MicroRNA­mediated regulation of muscular atrophy: Exploring molecular pathways and therapeutics (Review).

Muscular atrophy, which results in loss of muscle mass and strength, is a significant concern for patients with various diseases. It is crucial to comprehend the molecular mechanisms underlying this condition to devise targeted treatments. MicroRNAs (miRNAs) have emerged as key regulators of gene expression, serving vital roles in numerous cellular processes, including the maintenance of muscle stability. An intricate network of miRNAs finely regulates gene expression, influencing pathways related to muscle protein production, and muscle breakdown and regeneration. Dysregulation of specific miRNAs has been linked to the development of muscular atrophy, affecting important signaling pathways including the protein kinase B/mTOR and ubiquitin­proteasome systems. The present review summarizes recent work on miRNA patterns associated with muscular atrophy under various physiological and pathological conditions, elucidating its intricate regulatory networks. In conclusion, the present review lays a foundation for the development of novel treatment options for individuals affected by muscular atrophy, and explores other regulatory pathways, such as autophagy and inflammatory signaling, to ensure a comprehensive overview of the multifarious nature of muscular atrophy. The objective of the present review was to elucidate the complex molecular pathways involved in muscular atrophy, and to facilitate the development of innovative and specific therapeutic strategies for the prevention or reversal of muscular atrophy in diverse clinical scenarios.

AXL is required for hypoxia-mediated hypoxia-inducible factor-1 alpha function in glioblastoma.

Glioblastoma (GBM) is the most aggressive type of central nervous system tumor. Molecular targeting may be important when developing efficient GBM treatment strategies. Sequencing of GBMs revealed that the receptor tyrosine kinase (RTK)/RAS/phosphatidylinositol-3-kinase pathway was altered in 88% of samples. Interestingly, AXL, a member of RTK, was proposed as a promising target in glioma therapy. However, the molecular mechanism of AXL modulation of GBM genesis and proliferation is still unclear. In this study, we investigated the expression and localization of hypoxia-inducible factor-1 alpha (HIF-1α) by AXL in GBM. Both AXL mRNA and protein are overexpressed in GBM. Short-interfering RNA knockdown of AXL in U251-MG cells reduced viability and migration. However, serum withdrawal reduced AXL expression, abolishing the effect on viability. AXL is also involved in hypoxia regulation. In hypoxic conditions, the reduction of AXL decreased the level and nuclear localization of HIF-1α. The co-expression of HIF-1α and AXL was found in human GBM samples but not normal tissue. This finding suggests a mechanism for GBM proliferation and indicates that targeting AXL may be a potential GBM therapeutic. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-023-00195-z.

Thyroid storm caused by metastatic papillary thyroid carcinoma tissue after total thyroidectomy: a case report.

Thyroid storm is a life-threatening form of thyrotoxicosis and an endocrinological emergency. We present a case of thyroid storm in a patient with metastatic papillary thyroid cancer. A 67-year-old woman with a history of total thyroidectomy 4 years prior to presentation was admitted with deteriorating mental status, fever, and tachycardia. Laboratory tests revealed severe thyrotoxicosis. Although the patient had no residual thyroid tissue after total thyroidectomy, she had a previously diagnosed metastatic thyroid cancer lesion in the pelvic bone. Despite initial treatment with a standard thyroid storm regimen, the patient died 6 days after hospitalization. The patient had no history of Graves disease; however, a thyroxine receptor antibody was detected postmortem. The patient had a history of exposure to an iodine contrast agent, which is a rare cause of thyrotoxicosis. Thyroxine production from a differentiated thyroid carcinoma is rare but can be a source of clinically significant thyrotoxicosis in patients post-thyroidectomy. Overlapping Graves disease is a common stimulus; however, other causes, such as exogenous iodine, cannot be excluded. This case demonstrates that in the setting of metastatic thyroid carcinoma, thyrotoxicosis cannot be completely ruled out as a cause of suspicious symptoms, even in patients with a history of total thyroidectomy.

HDAC8 Deacetylates HIF-1α and Enhances Its Protein Stability to Promote Tumor Growth and Migration in Melanoma.

