Inhibitory Regulation of FOXO1 in PPARδ Expression Drives Mitochondrial Dysfunction and Insulin Resistance.

Forkhead box O1 (FOXO1) regulates muscle growth, but the metabolic role of FOXO1 in skeletal muscle and its mechanisms remain unclear. To explore the metabolic role of FOXO1 in skeletal muscle, we generated skeletal muscle-specific Foxo1 inducible knockout (mFOXO1 iKO) mice and fed them a high-fat diet to induce obesity. We measured insulin sensitivity, fatty acid oxidation, mitochondrial function, and exercise capacity in obese mFOXO1 iKO mice and assessed the correlation between FOXO1 and mitochondria-related protein in the skeletal muscle of patients with diabetes. Obese mFOXO1 iKO mice exhibited improved mitochondrial respiratory capacity, which was followed by attenuated insulin resistance, enhanced fatty acid oxidation, and improved skeletal muscle exercise capacity. Transcriptional inhibition of FOXO1 in peroxisome proliferator-activated receptor δ (PPARδ) expression was confirmed in skeletal muscle, and deletion of PPARδ abolished the beneficial effects of FOXO1 deficiency. FOXO1 protein levels were higher in the skeletal muscle of patients with diabetes and negatively correlated with PPARδ and electron transport chain protein levels. These findings highlight FOXO1 as a new repressor in PPARδ gene expression in skeletal muscle and suggest that FOXO1 links insulin resistance and mitochondrial dysfunction in skeletal muscle via PPARδ.

Therapeutic applications of ginseng for skeletal muscle-related disorder management.

Skeletal muscle (SM) is the largest organ of the body and is largely responsible for the metabolism required to maintain body functions. Furthermore, the maintenance of SM is dependent on the activation of muscle satellite (stem) cells (MSCs) and the subsequent proliferation and fusion of differentiating myoblasts into mature myofibers (myogenesis). Natural compounds are being used as therapeutic options to promote SM regeneration during aging, muscle atrophy, sarcopenia, cachexia, or obesity. In particular, ginseng-derived compounds have been utilized in these contexts, though ginsenoside Rg1 is mostly used for SM mass management. These compounds primarily function by activating the Akt/mTOR signaling pathway, upregulating myogenin and MyoD to induce muscle hypertrophy, downregulating atrophic factors (atrogin1, muscle ring-finger protein-1, myostatin, and mitochondrial reactive oxygen species production), and suppressing the expressions of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in cachexia. Ginsenoside compounds are also used for obesity management, and their anti-obesity effects are attributed to peroxisome proliferator activated receptor gamma (PPARγ) inhibition, AMPK activation, glucose transporter type 4 (GLUT4) translocation, and increased phosphorylations of insulin resistance (IR), insulin receptor substrate-1 (IRS-1), and Akt. This review was undertaken to provide an overview of the use of ginseng-related compounds for the management of SM-related disorders.

Insight into the function of tetranectin in human diseases: A review and prospects for tetranectin-targeted disease treatment.

Tetranectin (TN), a serum protein, is closely associated with different types of cancers. TN binds plasminogen and promotes the proteolytic activation of plasminogen into plasmin, which suggests that TN is involved in remodeling the extracellular matrix and cancer tissues during cancer development. TN is also associated with other diseases, such as developmental disorders, cardiovascular diseases, neurological diseases, inflammation, and diabetes. Although the functional mechanism of TN in diseases is not fully elucidated, TN binds different proteins, such as structural protein, a growth factor, and a transcription regulator. Moreover, TN changes and regulates protein functions, indicating that TN-binding proteins mediate the association between TN and diseases. This review summarizes the current knowledge of TN-associated diseases and TN functions with TN-binding proteins in different diseases. In addition, potential TN-targeted disease treatment by inhibiting the interaction between TN and its binding proteins is discussed.

Therapeutic Applications of Ginseng Natural Compounds for Health Management.

