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pancreatic cancer, long noncoding RNA, N6-methyladenosine, Biology (General), and QH301-705.5

Pancreatic cancer is a malignant tumor of the digestive system that is highly malignant, difficult to treat, and confers a poor prognosis for patients. BRAF-activated noncoding RNA (BANCR) has been proven to play an important role in the invasion and metastasis of pancreatic cancer. In this study, we focused on BANCR as a potential therapeutic target for human pancreatic cancer. The BANCR level in pancreatic cancer tissues and cells is affected by m6A methylation. Based on this, the aim of our study was to investigate the effect of a highly potent and selective first-in-class catalytic inhibitor of METTL3 (STM2457) on BANCR m6A methylation and its malignant biological behaviors in pancreatic cancer. The relationship between BANCR expression and BANCR m6A modification was detected with RT-qPCR and MeRIP-PCR. The expression of methyltransferase-like 3 (METTL3), the key enzyme involved in m6A methylation, in pancreatic cancer tissues was detected using a Western blot. STM2457 was used in vitro to investigate its resistance to the proliferation, invasion, and metastasis of pancreatic cancer cells. BANCR was overexpressed in pancreatic cancer tissues and cells, which was associated with poor clinical outcomes and validated in pancreatic cancer cell lines. m6A modification was highly enriched within BANCR and enhanced its expression. Remarkably, STM2457 inhibited the proliferation, invasion, and metastasis of pancreatic cancer cells by down-regulating BANCR m6A modifications. This study demonstrates the promise of BANCR as a new diagnostic and therapeutic target for pancreatic cancer and reveals the therapeutic effect that STM2457 exerts on pancreatic cancer by down-regulating BANCR m6A modifications.

Agarum cribrosum, trifuhalol A, asthma, allergic, ovalbumin, inflammation, Biology (General), and QH301-705.5

Asthma is a chronic inflammatory disease involving structural changes to the respiratory system and severe immune responses mediated by allergic cytokines and pro-inflammatory mediators. Agarum cribrosum (AC) is a kind of seaweed which contains a phlorotannin, trifuhalol A. To evaluate its anti-allergic inflammatory effect against asthma, an ovalbumin inhalation-induced mouse asthma model was used. Histologic observations proved that trifuhalol A is minimizing the lung and tracheal structure changes as well as the infiltration of eosinophils and mast cells against ovalbumin inhalation challenge. From the serum and bronchoalveolar lavage fluid, ovalbumin-specific IgE and Th2-specific cytokines, IL-4, -5, and -13, were reduced with trifuhalol A treatment. In addition, IL-1β, IL-6, and TNF-α concentrations in lung homogenate were also significantly reduced via trifuhalol A treatment. Taken together, trifuhalol A, isolated from AC, was able to protect lung and airways from Th2-specific cytokine release, and IgE mediated allergic inflammation as well as the attenuation of IL-1β, IL-6, and TNF-α in lung, which results in the suppression of eosinophils and the mast cells involved asthmatic pathology.

long non-coding RNA, MIR4435-2HG, cancer, tumor microenvironment, Biology (General), and QH301-705.5

The long non-coding RNA MIR4435-2HG has been confirmed to play a crucial regulatory role in various types of tumors. As a novel type of non-coding RNA, MIR4435-2HG plays a key role in regulating the expression of tumor-related genes, interfering with cellular signaling pathways, and affecting tumor immune evasion. Its unique structure allows it to regulate the expression of various tumor-related genes through different pathways, participating in the regulation of tumor signaling pathways, such as regulating the expression of oncogenes and tumor suppressor genes, influencing the biological behaviors of proliferation, metastasis, and apoptosis in tumors. Numerous studies have found a high expression of MIR4435-2HG in various tumor tissues, closely related to the clinical pathological characteristics of tumors, such as staging, lymph node metastasis and prognosis. Some studies have discovered that MIR4435-2HG can regulate the sensitivity of tumor cells to chemotherapy drugs, affecting tumor cell drug resistance. This provides new insights into overcoming tumor drug resistance by regulating MIR4435-2HG. Therefore, studying its molecular mechanisms, expression regulation, and its relationship with the clinical features of tumors is of great significance for revealing the mechanisms of tumor occurrence and developing new therapeutic targets.

