bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Myostatin on Nuclear Morphology at the Myotendinous Junction
Authors: Amemiya Hikari , Yamamoto Masahito , Higa Kazunari , Watanabe Genji , Taniguchi Shuichiro , Kitamura Kei , Jeong Juhee , Yanagisawa Nobuaki , Fukuda Ken-ichi , Abe Shinichi
Published: April 2023

Myostatin (Myo) is known to suppress skeletal muscle growth, and was recently reported to control tendon homeostasis. The purpose of the present study was to investigate the regulatory involvement of Myo in the myotendinous junction (MTJ) in vivo and in vitro. After Achilles tendon injury in mice, we identified unexpected cell accumulation on the tendon side of the MTJ. At postoperative day 7 (POD7), the nuclei had an egg-like profile, whereas at POD28 they were spindle-shaped. The aspect ratio of nuclei on the tendon side of the MTJ differed significantly between POD7 and POD28 (p = 4.67 × 10−34). We then investigated Myo expression in the injured Achilles tendon. At the MTJ, Myo expression was significantly increased at POD28 relative to POD7 (p = 0.0309). To investigate the action of Myo in vitro, we then prepared laminated sheets of myoblasts (C2C12) and fibroblasts (NIH3T3) (a pseudo MTJ model). Myo did not affect the expression of Pax7 and desmin (markers of muscle development), scleraxis and temonodulin (markers of tendon development), or Sox9 (a common marker of muscle and tendon development) in the cell sheets. However, Myo changed the nuclear morphology of scleraxis-positive cells arrayed at the boundary between the myoblast sheet and the fibroblast sheet (aspect ratio of the cell nuclei, myostatin(+) vs. myostatin(-): p = 0.000134). Myo may strengthen the connection at the MTJ in the initial stages of growth and wound healing.
The Reduction of Uromodulin, Complement Factor H, and Their Interaction Is Associated with Acute Kidney Injury to Chronic Kidney Disease Transition in a Four-Time Cisplatin-Injected Rat Model
Authors: Xing Zheyu , Gong Kunjing , Hu Nan , Chen Yuqing
Published: April 2023

Uromodulin is recognized as a protective factor during AKI-to-CKD progression, but the mechanism remains unclear. We previously reported that uromodulin interacts with complement factor H (CFH) in vitro, and currently aimed to study the expression and interaction evolution of uromodulin and CFH during AKI-to-CKD transition. We successfully established a rat model of AKI-to-CKD transition induced by a four-time cisplatin treatment. The blood levels of BUN, SCR, KIM-1 and NGAL increased significantly during the acute injury phase and exhibited an uptrend in chronic progression. PAS staining showed the nephrotoxic effects of four-time cisplatin injection on renal tubules, and Sirius red highlighted the increasing collagen fiber. Protein and mRNA levels of uromodulin decreased while urine levels increased in acute renal injury on chronic background. An extremely diminished level of uromodulin correlated with severe renal fibrosis. RNA sequencing revealed an upregulation of the alternative pathway in the acute stage. Renal CFH gene expression showed an upward tendency, while blood CFH localized less, decreasing the abundance of CFH in kidney and following sustained C3 deposition. A co-IP assay detected the linkage between uromodulin and CFH. In the model of AKI-to-CKD transition, the levels of uromodulin and CFH decreased, which correlated with kidney dysfunction and fibrosis. The interaction between uromodulin and CFH might participate in AKI-to-CKD transition.
Assessment of BMP7, SMAD4, and CDH1 Expression Profile and Regulatory miRNA-542-3p in Eutopic and Ectopic Endometrium of Women with Endometriosis
Authors: Zubrzycka Anna , Migdalska-Sęk Monika , Jędrzejczyk Sławomir , Brzeziańska-Lasota Ewa
Published: April 2023

Alterations in the expression of numerous genes and the miRNAs that are recognized as their regulators in the endometrial cells of women with endometriosis may disrupt the intracellular signaling pathways associated with epithelial–mesenchymal transition (EMT). So far, the functional role of BMP7 in endometrial physiology has been confirmed, especially in the context of fertility, but the role of the activation of a specific mechanism operating through the BMP–SMAD–CDH1 axis in the formation of endometrial lesions remains unexplored. The aim of this study was to evaluate the expression profile of miR-542-3p and the EMT markers (BMP7, SMAD4, CDH1) in matched eutopic endometrium (EUE) and ectopic endometrium (ECE) samples from women with endometriosis in relation to healthy women. The levels of expression of the studied genes and miRNA in peripheral blood mononuclear cells (PBMCs) obtained from women diagnosed with endometriosis and those without the disease were also evaluated. Fifty-four patients (n = 54: with endometriosis—n = 29 and without endometriosis—n = 25) were included in the study. A comparative analysis of the relative mean expression values (RQ) of the studied mRNA and miRNA assessed by RT-qPCR demonstrated downregulation of BMP7, SMAD4, and CDH1 expression in ectopic lesions and upregulation in the eutopic endometrium compared with the control group. In the eutopic tissue of women with endometriosis, miR-542-3p expression was similar to that of the control but significantly lower than in endometrial lesions. We also confirmed a trend towards a negative correlation between miR-542-3p and BMP7 in ectopic tissue, and in PBMC, a significant negative correlation of miR-542-3p with further BMP signaling genes, i.e., SMAD4 and CDH1, was observed. These results indicate that the miRNA selected by us may be a potential negative regulator of BMP7-SMAD4-CDH1 signaling associated with EMT. The different patterns of BMP7, SMAD4, and CDH1 gene expression in ECE, EUE, and the control endometrium observed by us suggests the loss of the endometrial epithelium phenotype in women with endometriosis and demonstrates their involvement in the pathogenesis and pathomechanism of this disease.
Pegylated Gold Nanoparticles Conjugated with siRNA: Complexes Formation and Cytotoxicity
Authors: Okła Elżbieta , Białecki Piotr , Kędzierska Marta , Pędziwiatr-Werbicka Elżbieta , Miłowska Katarzyna , Takvor Samuel , Gómez Rafael , de la Mata Francisco Javier , Bryszewska Maria , Ionov Maksim
Published: April 2023