Melanoma is the most lethal type of skin cancer, and it causes more than 55,000 deaths annually. Although regional melanoma can be surgically removed, once melanoma metastasizes to other regions of the body, the survival rate drops dramatically. The current treatment options are chemotherapy, immunotherapy, and targeted therapy. However, the low response rate and the development of resistance necessitate the search for a novel therapeutic target in melanoma. Hypoxia-inducible factor-1 α (HIF-1α) is overexpressed in melanoma and plays a crucial role in driving malignant transformation in cancer cells. Here, we identified that histone deacetylase 8 (HDAC8) enhances the protein stability of HIF-1α. HDAC8 directly binds to and deacetylates HIF-1α, thereby promoting its protein stability. This, in turn, upregulates the transcriptional activity of HIF-1α and promotes the expressions of its target genes, such as hexokinase 2 (HK2) and glucose transporter 1 (GLUT1). The inhibition of HDAC8 suppresses the proliferation and metastasis of melanoma cells. Furthermore, HDAC8 is correlated with HIF1A expression and poor prognosis in samples from patients with melanoma. These findings uncover a novel epigenetic mechanism that maintains HIF-1α stability and implicates the potential of HDAC8 inhibitors for melanoma therapy.

Drawing a line between histone demethylase KDM5A and KDM5B: their roles in development and tumorigenesis.

Distinct epigenetic modifiers ensure coordinated control over genes that govern a myriad of cellular processes. Growing evidence shows that dynamic regulation of histone methylation is critical for almost all stages of development. Notably, the KDM5 subfamily of histone lysine-specific demethylases plays essential roles in the proper development and differentiation of tissues, and aberrant regulation of KDM5 proteins during development can lead to chronic developmental defects and even cancer. In this review, we adopt a unique perspective regarding the context-dependent roles of KDM5A and KDM5B in development and tumorigenesis. It is well known that these two proteins show a high degree of sequence homology, with overlapping functions. However, we provide deeper insights into their substrate specificity and distinctive function in gene regulation that at times divert from each other. We also highlight both the possibility of targeting KDM5A and KDM5B to improve cancer treatment and the limitations that must be overcome to increase the efficacy of current drugs.

Pathological Role of HDAC8: Cancer and Beyond.

Histone deacetylase 8 (HDAC8) is a class I HDAC that catalyzes the deacetylation of histone and non-histone proteins. As one of the best-characterized isoforms, numerous studies have identified interacting partners of HDAC8 pertaining to diverse molecular mechanisms. Consequently, deregulation and overexpression of HDAC8 give rise to diseases. HDAC8 is especially involved in various aspects of cancer progression, such as cancer cell proliferation, metastasis, immune evasion, and drug resistance. HDAC8 is also associated with the development of non-cancer diseases such as Cornelia de Lange Syndrome (CdLS), infectious diseases, cardiovascular diseases, pulmonary diseases, and myopathy. Therefore, HDAC8 is an attractive therapeutic target and various HDAC8 selective inhibitors (HDAC8is) have been developed. Here, we address the pathological function of HDAC8 in cancer and other diseases, as well as illustrate several HDAC8is that have shown anti-cancer effects.

Functional characteristics and research trends of PDE11A in human diseases (Review).

cAMP and cGMP are important secondary messengers involved in cell regulation and metabolism driven by the G protein­coupled receptor. cAMP is converted via adenylyl cyclase (AC) and activates protein kinase A to phosphorylate intracellular proteins that mediate specific responses. cAMP signaling serves a role at multiple steps in tumorigenesis. The level of cAMP is increased in association with cancer cell formation through activation of AC­stimulatory G protein by mutation. Phosphodiesterases (PDEs) hydrolyze cAMP and cGMP to AMP and GMP. PDEs are composed of 11 families, and each can hydrolyze cAMP and cGMP or both cAMP and cGMP. PDEs perform various roles depending on their location and expression site, and are involved in several diseases, including male erectile dysfunction, pulmonary hypertension, Alzheimer's disease and schizophrenia. PDE11A is the 11th member of the PDE family and is characterized by four splice variants with varying tissue expression and N­terminal regulatory regions. Among tissues, the expression of PDE11A was highest in the prostate, and it was also expressed in hepatic skeletal muscle, pituitary, pancreas and kidney. PDE11A is the first PDE associated with an adrenocortical tumor associated genetic condition. In several studies, three PDE11A mutations have been reported in patients with Cushing syndrome with primary pigmented nodular adrenocortical disease or isolated micronodular adrenocortical disease without other genetic defects. It has been reported that an increase in PDE11A expression affects the proliferation of glioblastoma and worsens patient prognosis. The present mini­review summarizes the location of PDE11A expression, the impact of structural differences and disease relevance.

