Modulation Of Signaling Pathways Research Articles

A randomized, placebo-controlled trial of purified anthocyanins on cognitive function in individuals at elevated risk for dementia: Analysis of inflammatory biomarkers toward personalized interventions

BackgroundDementia poses a significant global health challenge. Anthocyanins neutralize free radicals, modulate signaling pathways, inhibit pro-inflammatory genes, and suppress cytokine production and may thus have positive cognitive effects in people at increased risk of dementia. We aim to investigate the effects of purified anthocyanins on cognitive function in people at increased risk of dementia according to their inflammation status based on blood-based inflammatory biomarkers. MethodsThis is a secondary analysis of a 24-week randomized, double-blind, placebo-controlled trial. Cluster analysis was performed to categorize two groups based on their individual inflammatory biomarker profile using multiplex sandwich ELISA for the quantitative measurement of cytokines. Descriptive statistics and longitudinal models assessed cognitive outcomes. The primary comparison was the group difference at week 24 based on a modified intention-to-treat analysis. ResultsCluster analysis revealed two distinct inflammatory biomarker profiles. In Cluster 1 (high levels of inflammation biomarkers), anthocyanin treatment showed a statistically significant improvement on cognitive function compared to placebo at 24 weeks. No significant differences were observed in Cluster 2 (low levels of inflammation biomarkers). The demographic characteristics, cognitive scores, and biomarker distributions were similar between treatment groups at baseline. However, cluster 1 exhibited higher BMI, diabetes prevalence, medication usage, and lower HDL cholesterol levels. ConclusionIndividuals with elevated levels of inflammation markers benefited from anthocyanin treatment to enhance cognitive performance, whereas those with lower levels did not. The anti-inflammatory and antioxidant properties of anthocyanins make them a promising intervention, and future prospective trials in people with increased inflammation are warranted.

Lysosomes accumulate at the perinuclear region of muscle cells during chick myogenesis.

Lysosomes are involved in a myriad of cellular functions, such as degradation of macromolecules, endocytosis and exocytosis, modulation of several signaling pathways, and regulation of cell metabolism. To fulfill these diverse functions, lysosomes can undergo several dynamic changes in their content, size, pH, and location within cells. Here, we studied some of these parameters during embryonic chick skeletal muscle cells. We used an anti-lysosome-associated membrane protein 2 (LAMP2) antibody to specifically determine the intracellular localization of lysosomes in these cells. Our data shows that lysosomes are highly enriched in the perinuclear region of chick embryonic muscle cells. We also showed that the wingless signaling pathway (Wnt)/β-catenin signaling pathway can modulate the location of LAMP2 in chick myogenic cells. Our results highlight the role of lysosomes during muscle differentiation and particularly the presence of a subcellular population of lysosomes that are concentrated in the perinuclear region of muscle cells.

Modulation of inflammatory signaling pathways by natural products in osteoarthritis: Mechanisms, challenges, and future directions

Modulation of inflammatory signaling pathways by natural products in osteoarthritis: Mechanisms, challenges, and future directions

Synthesis of pH-sensitive polymeric micelle drug carries for potential cancer chemotherapy applications

Alpha mangostin, a natural xanthone derivative from mangosteen fruit pericarp, exhibits antiproliferative and apoptotic effects on different cancer cells by inhibiting cell cycle progression, inducing apoptosis, and modulating signaling pathways. However, this candidate is limited in medical treatment due to the poor water solubility. Nanoparticles have emerged as promising drug delivery systems to improve drug delivery efficiency but one of the problem of nanoparticles is the capability of endosomal escape. Therefore, pH-sensitive polymer nanosystems were utilized for targeted drug delivery, and enhanced efficacy by offering controlled release and endosomal escape capabilities. This study aimed to synthesize PEG- P(Asp-Hyd-Man) copolymer and create micelle for alpha mangostin delivery. The micelles were measured with particle size average of 80.2 ± 15 nm, and the PDI of 0.17. Additionally, the release behavior of alpha mangostin was examined in vitro that show pH-sensitive polymeric micelles rapidly release at pH 5.0 compared with the arterial pH 7.4. The findings of this study are significant in the development of an effective drug delivery system using alpha mangostin and other therapeutic agents.