Drug delivery systems such as dendrimers, liposomes, polymers or gold/silver nanoparticles could be used to advance modern medicine. One significant pharmacological problem is crossing biological barriers by commonly used drugs, e.g., in the treatment of neurodegenerative diseases, which have a problem of the blood-brain barrier (BBB) restricting drug delivery. Numerous studies have been conducted to find appropriate drug carriers that are safe, biocompatible and efficient. In this work, we evaluate pegylated gold nanoparticles AuNP14a and AuNP14b after their conjugation with therapeutic siRNA directed against APOE4. This genetic risk factor remains the strongest predictor for late-onset Alzheimer’s disease. The study aimed to assess the biophysical properties of AuNPs/siAPOE complexes and to check their biological safety on healthy cells using human brain endothelial cells (HBEC-5i). Techniques such as fluorescence polarization, circular dichroism, dynamic light scattering, ζ-potential measurements and gel retardation assay showed that AuNPs form stable complexes with siRNA. Subsequently, cytotoxicity assays proved the biological safety of formed conjugates. Obtained results enabled us to find effective concentrations of AuNPs when complexes are formed and non-toxic for healthy cells. One of the studied nanoparticles, AuNP14b complexed with siRNA, displayed lower cytotoxicity (MTT assay, cells viability −74.8 ± 3.1%) than free nanoparticles (44.7 ± 3.6%). This may be promising for further investigations in nucleic acid delivery and could have practical use in treating neurodegenerative diseases.
Intrinsic Permeation and Anti-Inflammatory Evaluation of Curcumin, Bisdemethoxycurcumin and Bisdemethylcurcumin by a Validated HPLC-UV Method
Authors: Alvarado Helen-Lissette , Limón David , Calpena-Campmany Ana-Cristina , Mallandrich Mireia , Rodríguez-Cid Laura , Aliaga-Alcalde Núria , González-Campo Arántzazu , Pérez-García Lluïsa
Published: April 2023

Curcumin shows anti-inflammatory activity, and it has been widely investigated for neurodegenerative diseases, adjuvant treatment in AIDS and antitumor activity against different tumors, among other activities. The goal of this work was to evaluate the capacity of curcumin and its derivatives (bisdemethoxycurcumin and bisdemethylcurcumin) in preventing the irritant effects of topically applied xylol and to assess the intrinsic capacity of curcuminoids in permeating human skin by ex vivo permeation tests. Its secondary goal was to validate an HPLC method to simultaneously determine the curcuminoids in the samples from the ex vivo permeation studies and drug extraction from the skin. Curcuminoid quantification was performed using an RP-C18 column, at isocratic conditions of elution and a detection wavelength of 265 nm. The method was specific with a suitable peak resolution, as well as linear, precise, and accurate in the range of 0.195–3.125 μg/mL for the three curcuminoids. Bisdemethylcurcumin showed the greatest permeation through the human skin, and it was the curcuminoid that was most retained within the human skin. The anti-inflammatory activity of the curcuminoids was evaluated in vivo using a xylol-induced inflammation model in rats. Histological studies were performed to observe any changes in morphology at the microscopic level, and these three curcuminoids were found to be respectful within the skin structure. These results show that these three curcuminoids are suitable for anti-inflammatory formulations for dermal applications, and they can be properly quantified using HPLC-UV.
Exploring the Pathological Effect of Aβ42 Oligomers on Neural Networks in Primary Cortical Neuron Culture
Authors: Ganbat Dulguun , Jeon Jae Kyong , Lee Yunjong , Kim Sang Seong
Published: April 2023

Alzheimer’s disease (AD) is a multifactorial disorder that affects cognitive functioning, behavior, and neuronal properties. The neuronal dysfunction is primarily responsible for cognitive decline in AD patients, with many causal factors including plaque accumulation of Aβ42. Neural hyperactivity induced by Aβ42 deposition causes abnormalities in neural networks, leading to alterations in synaptic activity and interneuron dysfunction. Even though neuroimaging techniques elucidated the underlying mechanism of neural connectivity, precise understanding at the cellular level is still elusive. Previous multielectrode array studies have examined the neuronal network modulation in in vitro cultures revealing the relevance of ion channels and the chemical modulators in the presence of Aβ42. In this study, we investigated neuronal connectivity and dynamic changes using a high-density multielectrode array, particularly looking at network-wide parameter changes over time. By comparing the neuronal network between normal and Aβ42treated neuronal cultures, it was possible to discover the direct pathological effect of the Aβ42 oligomer altering the network characteristics. The detrimental effects of the Aβ42 oligomer included not only a decline in spike activation but also a qualitative impairment in neural connectivity as well as a disorientation of dispersibility. As a result, this will improve our understanding of how neural networks are modified during AD progression.
STEAP1 Knockdown Decreases the Sensitivity of Prostate Cancer Cells to Paclitaxel, Docetaxel and Cabazitaxel
Authors: Rocha Sandra M. , Nascimento Daniel , Coelho Rafaella S. , Cardoso Ana Margarida , Passarinha Luís A. , Socorro Sílvia , Maia Cláudio J.
Published: April 2023