HDAC8-Selective Inhibition by PCI-34051 Enhances the Anticancer Effects of ACY-241 in Ovarian Cancer Cells.

HDAC6 is overexpressed in ovarian cancer and is known to be correlated with tumorigenesis. Accordingly, ACY-241, a selective HDAC6 inhibitor, is currently under clinical trial and has been tested in combination with various drugs. HDAC8, another member of the HDAC family, has recently gained attention as a novel target for cancer therapy. Here, we evaluated the synergistic anticancer effects of PCI-34051 and ACY-241 in ovarian cancer. Among various ovarian cancer cells, PCI-34051 effectively suppresses cell proliferation in wild-type p53 ovarian cancer cells compared with mutant p53 ovarian cancer cells. In ovarian cancer cells harboring wild-type p53, PCI-34051 in combination with ACY-241 synergistically represses cell proliferation, enhances apoptosis, and suppresses cell migration. The expression of pro-apoptotic proteins is synergistically upregulated, whereas the expressions of anti-apoptotic proteins and metastasis-associated proteins are significantly downregulated in combination treatment. Furthermore, the level of acetyl-p53 at K381 is synergistically upregulated upon combination treatment. Overall, co-inhibition of HDAC6 and HDAC8 through selective inhibitors synergistically suppresses cancer cell proliferation and metastasis in p53 wild-type ovarian cancer cells. These results suggest a novel approach to treating ovarian cancer patients and the therapeutic potential in developing HDAC6/8 dual inhibitors.

Phosphodiesterase 11 A (PDE11A), a potential biomarker for glioblastoma.

Phosphodiesterase 11A (PDE11A), a 3',5'-cyclic nucleotide phosphodiesterase, is a key regulator of intracellular signaling that functions by degrading cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). However, the function of PDE11A in brain tumors is currently unclear. In this study, we found that PDE11A may be involved in glioblastoma development. The protein and mRNA levels of PDE11A were significantly higher in U87-MG, U251-MG and U343-MG glioblastoma cell lines. Gene expression analyses by deep-sequencing revealed that PDE11A mRNA levels were higher in U87-MG and U251-MG cells compared to other cells in the cerebral cortex. A comprehensive analysis of The Cancer Genome Atlas (TCGA) data revealed that PDE11A expression was also elevated in glioblastoma patients. Taken together, these data indicate that PDE11A expression was increased in glioblastoma cell lines and glioma patients, suggesting that PDE11A could be a putative diagnostic marker and therapeutic target for glioma.

Scavenger receptor class F member 2 (SCARF2) as a novel therapeutic target in glioblastoma.

Scavenger receptor class F member 2 (SCARF2) is expressed by endothelial cells with very large cytoplasmic domains and is the second isotype, also known as scavenger receptor expressed by endothelial cells 2 (SREC-2). SREC-1 plays an important role in the binding and endocytosis of various endogenous and exogenous ligands. Many studies have been carried out on modified low-density lipoprotein internalization activity, but there have been few studies on SCARF2. Higher expression of SCARF2 has been found in glioblastoma (GBM) than normal brain tissue. Through analysis of The Cancer Genome Atlas database, it was confirmed that SCARF2 is widely expressed in GBM, and increased SCARF2 expression correlated with a poor prognosis in patients with glioma. The results of this study showed that the expression of SCARF2 is increased in GBM cell lines and patients, suggesting that SCARF2 may be a potential diagnostic marker and therapeutic molecule for cancers including glioma.