Ginseng is usually consumed as a daily food supplement to improve health and has been shown to benefit skeletal muscle, improve glucose metabolism, and ameliorate muscle-wasting conditions, cardiovascular diseases, stroke, and the effects of aging and cancers. Ginseng has also been reported to help maintain bone strength and liver (digestion, metabolism, detoxification, and protein synthesis) and kidney functions. In addition, ginseng is often used to treat age-associated neurodegenerative disorders, and ginseng and ginseng-derived natural products are popular natural remedies for diseases such as diabetes, obesity, oxidative stress, and inflammation, as well as fungal, bacterial, and viral infections. Ginseng is a well-known herbal medication, known to alleviate the actions of several cytokines. The article concludes with future directions and significant application of ginseng compounds for researchers in understanding the promising role of ginseng in the treatment of several diseases. Overall, this study was undertaken to highlight the broad-spectrum therapeutic applications of ginseng compounds for health management.

Diterpene and biflavone derivatives from Thuja koraiensis and their cytotoxicities against A549 cells.

During the screening of the cytotoxicity of rare Korean endemic plants, the extract of Thuja koraiensis Nakai displayed potent cytotoxicity against the adenocarcinomic human alveolar basal epithelial A549 cell line. Through a series of separations via column chromatography, three undescribed abietanes, an undescribed labdane along with a labdane, and a biflavonoid were purified from methylene chloride (CH2Cl2) fraction possessing a potent cytotoxic effect. Extensive 1D and 2D NMR spectroscopic data analyses, in combination with quantum chemical calculations were conducted to establish the planar and absolute configurations of thujakoraienes A-C. The chemical structure of thujakoraiene D was elucidated by spectroscopic data analysis and competing enantioselective acylation. Thujakoraienes A and C along with 7,7″-di-O-methylamentoflavone, showed cytotoxic effects on A549 cells, with IC50 values of 64.86, 47.97, and 16.14 µM, respectively. Finally, thujakoraiene C and 7,7″-di-O-methylamentoflavone were identified as potent cytotoxic compounds in A549 cells, followed by an additional cytotoxicity test in the normal human lung fibroblast MRC-5 cell line. This is the first study on the non-volatile chemicals in the extract of T. koraiensis and comparison of chemical profiles of T. orientalis and T. koraiensis.

Modulation of NLRP3 inflammasomes activation contributes to improved survival and function of mesenchymal stromal cell spheroids.

Mesenchymal stem cells (MSCs) are ubiquitous multipotent cells that exhibit significant therapeutic potentials in a variety of disorders. Nevertheless, their clinical efficacy is limited owing to poor survival, low rate of engraftment, and impaired potency upon transplantation. Spheroidal three-dimensional (3D) culture of MSCs (MSC3D) has been proven to better preserve their in vivo functional properties. However, the molecular mechanisms underlying the improvement in MSC function by spheroid formation are not clearly understood. NLRP3 inflammasomes, a key component of the innate immune system, have recently been shown to play a role in cell fate decision of MSCs. The present study examined the role of NLRP3 inflammasomes in the survival and potency of MSC spheroids. We found that MSC3D led to decreased activation of NLRP3 inflammasomes through alleviation of ER stress in an autophagy-dependent manner. Importantly, downregulation of NLRP3 inflammasomes signaling critically contributes to the enhanced survival rate in MSC3D through modulation of pyroptosis and apoptosis. The critical role of NLRP3 inflammasome suppression in the enhanced therapeutic efficacy of MSC spheroids was further confirmed in an in vivo mouse model of DSS-induced colitis. These findings suggest that 3D culture confers survival and functional advantages to MSCs by suppressing NLRP3 inflammasome activation.

Nanoliposome based biosensors for probing mycotoxins and their applications for food: A review.

Mycotoxins are the most common feed and food contaminants affecting animals and humans, respectively; continuous exposure causes tremendous health problems such as kidney disorders, infertility, immune suppression, liver inflammation, and cancer. Consequently, their control and quantification in food materials is crucial. Biosensors are potential tools for the rapid detection and quantification of mycotoxins with high sensitivity and selectivity. Nanoliposomes (NLs) are vesicular carriers formed by self-assembling phospholipids that surround the aqueous cores. Utilizing their biocompatibility, biodegradability, and high carrying capacity, researchers have employed NLs in biosensors for monitoring various targets in biological and food samples. The NLs are used for surface modification, signal marker delivery, and detection of toxins, bacteria, pesticides, and diseases. Here, we review marker-entrapped NLs used in the development of NL-based biosensors for mycotoxins. These biosensors are sensitive, selective, portable, and cost-effective analytical tools, and the resulting signal can be produced and/or amplified with or without destroying the NLs. In addition, this review emphasizes the benefits of the immunoliposome method in comparison with traditional detection approaches. We expect this review to serve as a valuable reference for researchers in this rapidly growing field. The insights provided may facilitate the rational design of next-generation NL-based biosensors.

