bluuebunny/crossref_metadata_2025 huggingface dataset:
Matrikines of Sea Cucumbers: Structure, Biological Activity and Mechanisms of Action
Authors: Popov Aleksandr , Kozlovskaya Emma , Rutckova Tatyana , Styshova Olga , Makhankov Vyacheslav , Vakhrushev Aleksey , Hushpulian Dmitry , Gazaryan Irina , Son Oksana , Tekutyeva Ludmila
Published: November 2024

Matrikines (MKs), the products of enzymatic fragmentation of various extracellular matrix (ECM) proteins, regulate cellular activity by interacting with specific receptors. MKs affect cell growth, proliferation, and migration, can induce apoptosis and autophagy, and are also effectively used in biomedicine and functional nutrition. Recently, there has been great interest in the structural features and biological activity of MKs from various sources. This review summarized and analyzed the results of modern research on MKs from sea cucumbers, primarily from trepang (MKT). Particular attention is paid to the analysis of the existing knowledge on the antioxidant, anti-inflammatory and adaptogenic activities of these MKs and the possible mechanisms of their protective action.
Determinants of Photodynamic Therapy Resistance in Cancer Cells
Authors: Dąbrowska Alicja , Mastalerz Jakub , Wilczyński Bartosz , Osiecka Beata , Choromańska Anna
Published: November 2024

Photodynamic therapy (PDT) has emerged as a promising therapeutic approach owing to its non-invasive nature and minimal toxicity. PDT involves the administration of a photosensitizing agent (PS), which, upon light activation, induces a photodynamic reaction (PDR), leading to targeted cell destruction. However, developing resistance to PDT poses a significant challenge to its effectiveness. Various factors, including properties and administration of PSs, mediate this resistance. Despite the widespread use of substances like 5-aminolevulinic acid (5-ALA) and protoporphyrin, their efficacy is limited due to restricted tumor penetration and a lack of tumor targeting. To address these limitations, nano-delivery techniques and newer PSs like Aza-BODIPY and its derivatives, which offer enhanced tissue penetration, are being explored. In this paper, we provide an overview of resistance mechanisms in PDT and discuss novel methods, substances, and technologies to overcome resistance to improve clinical outcomes in tumor treatment.
Transcriptomic and Metabolomic Insights into Age-Related Changes in Lung Tissue of Yaks Under Highland Stress
Authors: Cui Changze , Chen Shaopeng , Mi Baohong , Qi Youpeng , Jiao Chenyue , Zhang Meixian , Dai Yiduo , Wang Xiangyan , Hu Jiang , Shi Bingang , Wang Jiqing , Zhao Zhidong , Liu Xiu , Zhang Xiaolan
Published: November 2024

As an indigenous species on the Tibetan Plateau, the yak is well adapted to the plateau hypoxic environment. The high-altitude hypoxia adaptation of the yak requires the adaptive reshaping of multiple tissues and organs, especially the lungs. To reveal the adaptive development of yak lungs under hypoxic stress at the tissue and molecular levels, we conducted histomorphological observations as well as transcriptomic and metabolomic studies of yak lungs at three ages (0.5, 2.5, and 4.5 years). The results showed that the lung tissue developed significantly with age. The mean alveolar area was higher (p < 0.01) in 4.5 and 2.5-year-old yaks than in 0.5-year-old yaks. The percentage of elastic fibers, micro-arterial wall thickness, and micro-arterial area showed an increasing trend (p < 0.01) from 0.5-year-old yaks to 2.5-year-old yaks and then to 4.5-year-old yaks. In addition, some critical differentially expressed genes related to angiogenesis (MYC, EPHA2, TNF), fiber formation (EREG), smooth muscle proliferation (HBEGF), erythropoiesis (SOCS3), and hypoxia response (ZFP36) were identified. Some metabolites associated with these genes were also found simultaneously. These findings provide a deeper understanding of the molecular strategies underlying this species’ extraordinary ability to survive normally in low-oxygen environments. In conclusion, the lungs of yaks undergo continuous adaptive development under hypoxic stress, and these findings are crucial for understanding the molecular mechanisms by which native species of the Tibetan Plateau survive in harsh environments.
NBS-Mediated C(sp2)-H Bond Chlorination of Enaminones: Using DCE as Chlorine Source
Authors: Peng Menglin , Xie Yunhua , Song Siyu , Zhang Zhilai , Wei Yuanzheng , Hu Huimin , Wang Yongchao , Yu Fuchao
Published: November 2024