galectin-10, gestational diabetes mellitus, pregnancy, Biology (General), and QH301-705.5

Galectins are known to play an important role in immunoregulatory processes and autoimmune diseases. Galectin-10 is a cytoplasmic protein of human eosinophils and is involved in various eosinophilic diseases. Since increased galectin expression is already detected in the placentas of mothers with gestational diabetes mellitus (GDM), this study focuses on the specific role of galectin-10 and hints at consequences for the diagnosis and therapeutic options of GDM. It is hypothesized that the difference in galectin-10 expression will raise the pathophysiological understanding of gestational diabetes. The study population consists of 80 women: 40 healthy mothers and 40 women suffering from gestational diabetes mellitus. The expression of galectin-10 was analyzed in the syncytiotrophoblast (SCT) and the decidua of the placenta via immunohistochemistry and immunofluorescence double staining. The immunoreactivity score (IRS) was used for evaluation. The results in this study were significant for an overexpression of galectin-10 in GDM placentas compared with the control group. The syncytiotrophoblast showed overexpression in the nucleus and the cytoplasm, whereas expression of galectin-10 in the decidua was significant in the cytoplasm only. This study identified the expression changes in galectin-10 in placental tissue between healthy and GDM mothers and intensified the understanding of gestational diabetes. Assuming that gestational diabetes mellitus is involved in inflammatory processes, galectin-10 might play a role in the development and maintenance of GDM. Further investigation is required to strengthen these findings.

atherosclerosis, cardiovascular risk, immune system, inborn errors of immunity, primary immunodeficiencies, secondary immunodeficiencies, Biology (General), and QH301-705.5

A strong relationship exists between immune dysfunction and cardiovascular disease. Immune dysregulation can promote the development of cardiovascular diseases as well as exacerbate their course. The disorders may occur due to the presence of primary immune defects (currently known as inborn errors of immunity) and the more common secondary immune deficiencies. Secondary immune deficiencies can be caused by certain chronic conditions (such as diabetes, chronic kidney disease, obesity, autoimmune diseases, or cancer), nutritional deficiencies (including both lack of nutrients and bioactive non-nutrient compounds), and medical treatments and addictive substances. This article unravels the molecular linkage between the aforementioned immune system disorders and atherosclerosis.

tau protein, neuroinflammation, Alzheimer’s disease, amyloid-beta peptide, protein aggregation, hyperphosphorylation, Biology (General), and QH301-705.5

Neuroinflammation, a core pathological feature observed in several neurodegenerative diseases, including Alzheimer’s disease (AD), is rapidly gaining attention as a target in understanding the molecular underpinnings of these disorders. Glial cells, endothelial cells, peripheral immune cells, and astrocytes produce a variety of pro-inflammatory mediators that exacerbate the disease progression. Additionally, microglial cells play a complex role in AD, facilitating the clearance of pathological amyloid-beta peptide (Aβ) plaques and aggregates of the tau protein. Tau proteins, traditionally associated with microtubule stabilization, have come under intense scrutiny for their perturbed roles in neurodegenerative conditions. In this narrative review, we focus on recent advances from molecular insights that have revealed aberrant tau post-translational modifications, such as phosphorylation and acetylation, serving as pathological hallmarks. These modifications also trigger the activation of CNS-resident immune cells, such as microglia and astrocytes substantially contributing to neuroinflammation. This intricate relationship between tau pathologies and neuroinflammation fosters a cascading impact on neural pathophysiology. Furthermore, understanding the molecular mechanisms underpinning tau’s influence on neuroinflammation presents a frontier for the development of innovative immunotherapies. Neurodegenerative diseases have been relatively intractable to conventional pharmacology using small molecules. We further comprehensively document the many alternative approaches using immunotherapy targeting tau pathological epitopes and structures with a wide array of antibodies. Clinical trials are discussed using these therapeutic approaches, which have both promising and disappointing outcomes. Future directions for tau immunotherapies may include combining treatments with Aβ immunotherapy, which may result in more significant clinical outcomes for neurodegenerative diseases.