TOR2 plays the central role in rapamycin-induced lifespan extension in budding yeast

The target of rapamycin (TOR) protein, renowned for its highly conserved nature across species, plays a pivotal role in modulating signaling pathways via its multiprotein complexes, TORC1 and TORC2. The relationship between TOR and its inhibitor, rapamycin, especially in the context of lifespan extension, has earned significant attention. Unlike mammals, which have a single TOR gene, the budding yeast Saccharomyces cerevisiae features two TOR paralogs: TOR1 and TOR2. Non-essential TOR1 gene has been the focus of extensive research, whereas the essential TOR2 gene has received relatively little attention in lifespan studies. In our research, we engineered a point mutation (Ser-1975-Ile) within the FKBP12-rapamycin-binding (FRB) domain of Tor2p to block rapamycin binding. Remarkably, this mutation negated the lifespan-extending benefits of rapamycin, irrespective of the TOR1 gene status. Our findings indicate that the TOR2 gene likely serves as the primary mammalian ortholog, playing a crucial role in mediating the effects of rapamycin on lifespan extension. This discovery opens a new avenue for the development of innovative anti-aging agents targeting the TOR. complex.

Noscapine Down-Regulates LPS-Induced Neuroinflammation in BV-2 Microglia Cells via Modulation of MAPK and NF-κB Signaling Pathways

Noscapine Down-Regulates LPS-Induced Neuroinflammation in BV-2 Microglia Cells via Modulation of MAPK and NF-κB Signaling Pathways

A Novel 3-Benzyloxychromone From Celastrus orbiculatus Thunb. Exhibits Anticancer Effects on Non-Small Cell Lung Cancer Cells via GSK-3β-Dependent c-Jun/ATF2 Pathway.

Celastrus orbiculatus Thunb. is a vine used as a traditional Chinese medicinal herb. In this study, we focused on the anticancer cytotoxicity and underlying mechanism of previously unreported 3-oxygen-substituted isoflavone analogue (3-benzyloxychromone, 3-Boc) from the herb. Initially, we established cell line-derived xenograft mouse model using H1299 non-small cell lung cancer (NSCLC) cells and found that the ethanol crude extracts of the stem part of C. orbiculatus (200 mg/kg) could substantially suppress the growth of xenograft tumors in athymic nu/nu mice. We compared 3-Boc with three other flavonoid analogues isolated from the stem part of C. orbiculatus. Among these, 3-Boc showed the most potent cytotoxicity against H1299 and H1975 NSCLC cells. Colony formation, EdU incorporation and Annexin V-FITC/PI apoptosis assays demonstrated that 3-Boc induced growth inhibition primarily by inhibiting DNA replication and inducing apoptotic death of NSCLC cells. Structure-based target prediction and MD simulation suggested that 3-Boc potentially suppressed the activity of glycogen synthase kinase-3β (GSK-3β) by interacting with the ATP-binding site. Western blot analysis indicated that 3-Boc triggered the phosphorylation of Serine 21 of GSK-3α or Serine 9 of GSK-3β in a time- and dose-dependent manner. To investigate the dependency of GSK-3β, we established GSK-3β knockout in H1299 cells. Depletion of GSK-3β enhanced 3-Boc-induced cytotoxicity compared with wild-type counterparts through activated c-Jun/ATF2 signaling pathway. Altogether, our study highlights the anticancer potential of C. orbiculatus and the discovery of novel 3-oxygen-substituted chromone from the herb, which may have important implications for screening promising modulators of GSK-3β and related signaling pathways in the treatment of cancer.

