bluuebunny/crossref_metadata_2025 huggingface dataset:
The Antitumor Effect of Timosaponin A3 through c-Myc Inhibition in Colorectal Cancer Cells and Combined Treatment Effect with 5-FU or Doxorubicin
Authors: Ko Hyun Min , Jee Wona , Park Do-il , Kim Kwan-Il , Jung Ji Hoon , Jang Hyeung-Jin
Published: October 2022

Timosaponin A3 (TA3), extracted from the rhizome of Anemarrhenaasphodeloides Bunge, has been reported to affect various diseases, such as cancer, Alzheimer’s disease, and allergies. However, the underlying molecular mechanisms and impacts are largely unknown. In the present study, we hypothesized that TA3 induces apoptosis through the inhibition of c-Myc expression via CNOT2 or MID1IP1 in HCT116. An MTT assay and colony formation assay were used to measure cell viability and proliferation. The protein expression of apoptotic markers and oncogenes was measured using immunoblotting and immunofluorescence assays. The interaction between MID1IP1 and c-Myc was confirmed by performing an immunoprecipitation assay. TA3 markedly inhibited colon cancer cell proliferation. Consistently, TA3 regulated the apoptotic proteins pro-PARP and caspase 3. TA3 inhibited the half-life of c-Myc and suppressed its expression in response to serum stimulation. In addition, TA3 enhanced the apoptotic effects of doxorubicin and 5-FU in colon cancer cells. Altogether, our results reveal a mechanism by which TA3 induces apoptosis through inhibiting c-Myc expression via CNOT2 or MID1IP1 in HCT116, which may help in the development of new therapies for colon cancer based on TA3 in the future.
Triphenylphosphonium Modified Mesoporous Silica Nanoparticle for Enhanced Algicidal Efficacy of Cyclohexyl-(3,4-dichlorobenzyl) Amine
Authors: Kim Ho-Joong , Kim Sung Tae , Park Dae Beom , Cho Hoon , Asadujjaman Md , Jee Jun-Pil
Published: October 2022

Mesoporous silica nanoparticles (MSNPs) have been widely used for the delivery of different hydrophilic and hydrophobic drugs owing to their large surface area and ease of chemical alteration. On the other hand, triphenylphosphonium cation (TPP+) with high lipophilicity has a great mitochondrial homing property that stimulates the internalization of drugs into cells. Therefore, we designed a TPP-modified MSNP to enhance the algicidal activity of our new algicidal agent cyclohexyl-(3,4-dichlorobenzyl) amine (DP92). In this study, algicidal activity was evaluated by assessing the growth rate inhibition of two harmful algal blooms (HABs), Heterosigma akashiwo and Heterocapsa circularisquama, after treatment with DP92-loaded MSNP or TPP-MSNP and DP92 in DMSO (as control). For H. akashiwo, the IC50 values of TPP-MSNP and MSNP are 0.03 ± 0.01 and 0.16 ± 0.03 µM, respectively, whereas the value of the control is 0.27 ± 0.02 µM. For H. circularisquama, the IC50 values of TPP-MSNP and MSNP are 0.10 ± 0.02 and 0.29 ± 0.02 µM, respectively, whereas the value of the control is 1.90 ± 0.09 µM. Results have indicated that TPP-MSNP efficiently enhanced the algicidal activity of DP92, signifying the prospect of using DP92-loaded TPP-MSNP as an algicidal agent for the superior management of HABs.
Assessment of DDAH1 and DDAH2 Contributions to Psychiatric Disorders via In Silico Methods
Authors: Kozlova Alena A. , Vaganova Anastasia N. , Rodionov Roman N. , Gainetdinov Raul R. , Bernhardt Nadine
Published: October 2022

The contribution of nitric oxide synthases (NOSs) to the pathophysiology of several neuropsychiatric disorders is recognized, but the role of their regulators, dimethylarginine dimethylaminohydrolases (DDAHs), is less understood. This study’s objective was to estimate DDAH1 and DDAH2 associations with biological processes implicated in major psychiatric disorders using publicly accessible expression databases. Since co-expressed genes are more likely to be involved in the same biologic processes, we investigated co-expression patterns with DDAH1 and DDAH2 in the dorsolateral prefrontal cortex in psychiatric patients and control subjects. There were no significant differences in DDAH1 and DDAH2 expression levels in schizophrenia or bipolar disorder patients compared to controls. Meanwhile, the data suggest that in patients, DDAH1 and DDHA2 undergo a functional shift mirrored in changes in co-expressed gene patterns. This disarrangement appears in the loss of expression level correlations between DDAH1 or DDAH2 and genes associated with psychiatric disorders and reduced functional similarity of DDAH1 or DDAH2 co-expressed genes in the patient groups. Our findings evidence the possible involvement of DDAH1 and DDAH2 in neuropsychiatric disorder development, but the underlying mechanisms need experimental validation.
Omega-3 Polyunsaturated Fatty Acids Protect against High-Fat Diet-Induced Morphological and Functional Impairments of Brown Fat in Transgenic Fat-1 Mice
Authors: Hao Lei , Nie Yong-Hui , Chen Chih-Yu , Li Xiang-Yong , Kaliannan Kanakaraju , Kang Jing X.
Published: October 2022

