hypofunction in a Mouse Model.

Radiotherapy and chemotherapy can impair salivary gland (SG) function, which causes xerostomia and exacerbate other side effects of chemotherapy and oral infection, reducing patients' quality of life. This animal study aimed to assess the efficacy of electroacupuncture (EA) as a means of preventing xerostomia induced by 5-fluorouracil (5-FU). A xerostomia mouse model was induced via four tail vein injections of 5-FU (80 mg/kg/dose). EA was performed at LI4 and LI11 for 7 days. The pilocarpine-stimulated salivary flow rate (SFR) and salivary glands weight (SGW) were recorded. Salivary immunoglobulin A (SIgA) and lysozyme were determined via enzyme-linked immunosorbent assay (ELISA). SG was collected for hematoxylin and eosin staining to measure acini number and acinar cell size. Tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and aquaporin 5 (AQP5) mRNA expressions in SG were quantified via RT-qPCR. 5-FU caused significant decreases in SFR, SGW, SIgA, lysozyme, AQP5 expression, and acini number, while TNF-α and IL-1ß expressions and acinar cell size were significantly increased. EA treatment can prevent 5-FU damage to the salivary gland, while pilocarpine treatment can only elevate SFR and AQP5 expression. These findings provide significant evidence to support the use of EA as an alternative treatment for chemotherapy-induced salivary gland hypofunction and xerostomia.

Nutritional Biochemistry.

Nutritional biochemistry involves a wide range of fields, and many studies on nutritional biochemistry have focused not only on uncovering the relationship between diet and disease but also on revealing the importance of nutritional intake in the development of cancer [...].

Caffeic Acid Phenethyl Ester and Caffeamide Derivatives Suppress Oral Squamous Cell Carcinoma Cells.

Caffeic acid phenethyl ester (CAPE) contains antibiotic and anticancer activities. Therefore, we aimed to investigate the anticancer properties and mechanisms of CAPE and caffeamide derivatives in the oral squamous cell carcinoma cell (OSCC) lines SAS and OECM-1. The anti-OSCC effects of CAPE and the caffeamide derivatives (26G, 36C, 36H, 36K, and 36M) were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test. Cell cycle and total reactive oxygen species (ROS) production were analyzed using flow cytometry. The relative protein expression of malignant phenotypes was determined via Western blot analysis. The results showed that 26G and 36M were more cytotoxic than the other compounds in SAS cells. After 26G or 36M treatment for 48 h, cell cycle S phase or G2/M phase arrest was induced, and cellular ROS increased at 24 h, and then decreased at 48 h in both cell lines. The expression levels of cell cycle regulatory and anti-ROS proteins were downregulated. In addition, 26G or 36M treatment inhibited malignant phenotypes through mTOR-ULK1-P62-LC3 autophagic signaling activated by ROS generation. These results showed that 26G and 36M induce cancer cell death by activating autophagy signaling, which is correlated with altered cellular oxidative stress.

Progesterone Signaling and Uterine Fibroid Pathogenesis; Molecular Mechanisms and Potential Therapeutics.

Uterine fibroids (UFs) are the most important benign neoplastic threat to women's health worldwide, with a prevalence of up to 80% in premenopausal women, and can cause heavy menstrual bleeding, pain, and infertility. Progesterone signaling plays a crucial role in the development and growth of UFs. Progesterone promotes the proliferation of UF cells by activating several signaling pathways genetically and epigenetically. In this review article, we reviewed the literature covering progesterone signaling in UF pathogenesis and further discussed the therapeutic potential of compounds that modulate progesterone signaling against UFs, including selective progesterone receptor modulator (SPRM) drugs and natural compounds. Further studies are needed to confirm the safety of SPRMs as well as their exact molecular mechanisms. The consumption of natural compounds as a potential anti-UFs treatment seems promising, since these compounds can be used on a long-term basis-especially for women pursuing concurrent pregnancy, unlike SPRMs. However, further clinical trials are needed to confirm their effectiveness.

Protective Potential of ß-Hydroxybutyrate against Glucose-Deprivation-Induced Neurotoxicity Involving the Modulation of Autophagic Flux and the Monomeric Aß Level in Neuro-2a Cells.

Hypoglycemia has been known as a potential contributory factor to neurodegenerative diseases, such as Alzheimer's disease. There may be shared pathogenic mechanisms underlying both conditions, and the ketone body, ß-hydroxybutyrate (BHB), as an alternative substrate for glucose may exert neuroprotection against hypoglycemia-induced injury. To investigate this, Neuro-2a cells were subjected to a 24 h period of glucose deprivation with or without the presence of BHB. Cell viability, reactive oxygen species (ROS) production, apoptosis, autophagy, and adenosine triphosphate (ATP) and beta-amyloid peptide (Aß) levels were evaluated. The results show that Neuro-2a cells deprived of glucose displayed a significant loss of cell survival with a corresponding decrease in ATP levels, suggesting that glucose deprivation was neurotoxic. This effect was likely attributed to the diverse mechanisms including raised ROS, defective autophagic flux and reduced basal Aß levels (particularly monomeric Aß). The presence of BHB could partially protect against the loss of cell survival induced by glucose deprivation. The mechanisms underlying the neuroprotective actions of BHB might be mediated, at least in part, through restoring ATP, and modulating ROS production, autophagy flux efficacy and the monomeric Aß level. Results imply that a possible link between the basal monomeric Aß and glucose deprivation neurotoxicity, and treatments designed for the prevention of energy impairment, such as BHB, may be beneficial for rescuing surviving cells in relation to neurodegeneration.