Potential active fractions and constituents in the flowers of Trollius chinensis Bunge responsible for treating acute pharyngitis

Ethnopharmacological relevanceTrollius chinensis Bunge has a long history of use in China as traditional Chinese medicine and functional tea for the treatment of respiratory infections, such as pharyngitis, tonsillitis and bronchitis. Pharyngitis can impact the entire throat and adjacent lymphoid tissues, and may lead to significant systemic complications. However, the active components and mechanism of Trollius chinensis Bunge for treating acute pharyngitis remains unclear. Aim of the studyTrollius chinensis Bunge is recognized in China both as a medicinal herb and a functional tea. Research into its properties aimed to establish its effectiveness against pharyngitis and to pinpoint the active components and mechanism. Materials and methodsA 70% ethanol extract from the herb was prepared, which was refined using chromatography through a column containing D101 macroporous resin and varying ethanol solutions. The efficacy of the initial and refined extracts was tested using a rat model of ammonia-induced acute pharyngitis. Pathological examination, HE staining and ELISA were applied to screen activity fraction. The compounds were isolated by silica gel, sephadex LH-20 column chromatography and semi-preparative HPLC chromatography from active fraction. All of the isolated compounds were assessed for anti-inflammatory activity by acting on LPS-induced RAW 264.7 macrophage cells in vitro. Cytotoxicity of compounds was detected by CCK-8 assay. The Griess reaction was applied to evaluate the inhibitory effects of isolated compounds on NO production in RAW 264.7 cells induced by LPS. TNF-α, IL-6, IL-1β and PGE2 levels in macrophage supernatant were detected by ELISA. Molecular docking and western blot analysis were applied to study the anti-inflammatory mechanism of active compound. ResultsThe fraction extracted with 30% ethanol proved particularly effective, significantly reducing pharyngitis symptoms. This was evidenced by decreased levels of cytokines (TNF-α, IL-6, IL-1β and PGE2) and visible improvements in the pharyngeal tissue histology. In pursuit of pharyngitis treatments, 23 phenolic acids and 13 flavonoids were isolated from the 30% ethanol fraction and identified using spectral analysis. Of these, three were newly discovered compounds and eight were first-time isolates from the Trollius genus. These compounds were further investigated for their ability to suppress nitric oxide production in RAW 264.7 cells triggered by lipopolysaccharide. Compounds 3, 19, and 26 exhibited strong anti-inflammatory properties. HPLC analysis of the 30% ethanol fraction revealed that orientin was the predominant component, accounting for 44.4% of this fraction. Western blot analysis demonstrated that orientin reduced the expression levels of the protein p-p65 relative to p65, p-IκBα relative to IκBα and iNOS, indicating an anti-inflammatory effect potentially through the modulation of the NF-κB signaling pathway. ConclusionThe finding of this study provided strong support for the use of T. chinensis as a potential functional food for treating pharyngitis.

Exploring the neuroprotective potential of Nrf2-pathway activators against annonacin toxicity

Modulation of the Nrf2 pathway, a master regulator of the antioxidant response and cellular metabolism, has been suggested as a promising therapeutic strategy in tauopathies, a heterogeneous group of neurodegenerative disorders characterized by intracellular proteinaceous inclusions of abnormally phosphorylated tau. Here, we explored the neuroprotective potential of different Nrf2-pathway activators in human immortalized dopaminergic neurons against annonacin-induced toxicity, a mitochondrial inhibitor associated with a PSP-like syndrome and capable of mimicking tauopathy-like features. Interestingly, we observed heterogenous and compound-dependent neuroprotective effects among the different Nrf2-pathway activators. With the exception of Fyn inhibitors, all the selected Nrf2-pathway activators improved cell viability and the oxidative status, and reduced the annonacin-induced tau hyperphosphorylation and neurite degeneration, particularly the p62-activators. However, improvement of the impaired mitochondrial function was only observed by the Bach-1 inhibitor. Surprisingly, we found evidence that ezetimibe, an approved drug for hypercholesterolemia, prevents the transcriptional upregulation of 4R-tau triggered by annonacin insult. Overall, our results suggest that the neuroprotective effects of the Nrf2-pathway activators against annonacin toxicity may rely on the specific mechanism of action, intrinsic to each compound, and possibly on the concomitant modulation of additional signaling pathways. Further research will be needed to fully understand how synergistic modulation of metabolic adaptation and cell survival can be exploit to develop new therapeutical strategies for tauopathies and eventually other neurodegenerative diseases.

Dietary plants for oral cancer prevention and therapy: A review of preclinical and clinical studies.