Heterochromatin Protein 1: A Multiplayer in Cancer Progression.

Dysregulation of epigenetic mechanisms as well as genomic mutations contribute to the initiation and progression of cancer. In addition to histone code writers, including histone lysine methyltransferase (KMT), and histone code erasers, including histone lysine demethylase (KDM), histone code reader proteins such as HP1 are associated with abnormal chromatin regulation in human diseases. Heterochromatin protein 1 (HP1) recognizes histone H3 lysine 9 methylation and broadly affects chromatin biology, such as heterochromatin formation and maintenance, transcriptional regulation, DNA repair, chromatin remodeling, and chromosomal segregation. Molecular functions of HP1 proteins have been extensively studied, although their exact roles in diseases require further study. Here, we comprehensively review the studies that have revealed the altered expression of HP1 and its functions in tumorigenesis. In particular, the distinctive effects of each HP1 subtype, namely HP1α, HP1ß, and HP1γ, have been thoroughly explored in various cancer types. We also highlight how HP1 can serve as a potential biomarker for cancer prognosis and therapeutic target for cancer patients.

Set1-mediated H3K4 methylation is required for Candida albicans virulence by regulating intracellular level of reactive oxygen species.

Candida albicans is an opportunistic human fungal pathogen that exists in normal flora but can cause infection in immunocompromised individuals. The transition to pathogenic C. albicans requires a change of various gene expressions. Because histone-modifying enzymes can regulate gene expression, they are thought to control the virulence of C. albicans. Indeed, the absence of H3 lysine 4 (H3K4) methyltransferase Set1 has been shown to reduce the virulence of C. albicans; however, Set1-regulated genes responsible for this attenuated virulence phenotype remain unknown. Here, we demonstrated that Set1 positively regulates the expression of mitochondrial protein genes by methylating H3K4. In particular, levels of cellular mitochondrial reactive oxygen species (ROS) were higher in Δset1 than in the wild-type due to the defect of those genes' expression. Set1 deletion also increases H2O2 sensitivity and prevents proper colony formation when interacting with macrophage in vitro, consistent with its attenuated virulence in vivo. Together, these findings suggest that Set1 is required to regulate proper cellular ROS production by positively regulating the expression of mitochondrial protein genes and subsequently sustaining mitochondrial membrane integrity. Consequently, C. albicans maintains proper ROS levels via Set1-mediated transcriptional regulation, thus establishing a rapid defense against external ROS generated by the host.

Transcriptomics-Based Repositioning of Natural Compound, Eudesmin, as a PRC2 Modulator.

Extensive epigenetic remodeling occurs during the cell fate determination of stem cells. Previously, we discovered that eudesmin regulates lineage commitment of mesenchymal stem cells through the inhibition of signaling molecules. However, the epigenetic modulations upon eudesmin treatment in genomewide level have not been analyzed. Here, we present a transcriptome profiling data showing the enrichment in PRC2 target genes by eudesmin treatment. Furthermore, gene ontology analysis showed that PRC2 target genes downregulated by eudesmin are closely related to Wnt signaling and pluripotency. We selected DKK1 as an eudesmin-dependent potential top hub gene in the Wnt signaling and pluripotency. Through the ChIP-qPCR and RT-qPCR, we found that eudesmin treatment increased the occupancy of PRC2 components, EZH2 and SUZ12, and H3K27me3 level on the promoter region of DKK1, downregulating its transcription level. According to the analysis of GEO profiles, DEGs by depletion of Oct4 showed an opposite pattern to DEGs by eudesmin treatment. Indeed, the expression of pluripotency markers, Oct4, Sox2, and Nanog, was upregulated upon eudesmin treatment. This finding demonstrates that pharmacological modulation of PRC2 dynamics by eudesmin might control Wnt signaling and maintain pluripotency of stem cells.

Corrigendum: Current Knowledge on the Function of α-Methyl Acyl-CoA Racemase in Human Diseases.

[This corrects the article DOI: 10.3389/fmolb.2020.00153.].

HDAC6-selective inhibitors enhance anticancer effects of paclitaxel in ovarian cancer cells.