asthma, MAP kinase kinase kinases, TWEAK, transforming growth factors-β, chemokine CCL5, Biology (General), and QH301-705.5

The mitogen-activated protein kinase (MAPK) signaling pathway is involved in the epithelial–mesenchymal transition (EMT) and asthma; however, the role of mitogen-activated protein kinase kinase kinase 19 (MAP3K19) remains uncertain. Therefore, we investigated the involvement of MAP3K19 in in vitro EMT and ovalbumin (OVA)-induced asthma murine models. The involvement of MAP3K19 in the EMT and the production of cytokines and chemokines were analyzed using a cultured bronchial epithelial cell line, BEAS-2B, in which MAP3K19 was knocked down using small interfering RNA. We also evaluated the involvement of MAP3K19 in the OVA-induced asthma murine model using Map3k19-deficient (MAP3K19−/−) mice. Transforming growth factor beta 1 (TGF-β1) and tumor necrosis factor-like weak inducer of apoptosis (TWEAK) induced the MAP3K19 messenger RNA (mRNA) expression in the BEAS-2B cells. The knockdown of MAP3K19 enhanced the reduction in E-cadherin mRNA and the production of regulated upon activation normal T cell express sequence (RANTES) via stimulation with TWEAK alone or with the combination of TGF-β1 and TWEAK. Furthermore, the expression of MAP3K19 mRNA was upregulated in both the lungs and tracheas of the mice in the OVA-induced asthma murine model. The MAP3K19−/− mice exhibited worsened eosinophilic inflammation and an increased production of RANTES in the airway epithelium compared with the wild-type mice. These findings indicate that MAP3K19 suppressed the TWEAK-stimulated airway epithelial response, including adhesion factor attenuation and RANTES production, and suppressed allergic airway inflammation in an asthma mouse model, suggesting that MAP3K19 regulates allergic airway inflammation in patients with asthma.

arthritis, autoimmunity, mastocytosis, multiple sclerosis, neurotrophins, autoimmune thyroiditis, Biology (General), and QH301-705.5

NGF plays a crucial immunomodulatory role and increased levels are found in numerous tissues during autoimmune states. NGF directly modulates innate and adaptive immune responses of B and T cells and causes the release of neuropeptides and neurotransmitters controlling the immune system activation in inflamed tissues. Evidence suggests that NGF is involved in the pathogenesis of numerous immune diseases including autoimmune thyroiditis, chronic arthritis, multiple sclerosis, systemic lupus erythematosus, mastocytosis, and chronic granulomatous disease. Furthermore, as NGF levels have been linked to disease severity, it could be considered an optimal early biomarker to identify therapeutic approach efficacy. In conclusion, by gaining insights into how these molecules function and which cells they interact with, future studies can devise targeted therapies to address various neurological, immunological, and other disorders more effectively. This knowledge may pave the way for innovative treatments based on NGF manipulation aimed at improving the quality of life for individuals affected by diseases involving neurotrophins.

metabolomics, analytical tools, mass spectrometry, plant metabolomics, crop improvement, Biology (General), and QH301-705.5

Plant metabolomics is a rapidly advancing field of plant sciences and systems biology. It involves comprehensive analyses of small molecules (metabolites) in plant tissues and cells. These metabolites include a wide range of compounds, such as sugars, amino acids, organic acids, secondary metabolites (e.g., alkaloids and flavonoids), lipids, and more. Metabolomics allows an understanding of the functional roles of specific metabolites in plants’ physiology, development, and responses to biotic and abiotic stresses. It can lead to the identification of metabolites linked with specific traits or functions. Plant metabolic networks and pathways can be better understood with the help of metabolomics. Researchers can determine how plants react to environmental cues or genetic modifications by examining how metabolite profiles change under various crop stages. Metabolomics plays a major role in crop improvement and biotechnology. Integrating metabolomics data with other omics data (genomics, transcriptomics, and proteomics) provides a more comprehensive perspective of plant biology. This systems biology approach enables researchers to understand the complex interactions within organisms.