The role of omega-3 polyunsaturated fatty acids (n-3 PUFAs) in the regulation of energy homeostasis remains poorly understood. In this study, we used a transgenic fat-1 mouse model, which can produce n-3 PUFAs endogenously, to investigate how n-3 PUFAs regulate the morphology and function of brown adipose tissue (BAT). We found that high-fat diet (HFD) induced a remarkable morphological change in BAT, characterized by “whitening” due to large lipid droplet accumulation within BAT cells, associated with obesity in wild-type (WT) mice, whereas the changes in body fat mass and BAT morphology were significantly alleviated in fat-1 mice. The expression of thermogenic markers and lypolytic enzymes was significantly higher in fat-1 mice than that in WT mice fed with HFD. In addition, fat-1 mice had significantly lower levels of inflammatory markers in BAT and lipopolysaccharide (LPS) in plasma compared with WT mice. Furthermore, fat-1 mice were resistant to LPS-induced suppression of UCP1 and PGC-1 expression and lipid deposits in BAT. Our data has demonstrated that high-fat diet-induced obesity is associated with impairments of BAT morphology (whitening) and function, which can be ameliorated by elevated tissue status of n-3 PUFAs, possibly through suppressing the effects of LPS on inflammation and thermogenesis.
Hair-Growth-Promoting Effects of the Fish Collagen Peptide in Human Dermal Papilla Cells and C57BL/6 Mice Modulating Wnt/β-Catenin and BMP Signaling Pathways
Authors: Hwang Su Bin , Park Hyeon Ju , Lee Bog-Hieu
Published: October 2022

Fish-derived collagen has recently emerged as an alternative collagen source with bioactive properties, including the enhancement of hair and skin health. It is also cost-effective and has high bioavailability, in addition to having fewer side-effects compared to collagen from porcine skin or bovine skin. Collagen peptides (CPs) extracted from the scales of Mozambique tilapia (Oreochromis mossambicus) reportedly promote hair and skin health. This study sought to evaluate the effects of CPs on hair growth using in vitro and in vivo models. CP significantly enhanced hair regrowth and the proliferation of human dermal papilla cells (hDPCs) in vitro. CP was orally administered to C57BL/6 mice for 6 weeks to confirm the hair-growth-promoting effects. The mice were divided into four groups: negative control (distilled water), positive control (1 mg/kg of finasteride), CP500 (500 mg/kg of CP), and CP1000 (1000 mg/kg of CP). CP treatment significantly enhanced the proliferation of hDPCs compared to 0.2 μM finasteride, in addition to enhancing hair regrowth. Particularly, CP1000 treatment achieved a hair-growth index similar to that of the PC. In H&E staining, the CP groups exhibited a high A/T ratio. Furthermore, CP increased the expression of hair growth factors (IGF-1, VEGF, krt27, Gprc5d, and Ki67) and decreased the growth inhibitory factor (TGF-β1). Furthermore, CP significantly upregulated the Wnt/β-catenin pathways and downregulated the BMP pathways. Therefore, these results indicate that CP could be used as food supplements and nutraceuticals for hair loss prevention as well as hair regrowth during alopecia.
Current Development and Future Application Prospects of Plants-Derived Polyphenol Bioactive Substance Curcumin as a Novel Feed Additive in Livestock and Poultry
Authors: Pan Shifeng , Yan Jie , Xu Xingyu , Chen Yongfang , Chen Xinyu , Li Fei , Xing Hua
Published: October 2022

Curcumin (CUR) is a kind of natural orange-yellow phenolic compound mainly extracted from the stems and roots of turmeric plants and other species in the genus Curcuma, furthermore, it is also the most important active ingredient exerting pharmacological functions in turmeric. In recent years, CUR has been frequently reported and has attracted widespread attention from scholars all over the world due to its numerous biological functions and good application prospects, such as anti-inflammatory, anticancer, antioxidant and providing lipid-lowering effects, etc. In addition, adding a certain dose of CUR to livestock and poultry feed is important for animal growth and development, which plays a key role in animal metabolism, reproduction, immunity and clinical health care. This review aims to summarize, based on the published papers and our own observations, the physical and chemical properties and the biological functions of the plant-derived bioactive ingredient CUR, especially regarding the latest research progress in regulating intestinal health as well as its current development and future application prospects in livestock and poultry as a novel feed additive, so as to provide theoretical and practical references for the further study of the application of CUR as a novel feed additive and a potential new antibiotic substitute, thereby improving the research field of plant-derived bioactive ingredients and promoting the healthy development of livestock and poultry.
Aquacobalamin Accelerates Orange II Destruction by Peroxymonosulfate via the Transient Formation of Secocorrinoid: A Mechanistic Study
Authors: Dereven’kov Ilia A. , Sakharova Ekaterina S. , Osokin Vladimir S. , Makarov Sergei V.
Published: October 2022

Besides its use in medicine, vitamin B12 (cobalamin) and its derivatives have found in numerous applications as catalysts. However, studies related to the activation of oxidants via cobalamin are scant. In this work, we showed how the addition of aquacobalamin (H2OCbl) accelerates the destruction of azo-dye Orange II by peroxymonosulfate (HSO5−) in aqueous solutions. In neutral and weakly alkaline media, the process is initiated by the modification of the corrin macrocycle with HSO5−, which requires the preliminary deprotonation of the aqua-ligand in H2OCbl to give hydroxocobalamin, producing 5,6-dioxo-5,6-secocobalamin or its isomer (14,15-dioxo-14,15-secocobalamin). In acidic solutions, where the concentration of hydroxocobalamin is negligible, the formation of dioxo-seco-species is not observed, and the reaction between H2OCbl and HSO5− results in slow chromophore bleaching. Using terephthalic acid, we demonstrated the formation of hydroxyl radicals in the mixture of H2OCbl with HSO5−, whereas the generation of sulfate radicals was proved by comparing the effects of ethanol and nitrobenzene on Orange II destruction using the H2OCbl/HSO5− system. The reaction mechanism includes the binding of HSO5− to the Co(III) ion of dioxo-secocobalamin, which results in its deprotonation and the labilization of the O-O bond, leading to the formation of sulfate and hydroxyl radicals which further react with Orange II.
P-Selectin is a Critical Factor for Platelet-Mediated Protection on Restraint Stress-Induced Gastrointestinal Injury in Mice
Authors: Pethaperumal Subhashree , Hung Shih-Che , Lien Te-Sheng , Sun Der-Shan , Chang Hsin-Hou
Published: October 2022