Molecular Mechanisms and Current Treatment Options for Cancer Cachexia.

Cancer cachexia is a condition marked by functional, metabolic, and immunological dysfunctions associated with skeletal muscle (SM) atrophy, adipose tissue loss, fat reduction, systemic inflammation, and anorexia. Generally, the condition is caused by a variety of mediators produced by cancer cells and cells in tumor microenvironments. Myostatin and activin signaling, IGF-1/PI3K/AKT signaling, and JAK-STAT signaling are known to play roles in cachexia, and thus, these pathways are considered potential therapeutic targets. This review discusses the current state of knowledge of the molecular mechanisms underlying cachexia and the available therapeutic options and was undertaken to increase understanding of the various factors/pathways/mediators involved and to identify potential treatment options.

Recombinant programmed cell death protein 1 functions as an immune check point blockade and enhances anti-cancer immunity.

Effective cancer therapy aims to treat not only primary tumors but also metastatic and recurrent cancer. Immune check point blockade-mediated immunotherapy showed promising effect against tumors; however, it still has a limited effect in metastatic or recurrent cancer. Here, we extracted recombinant murine programmed death-1 (rmPD-1) proteins. The extracted rmPD-1 effectively bound to CT-26 and 4T1 cells expressing PD-L1 and PD-L2. The rmPD-1 did not alter the activation of dendritic cells (DCs); however, rmPD-1 promoted T cell-mediated anti-cancer immunity against CT-26 tumors in mice. Moreover, rmPD-1 decorated thermal responsive hybrid nanoparticles (piHNPs) promoted apoptotic and necrotic cell death of CT-26 cells in response to laser irradiation at 808 nm consequently, it promoted anti-tumor effects against the 1st challenged CT-26 tumors in mice. In addition, piHNP-mediated cured mice from 1st challenged CT-26 was also prevented the 2nd challenged lung metastatic tumor growth, which was dependent of cancer antigen-specific memory T cell immunity. It was also confirmed that the lung metastatic growth of 2nd challenged 4T1 breast cancer was also prevented in cured mice from 1st challenged 4T1 by piHNP. Thus, these data demonstrate that rmPD-1 functions as an immune checkpoint blockade for the treatment of tumors, and piHNPs could be a novel therapeutic agent for preventing cancer metastasis and recurrence.

MIF1 and MIF2 Myostatin Peptide Inhibitors as Potent Muscle Mass Regulators.

The use of peptides as drugs has progressed over time and continues to evolve as treatment paradigms change and new drugs are developed. Myostatin (MSTN) inhibition therapy has shown great promise for the treatment of muscle wasting diseases. Here, we report the MSTN-derived novel peptides MIF1 (10-mer) and MIF2 (10-mer) not only enhance myogenesis by inhibiting MSTN and inducing myogenic-related markers but also reduce adipogenic proliferation and differentiation by suppressing the expression of adipogenic markers. MIF1 and MIF2 were designed based on in silico interaction studies between MSTN and its receptor, activin type IIB receptor (ACVRIIB), and fibromodulin (FMOD). Of the different modifications of MIF1 and MIF2 examined, Ac-MIF1 and Ac-MIF2-NH2 significantly enhanced cell proliferation and differentiation as compared with non-modified peptides. Mice pretreated with Ac-MIF1 or Ac-MIF2-NH2 prior to cardiotoxin-induced muscle injury showed more muscle regeneration than non-pretreated controls, which was attributed to the induction of myogenic genes and reduced MSTN expression. These findings imply that Ac-MIF1 and Ac-MIF2-NH2 might be valuable therapeutic agents for the treatment of muscle-related diseases.

PROX1, a Key Mediator of the Anti-Proliferative Effect of Rapamycin on Hepatocellular Carcinoma Cells.