α-humulene synthase, sesquiterpene, Aquilaria malaccensis, protein modeling, molecular docking, Biology (General), and QH301-705.5

This study describes the cloning, expression and functional characterization of α-humulene synthase, responsible for the formation of the key aromatic compound α-humulene in agarwood originating from Aquilaria malaccensis. The partial sesquiterpene synthase gene from the transcriptome data of A. malaccensis was utilized for full-length gene isolation via a 3′ RACE PCR. The complete gene, denoted as AmDG2, has an open reading frame (ORF) of 1671 bp and encodes for a polypeptide of 556 amino acids. In silico analysis of the protein highlighted several conserved motifs typically found in terpene synthases such as Asp-rich substrate binding (DDxxD), metal-binding residues (NSE/DTE), and cytoplasmic ER retention (RxR) motifs at their respective sites. The AmDG2 was successfully expressed in the E. coli:pET-28a(+) expression vector whereby an expected band of about 64 kDa in size was detected in the SDS-PAGE gel. In vitro enzyme assay using substrate farnesyl pyrophosphate (FPP) revealed that AmDG2 gave rise to two sesquiterpenes: α-humulene (major) and β-caryophyllene (minor), affirming its identity as α-humulene synthase. On the other hand, protein modeling performed using AlphaFold2 suggested that AmDG2 consists entirely of α-helices with short connecting loops and turns. Meanwhile, molecular docking via AutoDock Vina (Version 1.5.7) predicted that Asp307 and Asp311 act as catalytic residues in the α-humulene synthase. To our knowledge, this is the first comprehensive report on the cloning, expression and functional characterization of α-humulene synthase from agarwood originating from A. malaccensis species. These findings reveal a deeper understanding of the structure and functional properties of the α-humulene synthase and could be utilized for metabolic engineering work in the future.

inflammation, wound healing, anti-bacterial, medicinal plants, Nigella sativa, natural product, Biology (General), and QH301-705.5

Wound healing is a multifaceted process necessitating the collaboration of numerous elements to mend damaged tissue. Plant and animal-derived natural compounds have been utilized for wound treatment over the centuries, with many scientific investigations examining these compounds. Those with antioxidant, anti-inflammatory, and antibacterial properties are particularly noteworthy, as they target various wound-healing stages to expedite recovery. Thymoquinone, derived from Nigella sativa (N. sativa)—a medicinal herb with a long history of use in traditional medicine systems such as Unani, Ayurveda, Chinese, and Greco-Arabic and Islamic medicine—has demonstrated a range of therapeutic properties. Thymoquinone exhibits antimicrobial, anti-inflammatory, and antineoplastic activities, positioning it as a potential remedy for skin pathologies. This review examines recent research on how thymoquinone accelerates wound healing and the mechanisms behind its effectiveness. We carried out a comprehensive review of literature and electronic databases, including Google Scholar, PubMed, Science Direct, and MedlinePlus. Our aim was to gather relevant papers published between 2015 and August 2023. The main criteria for inclusion were that the articles had to be peer reviewed, original, written in English, and discuss the wound-healing parameters of thymoquinone in wound repair. Our review focused on the effects of thymoquinone on the cellular and molecular mechanisms involved in wound healing. We also examined the role of cytokines, signal transduction cascades, and clinical trials. We found sufficient evidence to support the effectiveness of thymoquinone in promoting wound healing. However, there is no consensus on the most effective concentrations of these substances. It is therefore essential to determine the optimal treatment doses and the best route of administration. Further research is also needed to investigate potential side effects and the performance of thymoquinone in clinical trials.

PTCL, epigenetic modifiers, therapy, mutations, Biology (General), and QH301-705.5