The Six Transmembrane Epithelial Antigen of the Prostate 1 (STEAP1) protein has been indicated as an overexpressed oncoprotein in prostate cancer (PCa), associated with tumor progression and aggressiveness. Taxane-based antineoplastic drugs such as paclitaxel, docetaxel, or cabazitaxel, have been investigated in PCa treatment, namely for the development of combined therapies with the improvement of therapeutic effectiveness. This study aimed to evaluate the expression of STEAP1 in response to taxane-based drugs and assess whether the sensitivity of PCa cells to treatment with paclitaxel, docetaxel, or cabazitaxel may change when the STEAP1 gene is silenced. Thus, wild-type and STEAP1 knockdown LNCaP and C4-2B cells were exposed to paclitaxel, docetaxel or cabazitaxel, and STEAP1 expression, cell viability, and survival pathways were evaluated. The results obtained showed that STEAP1 knockdown or taxane-based drugs treatment significantly reduced the viability and survival of PCa cells. Relatively to the expression of proliferation markers and apoptosis regulators, LNCaP cells showed a reduced proliferation, whereas apoptosis was increased. However, the effect of paclitaxel, docetaxel, or cabazitaxel treatment was reversed when combined with STEAP1 knockdown. Besides, these chemotherapeutic drugs may stimulate the cell growth of PCa cells knocked down for STEAP1. In conclusion, this study demonstrated that STEAP1 expression levels might influence the response of PCa cells to chemotherapeutics drugs, indicating that the use of paclitaxel, docetaxel, or cabazitaxel may lead to harmful effects in PCa cells with decreased expression of STEAP1.
Amelioration of Nicotine-Induced Conditioned Place Preference Behaviors in Mice by an FABP3 Inhibitor
Authors: Jia Wenbin , Kawahata Ichiro , Cheng An , Sasaki Takuya , Sasaoka Toshikuni , Fukunaga Kohji
Published: April 2023

We previously demonstrated that fatty acid-binding protein 3 null (FABP3−/−) mice exhibit resistance to nicotine-induced conditioned place preference (CPP). Here, we confirm that the FABP3 inhibitor, MF1 ((4-(2-(1-(2-chlorophenyl)-5-phenyl-1H-pyrazol-3-yl)phenoxy) butanoic acid), successfully reduces nicotine-induced CPP scores in mice. MF1 (0.3 or 1.0 mg/kg) was orally administered 30 min before nicotine, and CPP scores were assessed in the conditioning, withdrawal, and relapse phases. MF1 treatment decreased CPP scores in a dose-dependent manner. Failure of CPP induction by MF1 (1.0 mg/kg, p.o.) was associated with the inhibition of both CaMKII and ERK activation in the nucleus accumbens (NAc) and hippocampal CA1 regions. MF1 treatment reduced nicotine-induced increases in phosphorylated CaMKII and cAMP-response element-binding protein (CREB)-positive cells. Importantly, the increase in dopamine D2 receptor (D2R) levels following chronic nicotine exposure was inhibited by MF1 treatment. Moreover, the quinpirole (QNP)-induced increase in the level of CaMKII and ERK phosphorylation was significantly inhibited by MF1 treatment of cultured NAc slices from wild type (WT) mice; however, QNP treatment had no effect on CaMKII and ERK phosphorylation levels in the NAc of D2R null mice. Taken together, these results show that MF1 treatment suppressed D2R/FABP3 signaling, thereby preventing nicotine-induced CPP induction. Hence, MF1 can be used as a novel drug to block addiction to nicotine and other drugs by inhibiting the dopaminergic system.
Unraveling the Complex Interplay between Alpha-Synuclein and Epigenetic Modification
Authors: Sugeno Naoto , Hasegawa Takafumi
Published: April 2023

Alpha-synuclein (αS) is a small, presynaptic neuronal protein encoded by the SNCA gene. Point mutations and gene multiplication of SNCA cause rare familial forms of Parkinson’s disease (PD). Misfolded αS is cytotoxic and is a component of Lewy bodies, which are a pathological hallmark of PD. Because SNCA multiplication is sufficient to cause full-blown PD, gene dosage likely has a strong impact on pathogenesis. In sporadic PD, increased SNCA expression resulting from a minor genetic background and various environmental factors may contribute to pathogenesis in a complementary manner. With respect to genetic background, several risk loci neighboring the SNCA gene have been identified, and epigenetic alterations, such as CpG methylation and regulatory histone marks, are considered important factors. These alterations synergistically upregulate αS expression and some post-translational modifications of αS facilitate its translocation to the nucleus. Nuclear αS interacts with DNA, histones, and their modifiers to alter epigenetic status; thereby, influencing the stability of neuronal function. Epigenetic changes do not affect the gene itself but can provide an appropriate transcriptional response for neuronal survival through DNA methylation or histone modifications. As a new approach, publicly available RNA sequencing datasets from human midbrain-like organoids may be used to compare transcriptional responses through epigenetic alterations. This informatic approach combined with the vast amount of transcriptomics data will lead to the discovery of novel pathways for the development of disease-modifying therapies for PD.
Salinity-Triggered Responses in Plant Apical Meristems for Developmental Plasticity
Authors: Yang Soeun , Lee Horim
Published: April 2023