The MTOR signal is known to be activated in various cancer cells including hepatocellular carcinoma (HCC) cells. Rapamycin, a specific inhibitor of MTOR, has been widely used as an immunosuppressant in organ transplant patients, and its clinical application has been recently expanded to cancer therapy. In this study, the anti-proliferative effect of rapamycin was investigated in four different HCC cell lines. Rapamycin effectively inhibited the proliferation of Huh7 or Hep3B, but not that of HepG2 or SNU3160 cells. Interestingly, rapamycin increased Prospero-related homeobox 1 (PROX1) expression at the protein level, but did not affect its transcript in Huh7 as well as Hep3B cells. Moreover, immunoprecipitation assays showed that PROX1 ubiquitination was downregulated by rapamycin. Furthermore, PROX1 over-expression or siRNA knock-down in Huh7 and Hep3B cells reduced or increased proliferation, respectively. The effect of PROX1 over-expression on the sensitivity to rapamycin was not synergistic, but the effect of MTOR inhibition on cell proliferation was diminished by PROX1 siRNA. Finally, Huh7 cells were inoculated into the flanks of nude mice and rapamycin was injected daily for 14 days. The xenograft volume was decreased and PROX1 expression was increased by rapamycin. These results indicate that PROX1 plays a key role in the anti-proliferative effect of rapamycin and suggest that the increased PROX1 by MTOR inhibition can be used as a useful marker for predicting whether HCC cells can be affected by rapamycin.

Intra-articular acetabular osteochondroma in patients with multiple hereditary exostoses.

We report three additional cases of intra-articular acetabular osteochondroma in multiple hereditary exostoses patients in order to raise the awareness of this rare location, to prompt early diagnosis, and to present various treatment options according to the patient's condition. A 2.5-year-old boy presenting with an out-toeing gait had a large acetabular osteochondroma causing lateral displacement of the femoral head and acetabular dysplasia. Mass excision through hip subluxation via anterior approach and concomitant Dega osteotomy resulted in a congruent, well-developed, and well-covered hip joint at 11-year follow-up. A 10-year-old boy showing a pedunculated osteochondroma arising from the triradiate cartilage was successfully treated by arthroscopic excision. Normal development of the hip joint was observed at skeletal maturity. A 6-year-old boy presented with a painless limp. Acetabular osteochondroma could be confirmed by computed tomography scan, which was excised through hip subluxation by anterior approach. Persistent coxa valga and femoral head uncovering were addressed by femoral varization osteotomy at 9 years of age. A high index of suspicion is required to detect a lesion at this rare location. Various procedures may be considered according to the pathoanatomy. Acetabular dysplasia, coxa valga, and femoroacetabular impingement by femur neck mass, if associated, should be addressed in due time.

Analysis of S-glutathionylated proteins during adipocyte differentiation using eosin-glutathione and glutaredoxin 1.

Protein S-glutathionylation is a reversible post-translational modification on cysteine residues forming a mixed disulfide with glutathione. S-glutathionylation, not only protects proteins from oxidation but also regulates the functions of proteins involved in various cellular signaling pathways. In this study, we developed a method for the detection of S-glutathionylated proteins (ProSSG) using eosin-glutathione (E-GSH) and mouse glutaredoxin 1 (mGrx1). ProSSG was efficiently and specifically labeled with E-GSH to form ProSSG-E via thiol-disulfide exchange. ProSSG-E was readily luminescent allowing the detection of ProSSG with semi-quantitative determination. In addition, a deglutathionylation enzyme mGrx1 specifically released E-GSH from ProSSG-E, which increased fluorescence allowing a sensitive determination of ProSSG levels. Application of the method to the adipocyte differentiation of 3T3-L1 cells showed specific detection of ProSSG and its increase upon differentiation induction, which was consistent with the result obtained by conventional immunoblot analysis, but with greater specificity and sensitivity. [BMB Reports 2022; 55(3): 154-159].

CXCL16/CXCR6 Axis in Adipocytes Differentiated from Human Adipose Derived Mesenchymal Stem Cells Regulates Macrophage Polarization.