Psychological stress is associated with increased risk of gastrointestinal (GI) tract diseases. Evidence indicated that platelets facilitate GI tissue repair in intestinal anastomosis models. However, whether platelets are involved in native mechanism of the rescue of stress-induced GI injury for maintaining the GI homeostasis remains elusive. Because P-selectin-deficient (Selp−/−) mice displayed higher stress-induced GI injury compared to the wild-type (Selp+/+) mice, and P-selectin is specifically expressed in platelets, we hypothesize that P-selectin-expressing platelets play a protective role in the rescue of stress-induced GI injury. Our goal is to clarify the putative protective role of platelets in a GI system, thereby develop a feasible intervention strategy, such as platelet transfer, to overcome stress-induced GI injury. Through monitoring the plasma levels of GI-nonabsorbable Evans blue dye to reveal the progression course of GI injury in live mice, we found that intravenous treatments of purified platelets ameliorated stress-induced GI leakage. The transfer of platelets from wild-type mice was more potent than from Selp−/− mice in the rescue of stress-induced-GI leakage in the recipients. As such, platelet transfer-mediated rescue was conducted in a P-selectin dependent manner. Additionally, platelet-mediated protection is associated with corrections of stress-induced aberrant GI mRNA expressions, including tight junctions claudin 3 and occludin, as well as stress-induced genes activating transcription factor 3 and AMP-activated protein kinase, after the transfer of wild-type platelets into wild-type and Selp−/− mice. Furthermore, the stress-induced apoptosis of CD326+ GI epithelial cells was rescued by the transfer of wild type, but not P-selectin-deficient platelets. These results suggest that platelet plays a protective role for maintaining the GI homeostasis during stress in vivo, and that P-selectin is a molecular target for managing stress-induced GI tract injury.
A Screening of Epigenetic Therapeutic Targets for Non-Small Cell Lung Cancer Reveals PADI4 and KDM6B as Promising Candidates
Authors: Lesbon Jéssika Cristina Chagas , Garnica Taismara Kustro , Xavier Pedro Luiz Porfírio , Rochetti Arina Lázaro , Reis Rui Manuel , Müller Susanne , Fukumasu Heidge
Published: October 2022

Despite advances in diagnostic and therapeutic approaches for lung cancer, new therapies targeting metastasis by the specific regulation of cancer genes are needed. In this study, we screened a small library of epigenetic inhibitors in non-small-cell lung cancer (NSCLC) cell lines and evaluated 38 epigenetic targets for their potential role in metastatic NSCLC. The potential candidates were ranked by a streamlined approach using in silico and in vitro experiments based on publicly available databases and evaluated by real-time qPCR target gene expression, cell viability and invasion assays, and transcriptomic analysis. The survival rate of patients with lung adenocarcinoma is inversely correlated with the gene expression of eight epigenetic targets, and a systematic review of the literature confirmed that four of them have already been identified as targets for the treatment of NSCLC. Using nontoxic doses of the remaining inhibitors, KDM6B and PADI4 were identified as potential targets affecting the invasion and migration of metastatic lung cancer cell lines. Transcriptomic analysis of KDM6B and PADI4 treated cells showed altered expression of important genes related to the metastatic process. In conclusion, we showed that KDM6B and PADI4 are promising targets for inhibiting the metastasis of lung adenocarcinoma cancer cells.
MES SV40 Cells Are Sensitive to Lipopolysaccharide, Peptidoglycan, and Poly I:C Expressing IL-36 Cytokines
Authors: Pelcastre-Rodriguez Cesar G. , Vazquez-Sanchez Ernesto A. , Murrieta-Coxca José M. , Rodríguez-Martínez Sandra , Cancino-Diaz Juan C. , Cancino-Diaz Mario E.
Published: October 2022

Mesangial cells (MC) maintain the architecture and cellular communication and indirectly join in the glomerular filtration rate for the correct functioning of the glomerulus. Consequently, these cells are activated constantly in response to changes in the intraglomerular environment due to a metabolic imbalance or infection. IL-36, a member of the IL-1 family, is a cytokine that initiates and maintains inflammation in different tissues in acute and chronic pathologies, including the skin, lungs, and intestines. In the kidney, IL-36 has been described in the development of tubulointerstitial lesions, the production of an inflammatory environment, and is associated with metabolic and mesangioproliferative disorders. The participation of IL-36 in functional dysregulation and the consequent generation of the inflammatory environment by MCs in the presence of microbial stimulation is not yet elucidated. In this work, the MES SV40 cell cultures were stimulated with classical pathogen-associated molecular patterns (PAMPs), mimicking an infection by negative and positive bacteria as well as a viral infection. Lipopolysaccharide (LPS), peptidoglycan (PGN) microbial wall components, and a viral mimic poly I:C were used, and the mRNA and protein expression of the IL-36 members were assessed. We observed a differential and dose-dependent IL-36 mRNA and protein expression under LPS, PGN, and poly I:C stimulation. IL-36β was only found when the cells were treated with LPS, while IL-36α and IL-36γ were favored by PGN and poly I:C stimulation. We suggest that the microbial components participate in the activation of MCs, leading them to the production of IL-36, in which a specific member may participate in the origin and maintenance of inflammation in the glomerular environment that is associated with infections.
Design, Synthesis and Biological Evaluation of Neocryptolepine Derivatives as Potential Anti-Gastric Cancer Agents
Authors: Ma Yunhao , Tian Yanan , Zhou Zhongkun , Chen Shude , Du Kangjia , Zhang Hao , Jiang Xinrong , Lu Juan , Niu Yuqing , Tu Lixue , Wang Jie , Liu Huanxiang , Zhu Hongmei , Chen Peng , Liu Yingqian
Published: October 2022