Commercial DCE is excavated as both a “Cl” source and a solvent for the vinyl C(sp2)-H chlorination. The strategy involves a metal-free NBS-mediated C(sp2)-H chlorination of enaminones, and affords diverse, functionalized α-chlorinated enaminones with a Z-configuration. This mild and effective approach not only advances the vinyl C(sp2)-H chlorination, employing DCE as the “Cl” source, but also provides a new strategy for accessing chlorinated enaminone derivatives.
The Intricate Functional Networks of Pre-mRNA Alternative Splicing in Mammalian Spermatogenesis
Authors: Jiang Nan , Li Yi , Yin Lisha , Yuan Shuiqiao , Wang Fengli
Published: November 2024

Spermatogenesis is a highly coordinated process that requires the precise expression of specific subsets of genes in different types of germ cells, controlled both temporally and spatially. Among these genes, those that can exert an indispensable influence in spermatogenesis via participating in alternative splicing make up the overwhelming majority. mRNA alternative-splicing (AS) events can generate various isoforms with distinct functions from a single DNA sequence, based on specific AS codes. In addition to enhancing the finite diversity of the genome, AS can also regulate the transcription and translation of certain genes by directly binding to their cis-elements or by recruiting trans-elements that interact with consensus motifs. The testis, being one of the most complex tissue transcriptomes, undergoes unparalleled transcriptional and translational activity, supporting the dramatic and dynamic transitions that occur during spermatogenesis. Consequently, AS plays a vital role in producing an extensive array of transcripts and coordinating significant changes throughout this process. In this review, we summarize the intricate functional network of alternative splicing in spermatogenesis based on the integration of current research findings.
The SA-WRKY70-PR-Callose Axis Mediates Plant Defense Against Whitefly Eggs
Authors: Song Hong-Da , Zhang Feng-Bin , Ji Shun-Xia , Wang Xue-Qian , Wang Jun-Xia , Liu Yu-Xiao , Wang Xiao-Wei , Han Wen-Hao
Published: November 2024

The molecular mechanisms of plant responses to phytophagous insect eggs are poorly understood, despite their importance in insect–plant interactions. This study investigates the plant defense mechanisms triggered by the eggs of whitefly Bemisia tabaci, a globally significant agricultural pest. A transcriptome comparison of tobacco plants with and without eggs revealed that whitefly eggs may activate the response of defense-related genes, including those involved in the salicylic acid (SA) signaling pathway. SA levels are induced by eggs, resulting in a reduction in egg hatching, which suggests that SA plays a key role in plant resistance to whitefly eggs. Employing Agrobacterium-mediated transient expression, virus-induced gene silencing assays, DNA–protein interaction studies, and bioassays, we elucidate the regulatory mechanisms involved. Pathogenesis-related proteins NtPR1-L1 and NtPR5-L2, downstream of the SA pathway, also affect whitefly egg hatching. The SA-regulated transcription factor NtWRKY70a directly binds to the NtPR1-L1 promoter, enhancing its expression. Moreover, NtPR1-L1 promotes callose deposition, which may impede the eggs’ access to water and nutrients. This study establishes the SA-WRKY70-PR-callose axis as a key mechanism linking plant responses and defenses against whitefly eggs, providing new insights into the molecular interactions between plants and insect eggs.
Correction: Belosludtsev et al. Alisporivir Treatment Alleviates Mitochondrial Dysfunction in the Skeletal Muscles of C57BL/6NCrl Mice with High-Fat Diet/Streptozotocin-Induced Diabetes Mellitus. Int. J. Mol. Sci. 2021, 22, 9524
Authors: Belosludtsev Konstantin N. , Starinets Vlada S. , Talanov Eugeny Yu. , Mikheeva Irina B. , Dubinin Mikhail V. , Belosludtseva Natalia V.
Published: November 2024