Adipocytes interact with adipose tissue macrophages (ATMs) that exist as a form of M2 macrophage in healthy adipose tissue and are polarized into M1 macrophages upon cellular stress. ATMs regulate adipose tissue inflammation by secreting cytokines, adipokines, and chemokines. CXC-motif receptor 6 (CXCR6) is the chemokine receptor and interactions with its specific ligand CXC-motif chemokine ligand 16 (CXCL16) modulate the migratory capacities of human adipose-derived mesenchymal stem cells (hADMSCs). CXCR6 is highly expressed on differentiated adipocytes that are non-migratory cells. To evaluate the underlying mechanisms of CXCR6 in adipocytes, THP-1 human monocytes that can be polarized into M1 or M2 macrophages were co-cultured with adipocytes. As results, expression levels of the M1 polarization-inducing factor were decreased, while those of the M2 polarization-inducing factor were significantly increased in differentiated adipocytes in a co-cultured environment with additional CXCL16 treatment. After CXCL16 treatment, the anti-inflammatory factors, including p38 MAPK ad ERK1/2, were upregulated, while the pro-inflammatory pathway mediated by Akt and NF-κB was downregulated in adipocytes in a co-cultured environment. These results revealed that the CXCL16/CXCR6 axis in adipocytes regulates M1 or M2 polarization and displays an immunosuppressive effect by modulating pro-inflammatory or anti-inflammatory pathways. Our results may provide an insight into a potential target as a regulator of the immune response via the CXCL16/CXCR6 axis in adipocytes.

TJP1 Contributes to Tumor Progression through Supporting Cell-Cell Aggregation and Communicating with Tumor Microenvironment in Leiomyosarcoma.

Leiomyosarcoma (LMS) is a mesenchymal malignancy with a complex karyotype. Despite accumulated evidence, the factors contributing to the development of LMS are unclear. Here, we investigated the role of tight-junction protein 1 (TJP1), a membrane-associated intercellular barrier protein during the development of LMS and the tumor microenvironment. We orthotopically transplanted SK-LMS-1 cells and their derivatives in terms of TJP1 expression by intramuscular injection, such as SK-LMS-1 Sh-Control cells and SK-LMS-1 Sh-TJP1. We observed robust tumor growth in mice transplanted with LMS cell lines expressing TJP1 while no tumor mass was found in mice transplanted with SK-LMS-1 Sh-TJP1 cells with silenced TJP1 expression. Tissues from mice were stained and further analyzed to clarify the effects of TJP1 expression on tumor development and the tumor microenvironment. To identify the TJP1-dependent factors important in the development of LMS, genes with altered expression were selected in SK-LMS-1 cells such as cyclinD1, CSF1 and so on. The top 10% of highly expressed genes in LMS tissues were obtained from public databases. Further analysis revealed two clusters related to cell proliferation and the tumor microenvironment. Furthermore, integrated analyses of the gene expression networks revealed correlations among TJP1, CSF1 and CTLA4 at the mRNA level, suggesting a possible role for TJP1 in the immune environment. Taken together, these results imply that TJP1 contributes to the development of sarcoma by proliferation through modulating cell-cell aggregation and communication through cytokines in the tumor microenvironment and might be a beneficial therapeutic target.

Cell Types Used for Cultured Meat Production and the Importance of Myokines.

The world's population continues to increase, meaning we require more consistent protein supply to meet demand. Despite the availability of plant-based protein alternatives, animal meat remains a popular, high-quality protein source. Research studies have focused on cultured meat (meat grown in vitro) as a safe and more efficient alternative to traditional meat. Cultured meat is produced by in vitro myogenesis, which involves the processing of muscle satellite and mature muscle cells. Meat culture efficiency is largely determined by the culture conditions, such as the cell type and cell culture medium used and the biomolecular composition. Protein production can be enhanced by providing the optimum biochemical and physical conditions for skeletal muscle cell growth, while myoblasts play important roles in skeletal muscle formation and growth. This review describes the cell types used to produce cultured meat and the biological effects of various myokines and cytokines, such as interleukin-6, leukemia inhibitory factor, interleukin-4, interleukin-15, and interleukin-1ß, on skeletal muscle and myogenesis and their potential roles in cultured meat production.

Expedition into Exosome Biology: A Perspective of Progress from Discovery to Therapeutic Development.