Salt stress severely affects plant growth and development. The plant growth and development of a sessile organism are continuously regulated and reformed in response to surrounding environmental stress stimuli, including salinity. In plants, postembryonic development is derived mainly from primary apical meristems of shoots and roots. Therefore, to understand plant tolerance and adaptation under salt stress conditions, it is essential to determine the stress response mechanisms related to growth and development based on the primary apical meristems. This paper reports that the biological roles of microRNAs, redox status, reactive oxygen species (ROS), nitric oxide (NO), and phytohormones, such as auxin and cytokinin, are important for salt tolerance, and are associated with growth and development in apical meristems. Moreover, the mutual relationship between the salt stress response and signaling associated with stem cell homeostasis in meristems is also considered.
Sequence Characteristics and Expression Analysis of the Gene Encoding Sedoheptulose-1,7-Bisphosphatase, an Important Calvin Cycle Enzyme in Upland Cotton (Gossypium hirsutum L.)
Authors: Chao Maoni , Hu Genhai , Dong Jie , Chen Yu , Fu Yuanzhi , Zhang Jinbao , Wang Qinglian
Published: April 2023

Sedoheptulose-1,7-bisphosphatase (SBPase, EC 3.1.3.37) is a key enzyme in the plant Calvin cycle and one of the main rate-limiting enzymes in the plant photosynthesis pathway. Many studies have demonstrated that the SBPase gene plays an important role in plant photosynthetic efficiency, yield, and stress responses; however, few studies have been conducted on the function and expression of the GhSBPase gene in upland cotton. In this study, our results showed that the coding sequence (CDS) of GhSBPase gene was 1182 bp, encoding a protein with 393 amino acids. The GhSBPase protein had adenosine monophosphate (AMP) binding site and a FIG (FBPase/IMPase/glpX) domain, and had six Cys residues and a CGGT(A/Q)C motif that were involved in redox regulation in plants. Evolutionarily, the GhSBPase protein clustered into the dicotyledon subgroup and was most closely related to the tomato SlSBPase protein. Western-blot analysis further indicated that the GhSBPase gene was indeed the gene encoding the SBPase protein in upland cotton. The GhSBPase protein was localized in chloroplast, which was consistent with its function as a key enzyme in photosynthesis. The GhSBPase gene was specifically highly expressed in leaves, and its expression level was significantly lower in a yellow-green leaf mutant than in the wild type. Moreover, the GhSBPase expression was in response to drought, salt, high- and low-temperature stress, and exhibits different expression patterns. The GhSBPase promoter had the cis-acting elements in response to abiotic stress, phytohormone, and light. In addition, the GhSBPase expression was positively correlated with the chlorophyll fluorescence parameters, suggesting that changes in the expression of the GhSBPase had potential applicability in breeding for enhanced cotton photosynthetic efficiency. These results will help to understand the function of the GhSBPase gene in photosynthesis and the adaptability of plants to external stress and provide important gene information for the high-yield breeding of crops in the future.
VDAC as a Cellular Hub: Docking Molecules and Interactions
Authors: Kmita Hanna , Messina Angela Anna , De Pinto Vito
Published: April 2023

The voltage-dependent anion channel (VDAC) is the primary regulating pathway of water-soluble metabolites and ions across the mitochondrial outer membrane [...]
Src-FAK Signaling Mediates Interleukin 6-Induced HCT116 Colorectal Cancer Epithelial–Mesenchymal Transition
Authors: Huang Yu-Han , Chen Han-Kun , Hsu Ya-Fen , Chen Hsiu-Chen , Chuang Chin-Hui , Huang Shiu-Wen , Hsu Ming-Jen
Published: April 2023

Colorectal cancer is one of the most prevalent and lethal malignancies, affecting approximately 900,000 individuals each year worldwide. Patients with colorectal cancer are found with elevated serum interleukin-6 (IL-6), which is associated with advanced tumor grades and is related to their poor survival outcomes. Although IL-6 is recognized as a potent inducer of colorectal cancer progression, the detail mechanisms underlying IL-6-induced colorectal cancer epithelial–mesenchymal transition (EMT), one of the major process of tumor metastasis, remain unclear. In the present study, we investigated the regulatory role of IL-6 signaling in colorectal cancer EMT using HCT116 human colorectal cancer cells. We noted that the expression of epithelial marker E-cadherin was reduced in HCT116 cells exposed to IL-6, along with the increase in a set of mesenchymal cell markers including vimentin and α-smooth muscle actin (α-SMA), as well as EMT transcription regulators—twist, snail and slug. The changes of EMT phenotype were related to the activation of Src, FAK, ERK1/2, p38 mitogen-activated protein kinase (p38MAPK), as well as transcription factors STAT3, κB and C/EBPβ. IL-6 treatment has promoted the recruitment of STAT3, κB and C/EBPβ toward the Twist promoter region. Furthermore, the Src-FAK signaling blockade resulted in the decline of IL-6 induced activation of ERK1/2, p38MAPK, κB, C/EBPβ and STAT3, as well as the decreasing mesenchymal state of HCT116 cells. These results suggested that IL-6 activates the Src-FAK-ERK/p38MAPK signaling cascade to cause the EMT of colorectal cancer cells. Pharmacological approaches targeting Src-FAK signaling may provide potential therapeutic strategies for rescuing colorectal cancer progression.
The Roles of Innate Lymphoid Cells in the Gastric Mucosal Immunology and Oncogenesis of Gastric Cancer
Authors: Jiao Yuhao , Yan Zhiyu , Yang Aiming
Published: April 2023