Natural products play an important role in drug development and lead compound synthesis. Neocryptolepine is a polycyclic quinoline compound isolated from Cryptolepis sanguinolent. The cytotoxicity of neocryptolepine to gastric cancer cells AGS, MKN45, HGC27, and SGC7901 was not very strong, and it also had certain toxicity to gastric mucosa cells GES-1. Therefore, a series of neocryptolepine derivatives were synthesized by the modification of the structure of neocryptolepine, and their cytotoxicity was evaluated. The results showed that compounds C5 and C8 exhibited strong cytotoxicity to AGS cells. The cell colony formation and cell migration experiments suggested that compounds C5 and C8 could inhibit the proliferation and cell migration of AGS and HGC27 cells. Cell cycle and apoptosis experiments showed that compounds C5 and C8 did not cause the apoptosis of AGS and HGC27 cells but, mainly, caused cell necrosis. Compound C5 had no significant effect on AGS and HGC27 cell cycles at low concentration. After treatment with AGS cells for 24 h at high concentration, compound C5 could significantly arrest the AGS cell cycle in the G2/M phase. Compound C8 had no significant effect on the AGS and HGC27 cell cycles. The results of molecular docking and Western blot showed that compounds C5 and C8 might induce cytotoxicity through the PI3K/AKT signaling pathway. Therefore, compounds C5 and C8 may be promising lead compounds for the treatment of gastric cancer.
Nucleotide-Induced Nanoscale Changes in the Mechanical Properties of Rat Cerebellar Astrocytes: Selective Stimulation and Blocking of the Purinergic Receptor P2X7
Authors: Gil-Redondo Juan Carlos , Iturri Jagoba , Trueba Yaiza , Benito-León María , Pérez-Sen Raquel , Delicado Esmerilda G. , Toca-Herrera José Luis , Ortega Felipe
Published: October 2022

As members of the family of nucleotide receptors, P2X7 receptors are of particular interest due to their unique structural and pharmacological characteristics. As ATP-gated ionic channels, P2X7 receptors in their activation elicit membrane depolarization; extracellular calcium influx; and activation of several downstream intracellular signaling pathways, some of them independent of the ionic channel activity. Further interactions of P2X7 receptors and cytoskeleton-related proteins have also been confirmed, and we previously described the effects of P2X7 receptor stimulation on the morphology of rat cerebellar astrocytes. In the present work, we used time-lapse video microscopy and atomic force microscopy (AFM) to elucidate the effects of P2X7 receptor stimulation on the morphology, migratory capabilities, and mechanical properties of rat cerebellar astrocytes in vitro. Stimulation of P2X7 receptors with the selective agonist BzATP specifically caused an increase in cell size, motility, and number of membrane protrusions of the astrocytes in culture. These effects were reverted when cells were previously treated with the competitive antagonist of P2X7R, A 438079. AFM analysis also showed an increase in cell stiffness and viscosity after P2X7 receptor stimulation. Surprisingly, these effects on the mechanical properties of the cell were not blocked by the treatment with the antagonist. Fluorescence microscopy analysis of the actin cytoskeleton showed an increase in actin stress fibers after BzATP treatment, an effect that again was not blocked by previous treatment with the antagonist, further confirming that the effects of P2X7 receptors on the cytoskeleton of astrocytes are, at least in part, independent of the ionic channel activity.
Functional Heterogeneity of Bone Marrow Mesenchymal Stem Cell Subpopulations in Physiology and Pathology
Authors: Ning Kaiting , Yang Baoqiang , Chen Meng , Man Guigui , Liu Shuaiting , Wang Dong-en , Xu Huiyun
Published: October 2022

Bone marrow mesenchymal stem cells (BMSCs) are multi-potent cell populations and are capable of maintaining bone and body homeostasis. The stemness and potential therapeutic effect of BMSCs have been explored extensively in recent years. However, diverse cell surface antigens and complex gene expression of BMSCs have indicated that BMSCs represent heterogeneous populations, and the natural characteristics of BMSCs make it difficult to identify the specific subpopulations in pathological processes which are often obscured by bulk analysis of the total BMSCs. Meanwhile, the therapeutic effect of total BMSCs is often less effective partly due to their heterogeneity. Therefore, understanding the functional heterogeneity of the BMSC subpopulations under different physiological and pathological conditions could have major ramifications for global health. Here, we summarize the recent progress of functional heterogeneity of BMSC subpopulations in physiology and pathology. Targeting tissue-resident single BMSC subpopulation offers a potentially innovative therapeutic strategy and improves BMSC effectiveness in clinical application.
The Role of Virulence Factors in Neonatal Sepsis Caused by Enterobacterales: A Systematic Review
Authors: Barcellini Lucia , Ricci Giulia , Bresesti Ilia , Piazza Aurora , Comandatore Francesco , Sharland Mike , Zuccotti Gian Vincenzo , Folgori Laura
Published: October 2022