Oral cancer is a disease with high mortality and rising incidence worldwide. Although fragmentary literature on the anti-oral cancer effects of plant products has been published, a comprehensive analysis is lacking. In this work, a critical and comprehensive evaluation of oral cancer preventative or therapeutic effects of dietary plants was conducted. An exhaustive analysis of available data supports that numerous dietary plants exert anticancer effects, including suppression of cell proliferation, viability, autophagy, angiogenesis, invasion, and metastasis while promoting cell cycle arrest and apoptosis. Plant extracts and products target several cellular mechanisms, such as the reversal of epithelial-to-mesenchymal transition and the promotion of oxidative stress and mitochondrial membrane dysfunction by modulation of various signaling pathways. These agents were also found to regulate cellular growth signaling pathways by action on extracellular signal-regulated kinase and mitogen-activated protein kinase, inflammation via modulation of cyclooxygenase (COX)-1, COX-2, and nuclear factor-κB p65, and metastasis through influence of cadherins and matrix metalloproteinases. In vivo studies support these findings and demonstrate a decrease in tumor burden, incidence, and hyperplastic and dysplastic changes. Clinical studies also showed decreased oral cancer risk. However, high-quality studies should be conducted to establish the clinical efficacy of these plants. Overall, our study supports the use of dietary plants, especially garlic, green tea, longan, peppermint, purple carrot, saffron, tomato, and turmeric, for oral cancer prevention and intervention. However, further research is required before clinical application of this strategy.

Exploring potential roles of long non-coding RNAs in cancer immunotherapy: a comprehensive review.

Cancer treatment has long been fraught with challenges, including drug resistance, metastasis, and recurrence, making it one of the most difficult diseases to treat effectively. Traditional therapeutic approaches often fall short due to their inability to target cancer stem cells and the complex genetic and epigenetic landscape of tumors. In recent years, cancer immunotherapy has revolutionized the field, offering new hope and viable alternatives to conventional treatments. A particularly promising area of research focuses on non-coding RNAs (ncRNAs), especially long non-coding RNAs (lncRNAs), and their role in cancer resistance and the modulation of signaling pathways. To address these challenges, we performed a comprehensive review of recent studies on lncRNAs and their impact on cancer immunotherapy. Our review highlights the crucial roles that lncRNAs play in affecting both innate and adaptive immunity, thereby influencing the outcomes of cancer treatments. Key observations from our review indicate that lncRNAs can modify the tumor immune microenvironment, enhance immune cell infiltration, and regulate cytokine production, all of which contribute to tumor growth and resistance to therapies. These insights suggest that lncRNAs could serve as potential targets for precision medicine, opening up new avenues for developing more effective cancer immunotherapies. By compiling recent research on lncRNAs across various cancers, this review aims to shed light on their mechanisms within the tumor immune microenvironment.

Modulation of miR-466d-3p on Wnt signaling pathway in response to DEPs-induced blood-brain barrier disruption