Innate lymphoid cells (ILCs) are a group of innate immune cells that have garnered considerable attention due to their critical roles in regulating immunity and tissue homeostasis. They are particularly abundant in the gastrointestinal tract, where they have been shown to interact with commensal bacteria, pathogens, and other components of the local microenvironment to influence host immune responses to infection and oncogenesis. Their tissue-residency properties enable gastric ILCs a localized and rapid response to alert and stress, which indicates their key potential in regulating immunosurveillance. In this review, we discuss the current understanding of the role of ILCs in the gastric mucosa, with a focus on their interactions with the gastric microbiota and Helicobacter pylori and their contributions to tissue homeostasis and inflammation. We also highlight recent findings on the involvement of ILCs in the pathogenesis of gastric cancer and the implications of targeting ILCs as a therapeutic approach. Overall, this review provides an overview of the diverse functions of ILCs in gastric mucosa and highlights their potential as targets for future therapies for gastric cancer.
Dietary Evodiamine Inhibits Atherosclerosis-Associated Changes in Vascular Smooth Muscle Cells
Authors: Zha Yiwen , Yang Yongqi , Zhou Yue , Ye Bingqian , Li Hongliang , Liang Jingyan
Published: April 2023

Evodia rutaecarpa (Juss.) Benth is a traditional Chinese medicine. The active ingredient, evodiamine, is a quinolone alkaloid and is found in Evodiae fructus. We investigated the effect of evodiamine on atherosclerosis using LDLR−/− mice fed on a high-fat diet and ox-LDL-induced MOVAS cell lines to construct mouse models and cell-line models. We report a significant reduction in atherosclerotic plaque formation in mice exposed to evodiamine. Our mechanistic studies have revealled that evodiamine can regulate the proliferation, migration, and inflammatory response of and oxidative stress in vascular smooth muscle cells by inhibiting the activation of the PI3K/Akt axis, thus inhibiting the occurrence and development of atherosclerosis. In conclusion, our findings reveal a role for evodiamine in the regulation of vascular smooth muscle cells in atherosclerosis, highlighting a potential future role for the compound as an anti-atherosclerotic agent.
MYB Transcription Factor OsC1PLSr Involves the Regulation of Purple Leaf Sheath in Rice
Authors: Zou Ting , Wang Xinyi , Sun Tong , Rong Huazhen , Wu Linxuan , Deng Jing , Guo Tao , Wang Hui , Wang Jiafeng , Huang Ming
Published: April 2023

Although several regulators associated with purple traits in rice have been identified, the genetic basis of the purple sheath remains unclear. In the present study, F2-1 and F2-2 populations were constructed using purple sheath (H93S) and green sheath (R1173 and YHSM), respectively. In order to identify QTL loci in purple sheaths, BSA analyses were performed on the two F2 populations. A crucial QTL for purple sheath was identified, tentatively named qPLSr6, and was located in the 4.61 Mb to 6.03 Mb region of chromosome 6. Combined with expression pattern analysis of candidate genes, LOC_Os06g10350 (OsC1PLSr) was suggested as a candidate gene. The homozygous mutant KO-1 and KO-2 created through CRISPR/Cas9 editing, lost their purple leaf sheath. The RT-PCR revealed that OsC1PLSr, anthocyanin synthase (ANS), diflavonol-4-reductase (DFR), flavanone-3-hydroxylase (F3H), and flavanone-3′-hydroxylase (F3′H) expression levels were dramatically down-regulated in the mutants. The yeast report system indicated that the 145–272 aa region at the C-terminal of OsC1PLSr is a positive transcriptional activation domain. The results indicated that OsC1PLSr synthesized anthocyanins by regulating the expression of ANS, DFR, F3H, and F3′H. This study provides new insights into the genetic basis of the purple sheath.
Role of microRNAs in Congenital Diaphragmatic Hernia-Associated Pulmonary Hypertension
Authors: Pugnaloni Flaminia , Capolupo Irma , Patel Neil , Giliberti Paola , Dotta Andrea , Bagolan Pietro , Kipfmueller Florian
Published: April 2023

Epigenetic regulators such as microRNAs (miRNAs) have a key role in modulating several gene expression pathways and have a role both in lung development and function. One of the main pathogenetic determinants in patients with congenital diaphragmatic hernia (CDH) is pulmonary hypertension (PH), which is directly related to smaller lung size and pulmonary microarchitecture alterations. The aim of this review is to highlight the importance of miRNAs in CDH-related PH and to summarize the results covering this topic in animal and human CDH studies. The focus on epigenetic modulators of CDH-PH offers the opportunity to develop innovative diagnostic tools and novel treatment modalities, and provides a great potential to increase researchers’ understanding of the pathophysiology of CDH.
Syndecan-3 Coregulates Milk Fat Metabolism and Inflammatory Reactions in Bovine Mammary Epithelial Cells through AMPK/SIRT1 Signaling Pathway
Authors: Fan Jing , Zhao Zhihui , Wu Haochen , Fang Xibi , Miao Fengshuai , Chen Xuanxu , Jiang Xinyi , Li Jing , Jiang Ping , Yu Haibin
Published: April 2023