Neonatal sepsis is a life-threatening condition with high mortality. Virulence determinants relevant in causing Gram-negative (GN) neonatal sepsis are still poorly characterized. A better understanding of virulence factors (VFs) associated with GN neonatal sepsis could offer new targets for therapeutic interventions. The aim of this review was to assess the role of GN VFs in neonatal sepsis. We primarily aimed to investigate the main VFs leading to adverse outcome and second to evaluate VFs associated with increased invasiveness/pathogenicity in neonates. MEDLINE, Embase, and Cochrane Library were systematically searched for studies reporting data on the role of virulome/VFs in bloodstream infections caused by Enterobacterales among neonates and infants aged 0–90 days. Twenty studies fulfilled the inclusion criteria. Only 4 studies reported data on the association between pathogen virulence determinants and neonatal mortality, whereas 16 studies were included in the secondary analyses. The quality of reporting was suboptimal in the great majority of the published studies. No consistent association between virulence determinants and GN strains causing neonatal sepsis was identified. Considerable heterogeneity was found in terms of VFs analysed and reported, included population and microbiological methods, with the included studies often showing conflicting data. This variability hampered the comparison of the results. In conclusions, pathogens responsible for neonatal sepsis are widely heterogenous and can use different pathways to develop invasive disease. The recent genome-wide approach needs to include multicentre studies with larger sample sizes, analyses of VF gene profiles instead of single VF genes, alongside a comprehensive collection of clinical information. A better understanding of the roles of virulence genes in neonatal GN bacteraemia may offer new vaccine targets and new markers of highly virulent strains. This information can potentially be used for screening and preventive interventions as well as for new targets for anti-virulence antibiotic-sparing therapies.
Promyelocytic Leukemia Protein Potently Restricts Human Cytomegalovirus Infection in Endothelial Cells
Authors: Seitz Sven , Heusel Anna Theresa , Stamminger Thomas , Scherer Myriam
Published: October 2022

PML nuclear bodies (PML-NBs) are dynamic macromolecular complexes that mediate intrinsic immunity against viruses of different families, including human cytomegalovirus (HCMV). Upon HCMV infection, PML-NBs target viral genomes entering the nucleus and restrict viral immediate–early gene expression by epigenetic silencing. Studies from several groups performed in human fibroblast cells have shown that the major PML-NB components PML, Daxx, Sp100 and ATRX contribute to this repression in a cooperative manner. Their role for HCMV restriction in endothelial cells, however, has not yet been characterized although infected endothelium is thought to play a crucial role for HCMV dissemination and development of vascular disease in vivo. Here, we use conditionally immortalized umbilical vein endothelial cells (HEC-LTT) as a cell culture model to elucidate the impact of PML-NB proteins on lytic HCMV infection. Depletion of individual PML-NB proteins by lentiviral transduction showed a particularly strong antiviral effect of PML in HEC-LTT, compared to human fibroblasts. A closer characterization of this antiviral function revealed that PML may not only effectively inhibit HCMV immediate-early gene expression but also act at later steps of the viral replication cycle. At contrast, we surprisingly noted an antiviral behavior of Daxx in complementary approaches: Depletion of Daxx resulted in decreased viral gene expression, while overexpression of Daxx promoted HCMV infection. In summary, our data demonstrate a cell type-specific effect of PML-NB components on lytic HCMV infection and suggest an important role of PML in the inhibition of HCMV dissemination through infected endothelial cells.
PINK1 Phosphorylates Drp1S616 to Improve Mitochondrial Fission and Inhibit the Progression of Hypertension-Induced HFpEF
Authors: Shou Jian , Huo Yunlong
Published: October 2022

(1) Background: Heart failure with preserved ejection fraction (HFpEF) is a major subtype of HF with no effective treatments. Mitochondrial dysfunctions relevant to the imbalance of fusion and fission occur in HFpEF. Drp1 is a key protein regulating mitochondrial fission, and PINK1 is the upstream activator of Drp1, but their relationship with HF has not been clarified. The aim of the study is to investigate molecular mechanisms of mitochondrial dysfunctions in animals with hypertension-induced HFpEF. (2) Methods and Results: The hypertension-induced HFpEF model was established by feeding Dahl/SS rats with high salt, showing risk factors such as hypertension, mitochondrial dysfunctions, and so on. Physiological and biological measurements showed a decrease in the expression of mitochondrial function-related genes, ATP production, and mitochondrial fission index. PINK1 knockout in H9C2 cardiomyocytes showed similar effects. Moreover, PINK1 myocardium-specific overexpression activated Drp1S616 phosphorylation and enhanced mitochondrial fission to slow the progression of hypertension-induced HFpEF. (3) Conclusions: PINK1 could phosphorylate Drp1S616 to improve mitochondrial fission and relieve mitochondrial dysfunctions, which highlights potential treatments of HFpEF.
Caspase 3 and Cleaved Caspase 3 Expression in Tumorogenesis and Its Correlations with Prognosis in Head and Neck Cancer: A Systematic Review and Meta-Analysis
Authors: Silva Fábio , Padín-Iruegas María , Caponio Vito , Lorenzo-Pouso Alejandro , Saavedra-Nieves Paula , Chamorro-Petronacci Cintia , Suaréz-Peñaranda José , Pérez-Sayáns Mario
Published: October 2022