Histone deacetylase 6 (HDAC6)-selective inhibitors are potent anticancer agents that are gaining increasing attention and undergoing various developments. These have been approved or are under clinical trials for use with other anticancer agents, such as pomalidomide, anti-programmed death-ligand 1 antibody and paclitaxel, for various types of cancer, including solid tumors. In the present study, a second generation HDAC6-selective inhibitor, ACY-241 (citarinostat), and a novel inhibitor, A452, exhibited synergistic anticancer effects with paclitaxel in AT-rich interaction domain 1A-mutated ovarian cancer in vitro. Co-treatment of paclitaxel and the two HDAC6 inhibitors synergistically decreased cell growth and viability of TOV-21G. Furthermore, the protein expression levels of pro-apoptotic markers, such as poly(ADP-ribose) polymerase, cleaved caspase-3, Bak and Bax, were increased, whereas the expression levels of anti-apoptotic markers, such as Bcl-xL and Bcl-2, were decreased synergistically. Treatment with all drug combinations increased the portion of apoptotic cells in fluorescence-activated cell sorting analysis. These results demonstrated synergy between paclitaxel and HDAC6-selective inhibitors, providing further impetus for clinical trials of combination therapy using HDAC6-selective inhibitors, not only in ovarian cancer but also in other tumors.

Glutamine Synthetase as a Therapeutic Target for Cancer Treatment.

The significance of glutamine in cancer metabolism has been extensively studied. Cancer cells consume an excessive amount of glutamine to facilitate rapid proliferation. Thus, glutamine depletion occurs in various cancer types, especially in poorly vascularized cancers. This makes glutamine synthetase (GS), the only enzyme responsible for de novo synthesizing glutamine, essential in cancer metabolism. In cancer, GS exhibits pro-tumoral features by synthesizing glutamine, supporting nucleotide synthesis. Furthermore, GS is highly expressed in the tumor microenvironment (TME) and provides glutamine to cancer cells, allowing cancer cells to maintain sufficient glutamine level for glutamine catabolism. Glutamine catabolism, the opposite reaction of glutamine synthesis by GS, is well known for supporting cancer cell proliferation via contributing biosynthesis of various essential molecules and energy production. Either glutamine anabolism or catabolism has a critical function in cancer metabolism depending on the complex nature and microenvironment of cancers. In this review, we focus on the role of GS in a variety of cancer types and microenvironments and highlight the mechanism of GS at the transcriptional and post-translational levels. Lastly, we discuss the therapeutic implications of targeting GS in cancer.

HDAC6-Selective Inhibitor Overcomes Bortezomib Resistance in Multiple Myeloma.

Although multiple myeloma (MM) patients benefit from standard bortezomib (BTZ) chemotherapy, they develop drug resistance, resulting in relapse. We investigated whether histone deacetylase 6 (HDAC6) inhibitor A452 overcomes bortezomib resistance in MM. We show that HDAC6-selective inhibitor A452 significantly decreases the activation of BTZ-resistant markers, such as extracellular signal-regulated kinases (ERK) and nuclear factor kappa B (NF-κB), in acquired BTZ-resistant MM cells. Combination treatment of A452 and BTZ or carfilzomib (CFZ) synergistically reduces BTZ-resistant markers. Additionally, A452 synergizes with BTZ or CFZ to inhibit the activation of NF-κB and signal transducer and activator of transcription 3 (STAT3), resulting in decreased expressions of low-molecular-mass polypeptide 2 (LMP2) and LMP7. Furthermore, combining A452 with BTZ or CFZ leads to synergistic cancer cell growth inhibition, viability decreases, and apoptosis induction in the BTZ-resistant MM cells. Overall, the synergistic effect of A452 with CFZ is more potent than that of A452 with BTZ in BTZ-resistant U266 cells. Thus, our findings reveal the HDAC6-selective inhibitor as a promising therapy for BTZ-chemoresistant MM.

Beneficial effects of Diplectria barbata (Wall. Ex C. B. Clarke) Franken et Roos extract on aging and antioxidants in vitro and in vivo.