Peripheral T-cell lymphomas (PTCLs) are a group of diseases with a low incidence, high degree of heterogeneity, and a dismal prognosis in most cases. Because of the low incidence of these diseases, there have been few therapeutic novelties developed over time. Nevertheless, this fact is changing presently as epigenetic modifiers have been shown to be recurrently mutated in some types of PTCLs, especially in the cases of PTCLs not otherwise specified (PTCL-NOS), T follicular helper (TFH), and angioimmunoblastic T-cell lymphoma (AITL). These have brought about more insight into PTCL biology, especially in the case of PTCLs arising from TFH lymphocytes. From a biological perspective, it has been observed that ten-eleven translocators (TET2) mutated T lymphocytes tend to polarize to TFH, while Tregs lose their inhibitory properties. IDH2 R172 was shown to have inhibitory effects on TET2, mimicking the effects of TET2 mutations, as well as having effects on histone methylation. DNA methyltransferase 3A (DNMT3A) loss-of-function, although it was shown to have opposite effects to TET2 from an inflammatory perspective, was also shown to increase the number of T lymphocyte progenitors. Aside from bringing about more knowledge of PTCL biology, these mutations were shown to increase the sensitivity of PTCLs to certain epigenetic therapies, like hypomethylating agents (HMAs) and histone deacetylase inhibitors (HDACis). Thus, to answer the question from the title of this review: We found the Achilles heel, but only for one of the Achilles.

non-small cell lung cancer, NSCLC, CAR T cell therapy, imaging, solid tumors, Biology (General), and QH301-705.5

Since its first approval by the FDA in 2017, tremendous progress has been made in chimeric antigen receptor (CAR) T cell therapy, the adoptive transfer of engineered, CAR-expressing T lymphocyte. CAR T cells are all composed of three main elements: an extracellular antigen-binding domain, an intracellular signaling domain responsible for T cell activation, and a hinge that joins these two domains. Continuous improvement has been made in CARs, now in their fifth generation, particularly in the intracellular signaling domain responsible for T cell activation. CAR T cell therapy has revolutionized the treatment of hematologic malignancies. Nonetheless, the use of CAR T cell therapy for solid tumors has not attained comparable levels of success. Here we review the challenges in achieving effective CAR T cell therapy in solid tumors, and emerging CAR T cells that have shown great promise for non-small cell lung cancer (NSCLC). A growing number of clinical trials have been conducted to study the effect of CAR T cell therapy on NSCLC, targeting different types of surface antigens. They include epidermal growth factor receptor (EGFR), mesothelin (MSLN), prostate stem cell antigen (PSCA), and mucin 1 (MUC1). Potential new targets such as erythropoietin-producing hepatocellular carcinoma A2 (EphA2), tissue factor (TF), and protein tyrosine kinase 7 (PTK7) are currently under investigation in clinical trials. The challenges in developing CAR T for NSCLC therapy and other approaches for enhancing CAR T efficacy are discussed. Finally, we provide our perspective on imaging CAR T cell action by reviewing the two main radionuclide-based CAR T cell imaging techniques, the direct labeling of CAR T cells or indirect labeling via a reporter gene.

fenbendazole, EL-4 cells, lymphoma, anticancer effect, tumor microenvironment, Biology (General), and QH301-705.5

Fenbendazole (FBZ) has been safely used as an antiparasitic agent in animals for decades, and the anticancer effects of FBZ have been studied through various mechanisms. However, there is a lack of in vivo studies that include lymphoma. Therefore, this study examined the effects of FBZ on EL-4 cells and a mouse T lymphoma model. FBZ induced G2/M phase arrest in EL-4 cells, resulting in cell death and decreased metabolic activity. However, FBZ had no anticancer effects on an EL-4 mouse lymphoma model in vivo, as evident by rapid weight loss and tumor growth comparable to the control. The FBZ-treated EL-4 cells expressed higher levels of PD-L1 and CD86, which are associated with T cell immunity in the tumor microenvironment (TME), than the controls. Furthermore, the hematoxylin and eosin staining of the FBZ-treated tumor tissues showed a starry sky pattern, which is seen in actively proliferating cancer tissues, and an immunohistochemical analysis revealed a high percentage of immunosuppressive M2 macrophages. These changes in the immune activity in the TME contradict the results of the in vitro experiments, and further studies are needed to determine the detailed mechanisms by which FBZ induces these responses.

renal cell carcinoma, immune checkpoint inhibitors, repertoire analysis, ipilimumab, nivolumab, Biology (General), and QH301-705.5