The original publication [...]
Adeno-Associated Viral Vectors in the Treatment of Epilepsy
Authors: Mullagulova Aysilu I. , Timechko Elena E. , Solovyeva Valeriya V. , Yakimov Alexey M. , Ibrahim Ahmad , Dmitrenko Diana D. , Sufianov Albert A. , Sufianova Galina Z. , Rizvanov Albert A.
Published: November 2024

Epilepsy is a brain disorder characterized by a persistent predisposition to epileptic seizures. With various etiologies of epilepsy, a significant proportion of patients develop pharmacoresistance to antiepileptic drugs, which necessitates the search for new therapeutic methods, in particular, using gene therapy. This review discusses the use of adeno-associated viral (AAV) vectors in gene therapy for epilepsy, emphasizing their advantages, such as high efficiency of neuronal tissue transduction and low immunogenicity/cytotoxicity. AAV vectors provide the possibility of personalized therapy due to the diversity of serotypes and genomic constructs, which allows for increasing the specificity and effectiveness of treatment. Promising orientations include the modulation of the expression of neuropeptides, ion channels, transcription, and neurotrophic factors, as well as the use of antisense oligonucleotides to regulate seizure activity, which can reduce the severity of epileptic disorders. This review summarizes the current advances in the use of AAV vectors for the treatment of epilepsy of various etiologies, demonstrating the significant potential of AAV vectors for the development of personalized and more effective approaches to reducing seizure activity and improving patient prognosis.
Expression of Network Medicine-Predicted Genes in Human Macrophages Infected with Leishmania major
Authors: Caixeta Felipe , Martins Vinicius Dantas , Figueiredo Amanda Braga , Afonso Luis Carlos Crocco , Tieri Paolo , Castiglione Filippo , de Freitas Leandro Martins , Maioli Tatiani Uceli
Published: November 2024

Leishmania spp. commonly infects phagocytic cells of the immune system, particularly macrophages, employing various immune evasion strategies that enable their survival by altering the intracellular environment. In mammals, these parasites establish persistent infections by modulating gene expression in macrophages, thus interfering with immune signaling and response pathways, ultimately creating a favorable environment for the parasite’s survival and reproduction. In this study, our objective was to use data mining and subsequent filtering techniques to identify the genes that play a crucial role in the infection process of Leishmania spp. We aimed to pinpoint genes that have the potential to influence the progression of Leishmania infection. To achieve this, we exploited prior, curated knowledge from major databases and constructed 16 datasets of human molecular information consisting of coding genes and corresponding proteins. We obtained over 400 proteins, identifying approximately 200 genes. The proteins coded by these genes were subsequently used to build a network of protein–protein interactions, which enabled the identification of key players; we named this set Predicted Genes. Then, we selected approximately 10% of Predicted Genes for biological validation. THP-1 cells, a line of human macrophages, were infected with Leishmania major in vitro for the validation process. We observed that L. major has the capacity to impact crucial genes involved in the immune response, resulting in macrophage inactivation and creating a conducive environment for the survival of Leishmania parasites.
The Effect of Metformin and Hydrochlorothiazide on Cytochrome P450 3A4 Metabolism of Ivermectin: Insights from In Silico Experimentation
Authors: Mtambo Thuli R. , Machaba Kgothatso E. , Chellan Nireshni , Ramharack Pritika , Muller Christo J. F. , Mhlongo Ndumiso N. , Hlengwa Nokulunga
Published: November 2024