The purpose of this study is to explore the effects of Diplectria barbata (Wall. Ex C.B. Clarke) Franken & Roons (DFR) on wound healing, antioxidant and aging in Normal Human Dermal Fibroblast cell (NHDF) cells and mouse skin models. We investigated the effects of the aging process in vitro and in vivo. DFRtreated NHDF cells showed a concentration-dependent increase in the expression of extracellular matrix (ECM) proteins (Collagen-2.5-fold increase at 50 µg/ml, Elastin-1.5-fold increase at 1µg/ml) as well as an increase in proteins related to cell survival, differentiation, and development, while expression of aging proteins such as matrix metalloproteinase 3 (MMP-3) was decreased (5-fold decrease at 50 µg/ml). DFR treatment also led to enhanced expression of antioxidant proteins such as nuclear factor erythroid 2-related factor 2 (10-fold increase at 50 µg/ml) and heme oxygenase 1 (1.5-fold increase at 25 µg/ml). To further investigate the antioxidative effects of DFR extracts, the 2,2-diphenyl-1-picrylhydrazyl radical scavenging activities were also evaluated. DFR extracts improved wound healing and resulted in increased expression of ECM proteins, while enzymes involved in collagen degradation, including MMP-3, were decreased in NHDF cells as well as in a mouse model. This study demonstrates the anti-aging, antioxidant, and wound healing properties of DFR extracts. Therefore, DFR extracts present may facilitate skin protection and care.

Antioxidant Properties and Diet-Related α-Glucosidase and Lipase Inhibitory Activities of Yogurt Supplemented with Safflower (Carthamus tinctorius L.) Petal Extract.

Recently, yogurt has been extensively studied to further enhance its functions using edible plant extracts. This study was conducted to investigate whether safflower petal (SP) as a natural food additive can be used to develop functional yogurt with improved health benefits. SPs were extracted with ethanol (SPE) and hot water (SPW), and then safflower yogurt was prepared by adding 0%-1.0% of those extracts to plain yogurt. With an increase in the fermentation duration, the pH of SPE and SPW yogurt samples was decreased, whereas titratable acidity and microbial counts were increased. The concentration of total polyphenols and total flavonoids, the activity of antioxidants, and the inhibitory effect on reactive oxygen species (ROS) were higher in SPW yogurt than SPE yogurt. Furthermore, α-glucosidase and lipase activity inhibitory effects of SPW yogurt were higher than those of SPE yogurt. In particular, free radical-scavenging activities, ROS inhibitory effect, and α-glucosidase activity inhibitory effects were significantly increased in SPW yogurt in a dose-dependent manner. Overall, these results suggest that SP extract possesses antioxidant activities and that it can downregulate α-glucosidase and lipase activities. The SP extract may have potential benefits as a natural food additive for the development of functional yogurt.

Histone demethylase KDM4C controls tumorigenesis of glioblastoma by epigenetically regulating p53 and c-Myc.

Glioblastoma is the most lethal brain tumor and its pathogenesis remains incompletely understood. KDM4C is a histone H3K9 demethylase that contributes to epigenetic regulation of both oncogene and tumor suppressor genes and is often overexpressed in human tumors, including glioblastoma. However, KDM4C's roles in glioblastoma and the underlying molecular mechanisms remain unclear. Here, we show that KDM4C knockdown significantly represses proliferation and tumorigenesis of glioblastoma cells in vitro and in vivo that are rescued by overexpressing wild-type KDM4C but not a catalytic dead mutant. KDM4C protein expression is upregulated in glioblastoma, and its expression correlates with c-Myc expression. KDM4C also binds to the c-Myc promoter and induces c-Myc expression. Importantly, KDM4C suppresses the pro-apoptotic functions of p53 by demethylating p53K372me1, which is pivotal for the stability of chromatin-bound p53. Conversely, depletion or inhibition of KDM4C promotes p53 target gene expression and induces apoptosis in glioblastoma. KDM4C may serve as an oncogene through the dual functions of inactivation of p53 and activation of c-Myc in glioblastoma. Our study demonstrates KDM4C inhibition as a promising therapeutic strategy for targeting glioblastoma.