Immune checkpoint inhibitors (ICIs) are effective in treating renal cell carcinoma (RCC) but can also cause immune-related adverse events (irAEs). The relationship between irAEs and the T-cell receptor (TCR) repertoire in RCC patients treated with ICIs remains unclear. We analyzed the relationship between the severity and diversity of irAEs and the TCR repertoire in RCC patients who received dual checkpoint inhibitors (ipilimumab + nivolumab). The TCRβ (TRB) repertoires were characterized in peripheral blood samples from six patients with RCC before the initiation of ICI therapy. The diversity and clonality of the TCR repertoire were compared between patients with grade 2 and grade 3 irAEs. The median proportion of top 10 unique reads in the TCR repertoire was significantly higher in grade 3 compared with grade 2 irAEs in RCC patients receiving immune checkpoint inhibitors (grade 2: 0.196%; grade 3: 0.346%; p = 0.0038). We provide insight into the relationship between TCR repertoire and irAEs in RCC patients treated with ICIs. TCR repertoire clonality may be associated with the development of irAEs in RCC patients.

breastfeeding, obesity, metabolic inflammation, metabolic programming, energy metabolism, immunology, Biology (General), and QH301-705.5

Obesity has become an emerging health issue worldwide that continues to grow in females of reproductive age as well. Obesity, as a multisystem and chronic disease, is associated with metabolic inflammation, which is defined as chronic low-grade systemic inflammation mediated by, i.a., adipose tissue macrophages. Lactation has been proven to have a beneficial influence on maternal health and could help restore metabolic balance, especially in the state of maternal obesity. In this review, we aimed to analyze the influence of breastfeeding on chronic low-grade meta-inflammation caused by obesity. We performed a comprehensive literature review using the PubMed, Science Direct, and Google Scholar electronic databases. For this purpose, we searched for “metabolic inflammation”; “meta-inflammation”; “obesity”; “breastfeeding”; “fetal programming”; “energy metabolism”; “postpartum”; “immunity”; “immune system”; and “inflammation” keyword combinations. While the clinical impact of breastfeeding on maternal and offspring health is currently well known, we decided to gain insight into more specific metabolic effects of adiposity, lipid, and glucose homeostasis, and immunological effects caused by the activity of cytokines, macrophages, and other immune system cells. Further research on the immunological and metabolic effects of breastfeeding in obese patients is key to understanding and potentially developing obesity therapeutic strategies.

Sechium edule, chaylte vines, flavonoids, metabolomics, transcriptomics, Biology (General), and QH301-705.5

Chaylte vine, the tender shoot of Sechium edule, is popular among vegetable consumers because of its high nutritional content, crisp texture, and unique flavor. Existing studies on the nutrient composition of chaylte vines are mostly simple chemical determinations, which have limited the breeding of specialized cultivars and the development of related industries. Using metabolomics combined with transcriptomics, this study analyzed the metabolic characteristics and related molecular mechanisms of two common varieties of chaylte vines: green-skinned (SG) and white-skinned (SW). Between the two varieties, a total of 277 differentially accumulated metabolites (DAMs) and 739 differentially expressed genes (DEGs) were identified. Furthermore, chemical assays demonstrated that the SW exhibited a higher total flavonoid content and antioxidant capacity. In conclusion, it was found that the SG samples exhibited a higher diversity of flavonoid subclasses compared to the SW samples, despite having a lower total flavonoid content. This inconsistent finding was likely due to the differential expression of the phenylalanine ammonia-lyase (PAL) and chalcone synthase (CHS) genes in the two varieties. These results laid the foundation for investigating the mechanisms involved in flavonoid regulation and the breeding of specialized S. edule cultivars for chaylte vine production.