BackgroundDiesel exhaust particles (DEPs), a predominant component of ambient particulate matter (PM), are classified as ultrafine particles with the capacity to penetrate the cerebral blood-brain barrier (BBB). This penetration is implicated in the pathogenesis of central nervous system (CNS) disorders. The integrity of the BBB is inextricably linked to cerebrovascular homeostasis and the development of neurodegenerative disease, highlighting the importance of studying the effects and mechanisms of DEPs on BBB function damage. Methods and resultsUtilizing mouse cerebral microvascular endothelial cells (bEnd.3 cells) as an in vitro model of the BBB, we explored the detrimental effects of DEPs exposure on BBB permeability and integrity, with particular focus on inflammation, cell apoptosis, and miRNA expression profiles. Our findings revealed that exposure to DEPs at varying concentrations for 48 h resulted in the inhibition of bEND.3 cell proliferation, induction of cell apoptosis, and an upregulation in the secretion of inflammatory cytokines/chemokines and adhesion molecules. The BBB integrity was further compromised, as evidenced by a decrease in trans-epithelial electrical resistance(TEER), a reduction in cytoskeletal F-actin, and diminished tight junction (TJ) protein expression. Microarray analysis revealed that 23 miRNAs were upregulated and 11 were downregulated in response to a 50 μg/mL DEPs treatment, with miR-466d-3p being notably differentially expressed. Wnt3 was identified as a target of miR-466d-3p, with the Wnt signaling pathway being significantly enriched. We validated that miR-466d-3p expression was downregulated, and the protein expression levels of Wnt/β-catenin and Wnt/PCP signaling components were elevated. The modulation of the Wnt signaling pathway by miR-466d-3p was demonstrated by the transfection of miR-466d-3p mimic, which resulted in a downregulation of Wnt3 and β-catenin protein expression, and the mRNA level of Daam1, as well as an enhancement of TJ proteins ZO-1 and Claudin-5 expression. ConclusionsOur study further confirmed that DEPs can induce the disruption of BBB integrity through inflammatory processes. We identified alterations in the expression profile of microRNAs (miRNAs) in endothelial cells, with miR-466d-3p emerging as a key regulator of tight junction (TJ) proteins, essential for maintaining BBB integrity. Additionally, our findings primarily demonstrated that the Wnt/ β-catenin and Wnt/PCP signaling pathway can be activated by DEPs and are regulated by miR-466d-3p. Under the combined effects of Wnt/PCP and inflammation, there is an ultimate increase in BBB hyperpermeability.

Progress, pharmacokinetics and future perspectives of luteolin modulating signaling pathways to exert anticancer effects: A review.

Luteolin (3, 4, 5, 7-tetrahydroxyflavone) are natural flavonoids widely found in vegetables, fruits and herbs, with anti-tumor, anti-inflammatory and antioxidant effects, and also play an anti-cancer effect in various cancers such as lung, breast, prostate, and liver cancer, etc. Specifically, the anti-cancer mechanism includes regulation of various signaling pathways to induce apoptosis of tumor cells, inhibition of tumor cell proliferation and metastasis, anti-angiogenesis, regulation of immune function, synergistic anti-cancer drugs and regulation of reactive oxygen species levels of tumor cells. Specific anti-cancer mechanisms include regulation of various signaling pathways to induce apoptosis, inhibition of tumor cell proliferation and metastasis, anti-angiogenesis, reversal of epithelial-mesenchymal transition, regulation of immune function, synergism with anti-cancer drugs and regulation of reactive oxygen species levels in tumor cells. This paper integrates the latest cutting-edge research on luteolin and combines it with the prospect of future clinical applications, aiming to explore the mechanism of luteolin exerting different anticancer effects through the regulation of different signaling pathways, so as to provide a practical theoretical basis for the use of luteolin in clinical treatment and hopefully provide some reference for the future research direction of luteolin.

EZH2 Inhibition to Counteract Oral Cancer Progression through Wnt/β-Catenin Pathway Modulation.

Oral squamous cell carcinoma (OSCC) is one of the most common human malignancies worldwide. The molecular mechanisms of OSCC pathogenesis are still unknown; however, in recent years, several reports have focused on the role of enhancer of zeste homolog 2 (EZH2) in OSCC. Therefore, in this study we aimed to investigate the effects of GSK343, a selective EZH2 inhibitor, and its impact on the signaling pathways in OSCC, using an in vitro and in vivo orthotopic model. In the in vitro model, GSK343 (1, 10, and 25 μM) significantly decreased OSCC cell viability and cell migration through EZH2 inhibition, modulating NF-κB/IκBα pathway activation and eNOS, VEGF, and TGFβ expression, important markers of angiogenesis. In the in vivo model, GSK343 (5 mg/kg and 10 mg/kg) restored tongue tissue architecture and reduced tumor progression through EZH2 inhibition and Wnt/β-catenin signaling pathway modulation. Moreover, GSK343 reduced the expression of inflammatory mediators; eNOS and TGFβ, markers of angiogenesis; and CD31 and CD34, markers of micro vessel density, respectively. In conclusion, our data demonstrate that GSK343 counteracts oral cancer progression through EZH2/Wnt/β-catenin pathway modulation, suggesting that it could be a promising therapeutic approach for OSCC management.