Exosomes are membrane-enclosed distinct cellular entities of endocytic origin that shuttle proteins and RNA molecules intercellularly for communication purposes. Their surface is embossed by a huge variety of proteins, some of which are used as diagnostic markers. Exosomes are being explored for potential drug delivery, although their therapeutic utilities are impeded by gaps in knowledge regarding their formation and function under physiological condition and by lack of methods capable of shedding light on intraluminal vesicle release at the target site. Nonetheless, exosomes offer a promising means of developing systems that enable the specific delivery of therapeutics in diseases like cancer. This review summarizes information on donor cell types, cargoes, cargo loading, routes of administration, and the engineering of exosomal surfaces for specific peptides that increase target specificity and as such, therapeutic delivery.

Identification of Novel FNIN2 and FNIN3 Fibronectin-Derived Peptides That Promote Cell Adhesion, Proliferation and Differentiation in Primary Cells and Stem Cells.

In recent years, a major rise in the demand for biotherapeutic drugs has centered on enhancing the quality and efficacy of cell culture and developing new cell culture techniques. Here, we report fibronectin (FN) derived, novel peptides fibronectin-based intergrin binding peptide (FNIN)2 (18-mer) and FNIN3 (20-mer) which promote cell adhesion proliferation, and the differentiation of primary cells and stem cells. FNIN2 and 3 were designed based on the in silico interaction studies between FN and its receptors (integrin α5ß1, αvß3, and αIIbß3). Analysis of the proliferation of seventeen-cell types showed that the effects of FNINs depend on their concentration and the existence of expressed integrins. Significant rhodamine-labeled FNIN2 fluorescence on the membranes of HeLa, HepG2, A498, and Du145 cells confirmed physical binding. Double coating with FNIN2 or 3 after polymerized dopamine (pDa) or polymerized tannic acid (pTA) precoating increased HBEpIC cell proliferation by 30-40 percent, suggesting FNINs potently affect primary cells. Furthermore, the proliferation of C2C12 myoblasts and human mesenchymal stem cells (MSCs) treated with FNINs was significantly increased in 2D/3D culture. FNINs also promoted MSC differentiation into osteoblasts. The results of this study offer a new approach to the production of core materials (e.g., cell culture medium components, scaffolds) for cell culture.

Late recurrence of papillary thyroid cancer from needle tract implantation after core needle biopsy: A case report.

BACKGROUND: Papillary thyroid cancer (PTC) has good prognosis so that the local recurrence or distant metastasis can occur later on the lifetime follow up. In this study, we report recurrence of PTC in subcutaneous area combined with lymph node metastasis. A suspicion of needle tract implantation after core needle biopsy was found. CASE SUMMARY: A 66-year-old female patients who underwent right thyroid lobectomy for PTC complained of palpable nodule on anterior neck area. The location of the palpable nodule was not associated with her postoperative scar. After excision of the skin tumor, it was diagnosed as recurrence of PTC. Furthermore, results of subsequent imaging showed lymph node metastasis on her right cervical area. According to the previous medical records, the patient received core needle biopsy through the neck of the patient midline and hematoma was noted after the procedure. The time interval from the first diagnosis to local recurrence or metastasis to the skin and lymph nodes was ten years. As treatment, the patient underwent lymph node dissection in the right and completion thyroidectomy for radioisotope treatment. CONCLUSION: Needle tract implantation can occur after core needle biopsy. Further studies are needed to compare core-needle biopsy and fine-needle aspiration.

Targeting integrins for cancer management using nanotherapeutic approaches: Recent advances and challenges.

Integrins are the main cell surface receptors and execute multifaceted functions such as the bidirectional transmission of signals (i.e., inside-out and outside-in) and provide communication between cells and their microenvironments. Integrins are the key regulators of critical biological functions and contribute significantly to the promotion of cancer at almost every stage of disease progression from initial tumor formation to metastasis. Integrin expressions are frequently altered in different cancers, and consequently, several therapeutic strategies targeting integrins have been developed. Furthermore, nanotechnology-based approaches have been devised to overcome the intrinsic limitations of conventional therapies for cancer management, and have been shown to more precise, safer, and highly effective therapeutic tools. Although nanotechnology-based approaches have achieved substantial success for the management of cancer, certain obstacles remain such as inadequate knowledge of nano-bio interactions and the challenges associated with the three stages of clinical trials. This review highlights the different roles of integrins and of integrin-dependent signaling in various cancers and describes the applications of nanotherapeutics targeting integrins. In addition, we discuss RGD-based approaches and challenges posed to cancer management.