Head and neck cancer (HNC) is an ascending and agressive disease. The search for new molecular markers is emerging to solve difficulties in diagnosis, risk management, prognosis and effectiveness of treatments. Proteins related to apoptotic machinery have been identified as potential biomarkers. Caspase 3 is the main effector caspase and has a key role in apoptosis. The objective of this systematic review and meta-analysis is to review studies that analyze changes in Caspase 3 and Cleaved Caspase 3 expression both in oral premalignant disorders (OPMD) as well as in head and neck cancer (HNC). This study also proposes to review the prognostic values associated with HNC according to the expression of Caspase 3. Medline (via PubMed), EMBASE, Scopus, Cochrane, Web of Science and Grey Literature Database were screened from inception to june of 2022 and 18 studies were selected and 8 were included in the prognostic meta-analysis. Results related to the comparison of Caspase 3 expression demonstrated similar expression of Caspase 3 in HNC, with an average of 51.9% (9.5–98.1) showing high/moderate expression compared to 45.7% (14.6–84.7) in OPMD. Of interest, Cleaved Caspase 3 resulted incresed in HNC when compared with OPMD, being 73.3% (38.6–88.3) versus 22.9% (7.1–38.7). Pooled Fixed effect of HR values (95% CI) for OS related to Caspase 3 IHC expression in HNC patients was 1.48 (95% CI 0.95–2.28); also, the rate of heterogeneity was low, as revealed by I2 = 31%. For DFS was 1.07 (95% CI 0.79–1.45) with I2 = 0% and DSS showed a HR of 0.88 (95% CI 0.69–1.12) with I2 = 37%. Caspase 3 and Cleaved Caspase 3 expression could be linked with malignancy progression, but the expression of Caspase 3 did not influence the prognosis of patients with HNC.
A Fine Regulation of the Hippocampal Thyroid Signalling Protects Hypothyroid Mice against Glial Cell Activation
Authors: Chamas Lamis , Seugnet Isabelle , Poirier Roseline , Clerget-Froidevaux Marie-Stéphanie , Enderlin Valérie
Published: October 2022

Adult-onset hypothyroidism is associated with learning and cognitive dysfunctions, which may be related to alterations in synaptic plasticity. Local reduced levels of thyroid hormones (THs) may impair glia morphology and activity, and promote the increase of pro-inflammatory cytokine levels mainly in the hippocampus. Given that neuroinflammation induces memory impairments, hypothyroidism-related glia dysfunction may participate in brain disorders. Thus, we investigated the mechanisms linking hypothyroidism and neuroinflammation, from a protective perspective. We induced hypothyroidism in adult C57BL/6J and wild-derived WSB/EiJ male mice by a seven-week propylthiouracil (PTU) treatment. We previously showed that WSB/EiJ mice were resistant to high-fat diet (HFD)-induced obesity, showing no neuroinflammatory response through adaptive abilities, unlike C57BL/6J. As PTU and HFD treatments are known to induce comparable inflammatory responses, we hypothesized that WSB/EiJ mice might also be protected against hypothyroidism-induced neuroinflammation. We showed that hypothyroid WSB/EiJ mice depicted no hippocampal neuroinflammatory response and were able to maintain their hippocampal thyroid signalling despite low circulatisng TH levels. In contrast, C57BL/6J mice exhibited disturbed hippocampal TH signalling, accompanied by neuroinflammation and memory impairment. Our results reinforce the preponderance of the hippocampal TH regulatory system over TH circulating levels in the hippocampal glial reactivity.
The Defects of Epigenetic Reprogramming in Dox-Dependent Porcine-iPSCs
Authors: Jiang Aiwen , Ma Yangyang , Zhang Xue , Pan Qianqian , Luo Pengfei , Guo Hongyun , Wu Wangjun , Li Juan , Yu Tong , Liu Honglin
Published: October 2022

Porcine-induced pluripotent stem cells (piPSCs) are of great significance to animal breeding and human medicine; however, an important problem is that the maintenance of piPSCs mainly depends on exogenous expression of pluripotent transcription factors (TFs), and germline transmission-competent piPSCs have not yet been successfully established. In this study, we explore the defect of epigenetic reprogramming during piPSCs formation, including chromatin accessibility, DNA methylation, and imprinted gene expression, with high-throughput sequencing (ATAC-seq, WGBS, RNA-seq, and Re-seq) methods. We found the somatic features were successfully silenced by connecting closed chromatin loci with downregulated genes, while DNA methylation has limited effects on somatic silence. However, the incomplete chromatin remodeling and DNA demethylation in pluripotency genes hinder pluripotent activation, resulting in the low expression of endogenous pluripotency genes. In addition, the expression of potential imprinted genes was abnormal, and many allelic-biased expressed genes in porcine embryonic fibroblasts (PEFs) were erased, accompanied by establishment of new allelic-biased expressed genes in piPSCs. This study reveals the aberrant epigenetic reprogramming during dox-dependent piPSCs formation, which lays the foundation for research of porcine-iPSC reprogramming and genome imprinting.
Genome-Wide Identification and Expression Profiling Analysis of the Long-Chain Acyl-CoA Synthetases Reveal Their Potential Roles in Wheat Male Fertility
Authors: Liu Yongjie , Liu Zihan , Zhang Huishu , Yuan Shaohua , Li Yanmei , Zhang Tianbao , Bai Jianfang , Zhang Liping
Published: October 2022

Long-chain acyl-CoA synthetase (LACS), responsible for the conversion of free FAs into acyl-CoAs, is involved in multiple pathways of lipid metabolism. Although LACS genes in Arabidopsis have been well characterized, no detailed information concerning this family is available for wheat. In the present study, a systematic analysis was carried out for the wheat LACS family. As a result, 30 putative TaLACSs were identified. Expression analysis revealed that 22 Takacs were expressed in wheat anthers. Two orthologs of AtLACS1, TaLACS2 and TaLACS3, were repressed at the vacuolated stage in the cold-treated BS366 (a temperature-sensitive genic male-sterile line). Thus, TaLACS2 and TaLACS3 may function like AtLACS1 in wax biosynthesis in anthers, and the repression of both genes may be correlated with the male sterility of BS366. TaLACS5 is an ortholog of AtLACS5, which was expressed exclusively in anthers. TaLACS5 was repressed in the cold-treated BS366 at the tetrad, uninucleate, and vacuolated stages. The negative correlation between TaLACS5 and TaGAMYB-B, and the MYB domain found in the promoter sequence suggested that TaLACS5 may be negatively regulated by TaGAMYB-B to participate in wheat fertility. These findings will provide a valuable foundation for the understanding of the wheat LACS gene family in male fertility.
Intratumoral Treatment with 5-Androstene-3β, 17α-Diol Reduces Tumor Size and Lung Metastasis in a Triple-Negative Experimental Model of Breast Cancer
Authors: Ruiz Manzano Rocío Alejandra , Nava-Castro Karen Elizabeth , Palacios-Arreola Margarita Isabel , Hernández-Cervantes Rosalía , Del Río-Araiza Víctor Hugo , Segovia-Mendoza Mariana , Pérez-Torres Armando , Girón-Pérez Manuel Iván , Morales-Montor Jorge
Published: October 2022