Medium acidosis drives cardiac differentiation during mesendoderm cell fate specification from human pluripotent stem cells

Effective lineage-specific differentiation is essential to fulfilling the great potentials of human pluripotent stem cells (hPSCs). In this report, we investigate how modulation of medium pH and associated metabolic changes influence mesendoderm differentiation from hPSCs. We show that daily medium pH fluctuations are critical for the heterogeneity of cell fates in the absence of exogenous inducers. Acidic environment alone leads to cardiomyocyte generation without other signaling modulators. In contrast, medium alkalinization is inhibitory to cardiac fate even in the presence of classic cardiac inducers. We then demonstrate that acidic environment suppresses glycolysis to facilitate cardiac differentiation, while alkaline condition promotes glycolysis and diverts the differentiation toward other cell types. We further show that glycolysis inhibition or AMPK activation can rescue cardiac differentiation under alkalinization, and glycolysis inhibition alone can drive cardiac cell fate. This study highlights that pH changes remodel metabolic patterns and modulate signaling pathways to control cell fate.

Plant‐Derived Phytochemicals and Their Nanoformulations for Inducing Programed Cell Death in Cancer

AbstractPhytochemicals are a diverse class of compounds found in various plant‐based foods and beverages that have displayed the capacity to exert powerful anticancer effects through the induction of programed cell death (PCD) in malignancies. PCD is a sophisticated process that maintains in upholding tissue homeostasis and eliminating injured or neoplastic cells. Phytochemicals have shown the potential to induce PCD in malignant cells through various mechanisms, including modulation of cell signaling pathways, regulation of reactive oxygen species (ROS), and interaction with critical targets in cells such as DNA. Moreover, recent studies have suggested that nanomaterials loaded with phytochemicals may enhance cell death in tumors, which can also stimulate antitumor immunity. In this review, a comprehensive overview of the current understanding of the anticancer effects of phytochemicals and their potential as a promising approach to cancer therapy, is provided. The impacts of phytochemicals such as resveratrol, curcumin, apigenin, quercetin, and some approved plant‐derived drugs, such as taxanes on the regulation of some types of PCD, including apoptosis, pyroptosis, anoikis, autophagic cell death, ferroptosis, and necroptosis, are discussed. The underlying mechanisms and the potential of nanomaterials loaded with phytochemicals to enhance PCD in tumors are also explained.

Sphingosine 1-phosphate protective effect on human proximal tubule cells submitted to an in vitro ischemia model: the role of JAK2/STAT3.

Acute kidney injury is a serious public health problem worldwide, being ischemia and reperfusion (I/R) the main lesion-aggravating factor that contributes to the evolution towards chronic kidney disease. Nonetheless, intervention approaches currently available are just considered palliative options. In order to offer an alternative treatment, it is important to understand key factors involved in the development of the disease including the rescue of the affected cells and/or the release of paracrine factors that are crucial for tissue repair. Bioactive lipids such as sphingosine 1-phosphate (S1P) have significant effects on the modulation of signaling pathways involved in tissue regeneration, such as cell survival, proliferation, differentiation, and migration. The main objective of this work was to explore the protective effect of S1P using human kidney proximal tubule cells submitted to a mimetic I/R lesion, via ATP depletion. We observed that the S1P pre-treatment increases cell survival by 50% and preserves the cell proliferation capacity of injured cells. We showed the presence of different bioactive lipids notably related to tissue repair but, more importantly, we noted that the pre-treatment with S1P attenuated the ischemia-induced effects in response to the injury, resulting in higher endogenous S1P production. All receptors but S1PR3 are present in these cells and the protective and proliferative effect of S1P/S1P receptors axis occur, at least in part, through the activation of the SAFE pathway. To our knowledge, this is the first time that S1PR4 and S1PR5 are referred in these cells and also the first indication of JAK2/STAT3 pathway involvement in S1P-mediated protection in an I/R renal model.

HSP70 promotes pancreatic cancer cell epithelial-mesenchymal transformation and growth via the NF-κB signaling pathway.