Transcriptome sequencing showed that syndecan-3 (SDC3) was differentially expressed in high-fat and low-fat mammary epithelial cells of Chinese Holstein cows. Previous studies found that SDC3 plays an important role in inflammatory diseases and virus infection. However, those studies did not confirm whether or not the functional gene SDC3, which plays an important role in regulating milk fat metabolism, has an effect on susceptibility to breast tissue diseases. Therefore, we studied the effects of SDC3 on milk lipid metabolism and inflammation in bovine mammary epithelial cells (BMECs) and further explored the common regulatory pathway of SDC3 in both. The overexpression of SDC3 increased the contents of triglycerides and cholesterol, reduced the content of non-esterified fatty acids, inhibited the expression of inflammatory factors (IL-6, IL-1β, TNF-α and COX-2), and reduced the production of ROS in BMECs. However, silenced SDC3 had the opposite effect. Further exploring the mechanisms of SDC3, we found that SDC3 upregulated the expression of peroxisome proliferator-activated receptor gamma (PPARG) through the AMPK/SIRT1 signal pathway to promote milk fat synthesis. It also regulated the activation of the NF-κB pathway through the AMPK/SIRT1 signal pathway, reducing the expression of inflammatory factors and ROS production, thus inhibiting the inflammatory response of BMECs. Nuclear factor kappa B subunit 1 (NF-κB p50) was an important target of SDC3 in this process. To sum up, our results showed that SDC3 coregulated milk fat metabolism and inflammation through the AMPK/SIRT1 signaling pathway. This study laid a foundation for the comprehensive evaluation of breeding value based on multi-effect functional genes in dairy cow molecular breeding.
The Tetrel Bond and Tetrel Halide Perovskite Semiconductors
Authors: Varadwaj Pradeep R. , Varadwaj Arpita , Marques Helder M. , Yamashita Koichi
Published: April 2023

The ion pairs [Cs+•TtX3−] (Tt = Pb, Sn, Ge; X = I, Br, Cl) are the building blocks of all-inorganic cesium tetrel halide perovskites in 3D, CsTtX3, that are widely regarded as blockbuster materials for optoelectronic applications such as in solar cells. The 3D structures consist of an anionic inorganic tetrel halide framework stabilized by the cesium cations (Cs+). We use computational methods to show that the geometrical connectivity between the inorganic monoanions, [TtX3−]∞, that leads to the formation of the TtX64− octahedra and the 3D inorganic perovskite architecture is the result of the joint effect of polarization and coulombic forces driven by alkali and tetrel bonds. Depending on the nature and temperature phase of these perovskite systems, the Tt···X tetrel bonds are either indistinguishable or somehow distinguishable from Tt–X coordinate bonds. The calculation of the potential on the electrostatic surface of the Tt atom in molecular [Cs+•TtX3−] provides physical insight into why the negative anions [TtX3−] attract each other when in close proximity, leading to the formation of the CsTtX3 tetrel halide perovskites in the solid state. The inter-molecular (and inter-ionic) geometries, binding energies, and charge density-based topological properties of sixteen [Cs+•TtX3−] ion pairs, as well as some selected oligomers [Cs+•PbI3−]n (n = 2, 3, 4), are discussed.
Molecular Idiosyncratic Toxicology of Drugs in the Human Liver Compared with Animals: Basic Considerations
Authors: Teschke Rolf
Published: April 2023

Drug induced liver injury (DILI) occurs in patients exposed to drugs at recommended doses that leads to idiosyncratic DILI and provides an excellent human model with well described clinical features, liver injury pattern, and diagnostic criteria, based on patients assessed for causality using RUCAM (Roussel Uclaf Causality Assessment Method) as original method of 1993 or its update of 2016. Overall, 81,856 RUCAM based DILI cases have been published until mid of 2020, allowing now for an analysis of mechanistic issues of the disease. From selected DILI cases with verified diagnosis by using RUCAM, direct evidence was provided for the involvement of the innate and adapted immune system as well as genetic HLA (Human Leucocyte Antigen) genotypes. Direct evidence for a role of hepatic immune systems was substantiated by (1) the detection of anti-CYP (Cytochrome P450) isoforms in the plasma of affected patients, in line with the observation that 65% of the drugs most implicated in DILI are metabolized by a range of CYP isoforms, (2) the DIAIH (drug induced autoimmune hepatitis), a subgroup of idiosyncratic DILI, which is characterized by high RUCAM causality gradings and the detection of plasma antibodies such as positive serum anti-nuclear antibodies (ANA) and anti-smooth muscle antibodies (ASMA), rarely also anti-mitochondrial antibodies (AMA), (3) the effective treatment with glucocorticoids in part of an unselected RUCAM based DILI group, and (4) its rare association with the immune-triggered Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) caused by a small group of drugs. Direct evidence of a genetic basis of idiosyncratic DILI was shown by the association of several HLA genotypes for DILI caused by selected drugs. Finally, animal models of idiosyncratic DILI mimicking human immune and genetic features are not available and further search likely will be unsuccessful. In essence and based on cases of DILI with verified diagnosis using RUCAM for causality evaluation, there is now substantial direct evidence that immune mechanisms and genetics can account for idiosyncratic DILI by many but not all implicated drugs, which may help understand the mechanistic background of the disease and contribute to new approaches of therapy and prevention.
The Melanocortin System: A Promising Target for the Development of New Antidepressant Drugs
Authors: Markov Dmitrii D. , Dolotov Oleg V. , Grivennikov Igor A.
Published: April 2023

Major depression is one of the most prevalent mental disorders, causing significant human suffering and socioeconomic loss. Since conventional antidepressants are not sufficiently effective, there is an urgent need to develop new antidepressant medications. Despite marked advances in the neurobiology of depression, the etiology and pathophysiology of this disease remain poorly understood. Classical and newer hypotheses of depression suggest that an imbalance of brain monoamines, dysregulation of the hypothalamic-pituitary-adrenal axis (HPAA) and immune system, or impaired hippocampal neurogenesis and neurotrophic factors pathways are cause of depression. It is assumed that conventional antidepressants improve these closely related disturbances. The purpose of this review was to discuss the possibility of affecting these disturbances by targeting the melanocortin system, which includes adrenocorticotropic hormone-activated receptors and their peptide ligands (melanocortins). The melanocortin system is involved in the regulation of various processes in the brain and periphery. Melanocortins, including peripherally administered non-corticotropic agonists, regulate HPAA activity, exhibit anti-inflammatory effects, stimulate the levels of neurotrophic factors, and enhance hippocampal neurogenesis and neurotransmission. Therefore, endogenous melanocortins and their analogs are able to complexly affect the functioning of those body’s systems that are closely related to depression and the effects of antidepressants, thereby demonstrating a promising antidepressant potential.
Pathophysiological Roles of Transient Receptor Potential (Trp) Channels and Zinc Toxicity in Brain Disease
Authors: Hong Dae Ki , Kho A Ra , Lee Song Hee , Kang Beom Seok , Park Min Kyu , Choi Bo Young , Suh Sang Won
Published: April 2023