Pentatrichomonas hominis, zoonotic pathogen, LFD-RPA, dogs, rapid detection, Biology (General), and QH301-705.5

Pentatrichomonas hominis is a trichomonad protozoan that infects the cecum and colon of humans and other mammals. It is a zoonotic pathogen that causes diarrhea in both animals and humans. As companion animals, dogs infected with P. hominis pose a risk of transmitting it to humans. Current methods, such as direct smears and polymerase chain reaction (PCR), used for P. hominis detection have limitations, including low detection rates and the need for specialized equipment. Therefore, there is an urgent need to develop rapid, sensitive, and simple detection methods for clinical application. Recombinase polymerase amplification (RPA) has emerged as a technology for rapid pathogen detection. In this study, we developed a lateral flow dipstick (LFD)-RPA method based on the highly conserved SPO11-1 gene for detecting P. hominis infection by optimizing the primers, probes, and reaction conditions, and evaluating cross-reactivity with genomes of Giardia duodenalis and other parasites. The LFD-RPA method was then used to test 128 dog fecal samples collected from Changchun. The results confirmed the high specificity of the method with no cross-reactivity with the five other parasites. The lowest detection limit of the method was 102 copies/µL, and its sensitivity was 100 times higher than that of the conventional PCR method. Consistent with the positivity rate observed using nested PCR, 12 samples (out of 128) tested positive using this method (positivity rate, 9.38%). In conclusion, the LFD-RPA method developed in this study represents a simple and sensitive assay that allows for the rapid detection of P. hominis infection in dogs, especially in this field.

insulin resistance, NAFLD, hepatokines, ER stress, circadian clock, low-grade inflammation, Biology (General), and QH301-705.5

The central mechanism involved in the pathogenesis of MAFLD is insulin resistance with hyperinsulinemia, which stimulates triglyceride synthesis and accumulation in the liver. On the other side, triglyceride and free fatty acid accumulation in hepatocytes promotes insulin resistance via oxidative stress, endoplasmic reticulum stress, lipotoxicity, and the increased secretion of hepatokines. Cytokines and adipokines cause insulin resistance, thus promoting lipolysis in adipose tissue and ectopic fat deposition in the muscles and liver. Free fatty acids along with cytokines and adipokines contribute to insulin resistance in the liver via the activation of numerous signaling pathways. The secretion of hepatokines, hormone-like proteins, primarily by hepatocytes is disturbed and impairs signaling pathways, causing metabolic dysregulation in the liver. ER stress and unfolded protein response play significant roles in insulin resistance aggravation through the activation of apoptosis, inflammatory response, and insulin signaling impairment mediated via IRE1/PERK/ATF6 signaling pathways and the upregulation of SREBP 1c. Circadian rhythm derangement and biological clock desynchronization are related to metabolic disorders, insulin resistance, and NAFLD, suggesting clock genes as a potential target for new therapeutic strategies. This review aims to summarize the mechanisms of hepatic insulin resistance involved in NAFLD development and progression.

glycomic profiling, N-glycans, N-acetylglucosaminyltransferase, GnT-I, zebrafish, embryogenesis, Biology (General), and QH301-705.5

A lack of complex and hybrid types of N-glycans in mice is embryonically lethal due to neural tube maldevelopment. N-acetylglucosaminyltransferase-I (GnT-I; Mgat1) catalyzes a required step for converting oligomannose N-glycans into hybrid and complex N-glycans. Unlike mice, zebrafish have two Mgat1a/b genes. Herein, CRISPR/Cas9 technology was used to knockdown GnT-Ib activity in zebrafish, referred to as Mgat1b−/−, to examine the impact of a decrease in complex types of N-glycans on survival and development, and sensory and motor functions. Genotyping verified the occurrence of edited Mgat1b, and LC-ESI-MS and lectin blotting identified higher levels of oligomannose and lower levels of complex N-glycans in Mgat1b−/− relative to Wt AB. The microscopic visualization of developmental stages and locomotor studies using an automated tracking unit and manual touch assays revealed reduced survivability, and delayed motor and sensory functions in Mgat1b−/−. Moreover, embryonic staging linked reduced survivability of Mgat1b−/− to disruption in brain anlagen formation. Birefringence measurements supported delayed skeletal muscle development, which corresponded with motor and sensory function impediments in Mgat1b−/−. Furthermore, GnT-Ib knockdown hindered cardiac activity onset. Collectively, Mgat1b−/− displayed incomplete penetrance and variable expressivity, such that some died in early embryonic development, while others survived to adulthood, albeit, with developmental delays. Thus, the results reveal that reducing the amount of complex-type N-glycans is unfavorable for zebrafish survival and development. Moreover, our results support a better understanding of human congenital disorders of glycosylation.