To study the effects of HSP70 on proliferation, migration, invasion, and epithelial-mesenchymal transformation (EMT) of pancreatic cancer cells and explore its underlying mechanisms. Pancreatic cancer cell models with either reduced HSP70 or increased HSP70 expression were established. RT-qPCR and Western blot assays were used to determine mRNA and protein levels of HSP70, IKK/IκBa/NF-κB signaling pathway-related genes, and EMT markers. The CCK-8 and cell cloning assays were used to evaluate cell proliferation and cloning abilities. Transwell and wound healing assays were used to assess the invasive and migratory properties of the cells. Effects of NF-κB signaling modulation were explored using an IKK inhibitor (BAY11-7082) and an IKK overexpression vector (pCMV-IKK). Electrophoretic mobility shift assay (EMSA) and luciferase reporter assays were conducted to analyze NF-κB's promoter binding and transcriptional activities. HSP70 knockdown inhibited p-p65 nuclear translocation and reduced the expression of p-p65, p-IKKα/β, p-IκBα, N-cadherin, Vimentin, and Twist. It also decreased NF-κB's promoter binding and transcriptional activities, increased E-cadherin levels, and suppressed pancreatic cancer cell proliferation, cloning, migration, and invasion. In contrast, HSP70 overexpression led to increased expression of p-p65, p-IKKα/β, p-IκBα, N-cadherin, Vimentin, and Twist, decreased E-cadherin levels, and enhanced cell proliferation, cloning, migration, and invasion capabilities. NF-κB signaling pathway modulation reversed EMT changes induced by altered HSP70 expression levels. rhHSP70 also increased p-IKKα/β and p-IκBα protein levels. HSP70 promotes the EMT and enhances pancreatic cancer cell proliferation, migration, and invasion by activating the NF-κB pathway.

Pharmacological impacts of tanshinone on osteogenesis and osteoclastogenesis: a review.

Tanshinone, a lipophilic component of Salvia miltiorrhiza, is used to treat diseases like atherosclerosis, hypertension, Alzheimer's disease, and diabetes mellitus through its pharmacological activities like anti-inflammatory, anti-oxidant, and anti-tumor. Excessive inflammation is the primary cause of bone diseases such as osteoporosis and rheumatoid arthritis, affecting more than millions of people across the globe. Recently, tanshinone has shown potential benefits against bone diseases by modulating signaling pathways accountable for the proliferation and differentiation of bone cells. In vitro and in vivo studies reported that tanshinone promotes osteoblast formation and mineralization and suppresses excessive bone resorption during disease conditions. In this review, we have summarized the beneficial effects of tanshinone and other extracts of Salvia miltiorrhiza for bone health and their potential molecular targets in signaling.

Role of MicroRNA-204 in Regulating the Hallmarks of Breast Cancer: An Update.

microRNA-204-5p (miR-204) is a small noncoding RNA with diverse regulatory roles in breast cancer (BC) development and progression. miR-204 is implicated in the instauration of fundamental traits acquired during the multistep development of BC, known as the hallmarks of cancer. It may act as a potent tumor suppressor by inhibiting key cellular processes like angiogenesis, vasculogenic mimicry, invasion, migration, and metastasis. It achieves this by targeting multiple master genes involved in these processes, including HIF-1α, β-catenin, VEGFA, TGFBR2, FAK, FOXA1, among others. Additionally, miR-204 modulates signaling pathways like PI3K/AKT and interacts with HOTAIR and DSCAM-AS1 lncRNAs, further influencing tumor progression. Beyond its direct effects on tumor cells, miR-204 shapes the tumor microenvironment by regulating immune cell infiltration, suppressing pro-tumorigenic cytokine production, and potentially influencing immunotherapy response. Moreover, miR-204 plays a crucial role in metabolic reprogramming by directly suppressing metabolic genes within tumor cells, indirectly affecting metabolism through exosome signaling, and remodeling metabolic flux within the tumor microenvironment. This review aims to present an update on the current knowledge regarding the role of miR-204 in the hallmarks of BC. In conclusion, miR-204 is a potential therapeutic target and prognostic marker in BC, emphasizing the need for further research to fully elucidate its complex roles in orchestrating aggressive BC behavior.