Breast cancer treatment failure is related to low response rates, high costs, and long-term toxicities. Thus, it is necessary to find less toxic, cheaper, and more effective treatments. In situ administration ensures drug delivery to tumor cells and decreases systemic toxic effects. The androstene-3β, 17α-diol (α-AED) reduces breast tumor cell proliferation and is an ideal candidate to treat mammary tumors. This study aims to identify the in vitro and in vivo effects of α-AED on a triple-negative mammary tumor model. An in vitro biphasic steroid effect was observed in mouse and human mammary tumor cells treated with α-AED. In this sense, cells treated with higher doses (100 and 200 μM) showed an antiproliferative effect. The α-AED administrated intratumorally reduced average tumor weight and increased the percentage of natural killer cells (NK), plasmatic, and plasmablast cells in mice tumors. Of note, VEGF levels in all α-AED-treated tumors was lower than in the control and vehicle groups. The tumor in situ increased response was reflected systemically by higher anti-4T1 IgG concentration in serum from α-AED-treated mice, but no other associated systemic changes were detected. The reduction in tumor size for the local injection of α-AED is associated with the anti-proliferative effect of this steroid, and the lower local levels of VEGF may be related to the imperceptible macroscopic metastasis in α-AED-treated mice. The above suggests that α-AED may be used in clinical studies to prove its efficacy as an alternative breast tumor treatment or in conjunction with already established therapies.
Sphingolipids in Atherosclerosis: Chimeras in Structure and Function
Authors: Peters Lisa , Kuebler Wolfgang M. , Simmons Szandor
Published: October 2022

Atherosclerosis—a systemic inflammatory disease—is the number one cause of mortality and morbidity worldwide. As such, the prevention of disease progression is of global interest in order to reduce annual deaths at a significant scale. Atherosclerosis is characterized by plaque formation in the arteries, resulting in vascular events such as ischemic stroke or myocardial infarction. A better understanding of the underlying pathophysiological processes at the cellular and molecular level is indispensable to identify novel therapeutic targets that may alleviate disease initiation or progression. Sphingolipids—a lipid class named after the chimeric creature sphinx—are considered to play a critical and, metaphorically, equally chimeric regulatory role in atherogenesis. Previous studies identified six common sphingolipids, namely dihydroceramide (DhCer), ceramide (Cer), sphingosine-1-phosphate (S1P), sphingomyelin (SM), lactosylceramide (LacCer), and glucosylceramide (GluCer) in carotid plaques, and demonstrated their potential as inducers of plaque inflammation. In this review, we point out their specific roles in atherosclerosis by focusing on different cell types, carrier molecules, enzymes, and receptors involved in atherogenesis. Whereas we assume mainly atheroprotective effects for GluCer and LacCer, the sphingolipids DhCer, Cer, SM and S1P mediate chimeric functions. Initial studies demonstrate the successful use of interventions in the sphingolipid pathway to prevent atherosclerosis. However, as atherosclerosis is a multifactorial disease with a variety of underlying cellular processes, it is imperative for future research to emphasize the circumstances in which sphingolipids exert protective or progressive functions and to evaluate their therapeutic benefits in a spatiotemporal manner.
Novel Insights into Floral Thermogenesis: In Vivo Analyses of Mitochondrial Dynamics in Nelumbo nucifera Flowers
Authors: Li Ruoyi , Li Jing , Wang Siqin , Wang Ruohan
Published: October 2022

Animal-like thermogenic (TM) activities in flowers have been reported in several families of seed plants. While an association of mitochondria with floral thermogenesis has been described, how mitochondrial dynamics are involved in the regulation of floral thermogenesis is unclear. In this study, the morphological and functional dynamics of mitochondria in vivo were assessed in Nelumbo nucifera Gaertn. flowers during floral thermogenesis. The results showed that mitochondrial biogenesis increased considerably in N. nucifera flowers during thermogenesis, accompanied by notable morphological changes in the mitochondria, including long elliptical, rod-shaped, and dumbbell-shaped morphologies, as well as increased mitochondrial reactive oxygen species (ROS) levels in TM cells. An increase in the expression of alternative oxidase (AOX) during the thermogenesis of N. nucifera flowers was also observed. These observations suggested the rapid change in mitochondrial morphology and increased density during thermogenesis implied activation of mitochondrial fission, which combined with elevated levels of mitochondrial ROS trigger a substantial increase in AOX within the respiratory pathway of TM N. nucifera.
Familial Linkage and Association of the NR3C1 Gene with Type 2 Diabetes and Depression Comorbidity
Authors: Amin Mutaz , Syed Shumail , Wu Rongling , Postolache Teodor Tudorel , Gragnoli Claudia
Published: October 2022