Maintaining the correct ionic gradient from extracellular to intracellular space via several membrane-bound transporters is critical for maintaining overall cellular homeostasis. One of these transporters is the transient receptor potential (TRP) channel family that consists of six putative transmembrane segments systemically expressed in mammalian tissues. Upon the activation of TRP channels by brain disease, several cations are translocated through TRP channels. Brain disease, especially ischemic stroke, epilepsy, and traumatic brain injury, triggers the dysregulation of ionic gradients and promotes the excessive release of neuro-transmitters and zinc. The divalent metal cation zinc is highly distributed in the brain and is specifically located in the pre-synaptic vesicles as free ions, usually existing in cytoplasm bound with metallothionein. Although adequate zinc is essential for regulating diverse physiological functions, the brain-disease-induced excessive release and translocation of zinc causes cell damage, including oxidative stress, apoptotic cascades, and disturbances in energy metabolism. Therefore, the regulation of zinc homeostasis following brain disease is critical for the prevention of brain damage. In this review, we summarize recent experimental research findings regarding how TRP channels (mainly TRPC and TRPM) and zinc are regulated in animal brain-disease models of global cerebral ischemia, epilepsy, and traumatic brain injury. The blockade of zinc translocation via the inhibition of TRPC and TRPM channels using known channel antagonists, was shown to be neuroprotective in brain disease. The regulation of both zinc and TRP channels may serve as targets for treating and preventing neuronal death.
Botryococcus terribilis Ethanol Extract Exerts Anti-inflammatory Effects on Murine RAW264 Cells
Authors: Takahashi Shinya , Ferdousi Farhana , Yamamoto Seri , Hirano Atsushi , Nukaga Sachiko , Nozaki Hiroyuki , Isoda Hiroko
Published: April 2023

The present study aimed to evaluate the effects of Botryococcus terribilis ethanol extract (BTEE) on lipopolysaccharide (LPS)-induced inflammation in RAW264 cells. BTEE significantly attenuated LPS-induced nitric oxide production and inflammatory cytokines release, including Ccl2, Cox2, and Il6. On the other hand, several anti-inflammatory mediators, such as Pgc1β and Socs1, were increased in BTEE-treated cells. Further, we performed an untargeted whole-genome microarray analysis to explore the anti-inflammatory molecular mechanism of BTEE. Enrichment analysis showed BTEE significantly downregulated ‘response to stimulus’, ‘locomotion’, and ‘immune system response’ and upregulated ‘cell cycle’ gene ontologies in both 6- and 17-h post-LPS stimulation conditions. Pathway analysis revealed BTEE could downregulate the expressions of chemokines of the CC and CXC subfamily, and cytokines of the TNF family, TGFβ family, IL1-like, and class I helical. PPI analysis showed AXL receptor tyrosine kinase (Axl), a receptor tyrosine kinase from the TAM family, and its upstream transcription factors were downregulated in both conditions. Node neighborhood analysis showed several Axl coexpressed genes were also downregulated. Further, kinase enrichment and chemical perturbation analyses supported Axl inhibition in BTEE-treated conditions. Altogether, these findings suggest anti-inflammatory effects of BTEE that are mediated via the suppression of pro-inflammatory cytokines and predict its potential as an Axl inhibitor.
Past, Present and Future of the Section “Molecular Toxicology”
Authors: Haenen Guido R. M. M.
Published: April 2023

‘Forever’ chemicals that unintendedly in the long run pollute the environment, climate change, COVID; life continuously faces all sorts of unforeseen challenges that are an inevitable side product of ‘progress’ [...]
Exploring the Association between Low-Density Lipoprotein Subfractions and Major Adverse Cardiovascular Outcomes—A Comprehensive Review
Authors: Stanciulescu Laura Adina , Scafa-Udriste Alexandru , Dorobantu Maria
Published: April 2023

Cardiovascular disease (CVD) impacts hundreds of millions of people each year and is the main cause of death worldwide, with atherosclerosis being its most frequent form of manifestation. Low-density lipoproteins (LDL) have already been established as a significant cardiovascular risk factor, but more recent studies have shown that small, dense LDLs are the ones more frequently associated with a higher overall risk for developing atherosclerotic cardiovascular disease. Ever since atherogenic phenotypes were defined for the first time, LDL subfractions have been continuously analyzed in order to identify those with a higher atherogenic profile that could further become not only high-accuracy, effective prognostic biomarkers, but also treatment targets for novel lipid-lowering molecules. This review sets out to comprehensively evaluate the association between various LDL-subfractions and the risk of further developing major adverse cardiovascular events, by assessing both genetical and clinical features and focusing on their physiopathological characteristics, chemical composition, and global ability to predict long-term cardiovascular risk within the general population. Further research is required in order to establish the most beneficial range of LDL-C levels for both primary and secondary prevention, as well as to implement LDL subfraction testing as a routine protocol, separately from the general assessment of the other traditional cardiovascular risk factors.
Influence of Sintering Additives on Modified (Ba,Sr)(Sn,Ti)O3 for Electrocaloric Application
Authors: Li Zhenglyu , Molin Christian , Gebhardt Sylvia E.
Published: April 2023

This paper reports on the influence of sintering additives CuO and MgO on the recently developed lead-free electrocaloric (EC) material Ba0.82Sr0.18Sn0.065Ti0.935O3 (BSSnT-18-6.5). Details on the sintering behavior and the resulting microstructure of bulk ceramic samples prepared through solid-state synthesis and their dielectric, ferroelectric, and electrocaloric properties are presented. On the one hand, the addition of CuO (xCuO = 2%) significantly reduced the sintering temperature from 1400 °C to 1150 °C. On the other hand, the addition of MgO (xMgO = 1%) dramatically reduced the average grain size from 40 µm to 0.4 µm, leading to an increase in dielectric breakdown strength from 4.4 V µm−1 to 7.7 V µm−1. Thus, BSSnT-18-6.5 with the addition of MgO to bulk ceramic samples could achieve maximum EC temperature changes (|ΔTEC|) of 0.27 K around 30 °C with almost no aberration within a broad temperature range from 5 °C to 50 °C under an applied electric field change of 5 V µm−1. The results show the potential of this material for the fabrication of multilayer ceramic (MLC) components for future electrocaloric applications.
Complexes of 2-Amino-3-methylpyridine and 2-Amino-4-methylbenzothiazole with Ag(I) and Cu(II): Structure and Biological Applications
Authors: Hanif Muhammad , Noor Awal , Muhammad Mian , Ullah Farhat , Tahir Muhammad Nawaz , Khan Gul Shahzada , Khan Ezzat
Published: April 2023

Coordination complexes (1–4) of 2-amino-4-methylbenzothiazole and 2-amino-3-methylpyridine with Cu(CH3COO)2 and AgNO3 were prepared and characterized by UV/Vis and FT-IR spectroscopy. The molecular structure for single crystals of silver complexes (2 and 4) were determined by X-ray diffraction. The coordination complex (2) is monoclinic with space group P21/c, wherein two ligands are coordinated to a metal ion, affording distorted trigonal geometry around the central Ag metal ion. The efficient nucleophilic center, i.e., the endocyclic nitrogen of the organic ligand, binds to the silver metal. Ligands are coordinated to adopt cis arrangement, predominantly due to steric reasons. The O(2) and O(3) atoms of the NO3− group further play an important role in such type of ligand arrangement by hydrogen bonding with the NH2 group of ligands. Complex (4) is orthorhombic, P212121, comprising two molecules of 2-amino-3-methylpyridine as ligand coordinated with the metal ion, affording a polymeric structure. The coordination behavior of the ligand is identical to that in complex 2, wherein ring nitrogen is coordinated to the metal center and bridged to another metal ion through an NH2 group. The resulting product is polymeric in nature with the Ag metal in the backbone and ligand as the bridge. Compounds (2–4) were found to be luminescent, while 1 did not show such activity. All compounds were screened for their preliminary biological activities such as antibacterial, antioxidant and enzyme inhibition. Compounds exhibited moderate activity in these tests.
Economic Benefits from Managing Coffee Berry Borer (Hypothenemus hampei) in Hawaii
Authors: Lee Donna , Johnson Melissa , Aristizábal Luis , Shriner Suzanne , Chan Catherine , Miyasaka Susan , Wall Marisa
Published: April 2023

Coffee berry borer (CBB) is considered the most damaging insect pest of coffee worldwide. CBB was first detected on Hawai‘i Island in 2010, and quickly spread throughout the state’s coffee-growing regions. With the introduction of this pest, Hawaii’s small yet economically important coffee industry was changed forever with growers facing significantly higher production and labor costs, as well as decreased yield and coffee quality. We assessed the economic benefits of managing CBB based on three strategies that emerged in Hawaii over the last decade: (1) the use of the entomopathogenic fungus Beauveria bassiana alone, (2) early integrated pest management (IPM), which combined monitoring and sanitation with spraying B. bassiana, and (3) research-based IPM, which focused on CBB biology in Hawaii, optimization of monitoring, B. bassiana applications, and cultural controls. From 2011 to 2021, the economic benefits from managing CBB were USD 52 million using B. bassiana alone, USD 69 million from early IPM, and USD 130 million from research-based IPM, for a total of USD 251 million from all management. Our findings suggest that all types of management provide economic benefits to Hawaii growers, but management strategies based on Hawaii-specific research have provided the greatest gains in coffee yield, price, and revenue.
The Heart–Brain Interplay in Multiple Sclerosis from Pathophysiology to Clinical Practice: A Narrative Review
Authors: Zavarella Matteo , Villatore Andrea , Rocca Maria Assunta , Peretto Giovanni , Filippi Massimo
Published: April 2023

Multiple sclerosis (MS) is a chronic neurological disorder characterized by inflammation in the central nervous system (CNS) that leads to neurodegeneration. The clinical course is highly variable, but its prevalence is rising worldwide, partly thanks to novel disease-modifying therapies. Additionally, the lifespan of people with MS is increasing, and for this reason, it is fundamental to have a multidisciplinary approach to MS. MS may be associated with cardiovascular diseases (CVD), but there is scarce attention on this issue. In particular, CNS is essential in regulating the autonomic system and heart activity. Moreover, cardiovascular risk factors show a higher prevalence in MS patients. On the other hand, conditions like Takotsubo syndrome are rare complications of MS. The parallelism between MS and myocarditis is also interesting. Finally, cardiac toxicity represents a not infrequent adverse reaction to MS drugs. This narrative review aims to provide an overview of cardiovascular complications in MS and their management to prompt further clinical and pre-clinical research on this topic.