Impairment in the hypothalamic-pituitary-adrenal (HPA) axis and cortisol pathway may be major contributing factors to the common pathogenesis of major depressive disorders (MDD) and type 2 diabetes (T2D). A significant player in the neuroendocrine HPA axis and cortisol response is the glucocorticoid receptor (GR), which is encoded by the nuclear receptor subfamily 3 group C member (NR3C1) gene. Variants in the NR3C1 gene have been reported in patients with MDD and obesity and found to confer reduced risk for quantitative metabolic traits and T2D in Cushing syndrome; variants have not been reported in T2D and MDD-T2D comorbid patients. We studied 212 original Italian families with a rich family history for T2D and tested 24 single nucleotide polymorphisms (SNPs) in the NR3C1 gene for linkage to and linkage disequilibrium (LD) with T2D and MDD across different inheritance models. We identified a total of 6 novel SNPs significantly linked/in LD to/with T2D (rs6196, rs10482633, rs13186836, rs13184611, rs10482681 and rs258751) and 1 SNP (rs10482668) significantly linked to/in LD with both T2D and MDD. These findings expand understanding of the role that NR3C1 variants play in modulating the risk of T2D-MDD comorbidity. Replication and functional studies are needed to confirm these findings.
The Roles of Androgens in Humans: Biology, Metabolic Regulation and Health
Authors: Alemany Marià
Published: October 2022

Androgens are an important and diverse group of steroid hormone molecular species. They play varied functional roles, such as the control of metabolic energy fate and partition, the maintenance of skeletal and body protein and integrity and the development of brain capabilities and behavioral setup (including those factors defining maleness). In addition, androgens are the precursors of estrogens, with which they share an extensive control of the reproductive mechanisms (in both sexes). In this review, the types of androgens, their functions and signaling are tabulated and described, including some less-known functions. The close interrelationship between corticosteroids and androgens is also analyzed, centered in the adrenal cortex, together with the main feedback control systems of the hypothalamic–hypophysis–gonads axis, and its modulation by the metabolic environment, sex, age and health. Testosterone (T) is singled out because of its high synthesis rate and turnover, but also because age-related hypogonadism is a key signal for the biologically planned early obsolescence of men, and the delayed onset of a faster rate of functional losses in women after menopause. The close collaboration of T with estradiol (E2) active in the maintenance of body metabolic systems is also presented Their parallel insufficiency has been directly related to the ravages of senescence and the metabolic syndrome constellation of disorders. The clinical use of T to correct hypoandrogenism helps maintain the functionality of core metabolism, limiting excess fat deposition, sarcopenia and cognoscitive frailty (part of these effects are due to the E2 generated from T). The effectiveness of using lipophilic T esters for T replacement treatments is analyzed in depth, and the main problems derived from their application are discussed.
Myotonic Dystrophy: From Molecular Pathogenesis to Therapeutics
Authors: Timchenko Lubov
Published: October 2022

Current studies concerning myotonic dystrophy type 1 (DM1) are in the process of transitioning from molecular investigations to preclinical and clinical trials [...]
Cloning and Molecular Characterization of Hsp Genes from Anoplophora glabripennis and Their Responses to Cold Stress
Authors: Xu Yabei , Li Yurong , Shi Fengming , Zhang Sainan , Zong Shixiang , Tao Jing
Published: October 2022

Anoplophora glabripennis (Agla) is an important global quarantine pest due to its highly destructive impacts on forests. It is widely distributed in many countries in Asia, Europe, and North America. The survival of A. glabripennis larvae has been facilitated by its high adaptability to low temperature. When insects are subjected to temperature stress, heat shock proteins (Hsps) limit cell damage and improve cell tolerance via their protein folding, localization, and degradation activities. However, the temperature adaptation mechanisms of A. glabripennis Hsps remain unclear. In this study, four A. glabripennis Hsp genes, AglaHsp20.43, AglaHsp71.18, AglaHsp82.09, and AglaHsp89.76, were cloned. Sequence analysis showed that all four Hsps had specific conserved domains. Phylogenetic analysis revealed that Hsps from different subfamilies were evolutionarily conserved, and that AglaHsps were highly similar to those of Coleoptera species. Protein expression vectors (pET30a-AglaHsps) were constructed and used to express AglaHsps in E. coli, where all four proteins were expressed in inclusion bodies. Western blot analysis showed that AglaHsps were expressed at a range of temperatures, from −10 °C to 25 °C. AglaHsp82.09 and AglaHsp89.76 showed high expressions with treatment at 0 °C. Our results will facilitate clarification of the molecular mechanisms underlying A. glabripennis responses to environmental stress.
Regulation of Mesothelial Cell Fate during Development and Human Diseases
Authors: Taniguchi Toshiaki , Tomita Hiroyuki , Kanayama Tomohiro , Mogi Kazumasa , Koya Yoshihiro , Yamakita Yoshihiko , Yoshihara Masato , Kajiyama Hiroaki , Hara Akira
Published: October 2022

Mesothelial cells (MCs) play a classic role in maintaining homeostasis in pleural, peritoneal, and pericardial cavities. MCs work as lubricants to reduce friction between organs, as regulators of fluid transport, and as regulators of defense mechanisms in inflammation. MCs can differentiate into various cells, exhibiting epithelial and mesenchymal characteristics. MCs have a high potential for differentiation during the embryonic period when tissue development is active, and this potential decreases through adulthood. The expression of the Wilms’ tumor suppressor gene (Wt1), one of the MC markers, decreased uniformly and significantly from the embryonic period to adulthood, suggesting that it plays a major role in the differentiation potential of MCs. Wt1 deletion from the embryonic period results in embryonic lethality in mice, and even Wt1 knockout in adulthood leads to death with rapid organ atrophy. These findings suggest that MCs expressing Wt1 have high differentiation potential and contribute to the formation and maintenance of various tissues from the embryonic period to adulthood. Because of these properties, MCs dynamically transform their characteristics in the tumor microenvironment as cancer-associated MCs. This review focuses on the relationship between the differentiation potential of MCs and Wt1, including recent reports using lineage tracing using the Cre-loxP system.