The spread of SARS-CoV-2 has led to an interest in using ivermectin (a potent antiparasitic agent) as an antiviral agent despite the lack of convincing in vivo clinical data for its use against COVID-19. The off-target prophylactic use of ivermectin adds a substantial risk of drug–drug interactions with pharmaceutical medications used to treat chronic conditions like diabetes and hypertension (metformin and hydrochlorothiazide, respectively). Therefore, this study aims to evaluate the potential drug–drug interactions between ivermectin with either metformin or hydrochlorothiazide. In silico experiments and high-throughput screening assays for CYP3A4 were conducted to understand how metformin and hydrochlorothiazide might affect CYP3A4’s role in metabolizing ivermectin. The study findings indicated that hydrochlorothiazide is more stable than both ivermectin and metformin. This conclusion was further supported by root mean square fluctuation analysis, which showed that hydrochlorothiazide is more flexible. The variation in the principal component analysis scatter plot across the first three normal modes suggests hydrochlorothiazide has a more mobile conformation than ivermectin and metformin. Additionally, a strong inhibition of CYP3A4 by hydrochlorothiazide was observed, suggesting that hydrochlorothiazide’s regulatory effects could significantly impede CYP3A4 activity, potentially leading to a reduced metabolism and clearance of ivermectin in the body. Concurrent administration of these drugs may result in drug–drug interactions and hinder the hepatic metabolism of ivermectin.
Edible Alginate–Lecithin Films Enriched with Different Coffee Bean Extracts: Formulation, Non-Cytotoxic, Anti-Inflammatory and Antimicrobial Properties
Authors: Socha Robert , Such Aleksandra , Wisła-Świder Anna , Juszczak Lesław , Nowak Ewelina , Bulski Karol , Frączek Krzysztof , Doskocil Ivo , Lampova Barbora , Koronowicz Aneta
Published: November 2024

The aim of this study was to analyze the functional properties of newly obtained films based on sodium alginate and lecithin with the addition of antioxidant-rich coffee extracts and to verify their potential as safe edible food packaging materials. In our study, we developed alginate–lecithin films enriched with green or roasted coffee bean extracts. The roasting process of coffee beans had a significant impact on the total phenolic content (TPC) in the studied extracts. The highest value of TPC (2697.2 mg GAE/dm3), as well as antioxidant activity (AA) (17.6 mM T/dm3), was observed for the extract of light-roasted coffee beans. Films with the addition of medium-roasted coffee extracts and baseline films had the highest tensile strength (21.21 ± 0.73 N). The addition of coffee extract improved the barrier properties of the films against UV light with a decrease in the transmittance values (200–400 nm), regardless of the type of extract added. Studies on Caco-2, HepG2 and BJ cells showed that digestated films were non-cytotoxic materials (100–0.1 μg/cm3) and had no negative effect on cell viability; an increase was noted for all cell lines, the highest after 48 h in a dose of 1 μg/cm3 for a film with medium-roasted coffee (194.43 ± 38.30) for Caco-2. The tested films at 20% digestate concentrations demonstrated the ability to reduce nitric oxide (NO) production in the RAW264.7 cell line by 25 to 60% compared to the control. Each of the tested films with coffee extracts had growth inhibitory properties towards selected species of bacteria.
Delineating MYC-Mediated Escape Mechanisms from Conventional and T Cell-Redirecting Therapeutic Antibodies
Authors: de Jonge Anna Vera , Csikós Tamás , Eken Merve , Bulthuis Elianne P. , Poddighe Pino J. , Roemer Margaretha G. M. , Chamuleau Martine E. D. , Mutis Tuna
Published: November 2024

In B-cell malignancies, the overexpression of MYC is associated with poor prognosis, but its mechanism underlying resistance to immunochemotherapy remains less clear. In further investigations of this issue, we show here that the pharmacological inhibition of MYC in various lymphoma and multiple myeloma cell lines, as well as patient-derived primary tumor cells, enhances their susceptibility to NK cell-mediated cytotoxicity induced by conventional antibodies targeting CD20 (rituximab) and CD38 (daratumumab), as well as T cell-mediated cytotoxicity induced by the CD19-targeting bispecific T-cell engager blinatumomab. This was associated with upregulation of the target antigen only for rituximab, suggesting additional escape mechanisms. To investigate these mechanisms, we targeted the MYC gene in OCI-LY18 cells using CRISPR-Cas9 gene-editing technology. CRISPR-Cas9-mediated MYC targeting not only upregulated CD20 but also triggered broader apoptotic pathways, upregulating pro-apoptotic PUMA and downregulating anti-apoptotic proteins BCL-2, XIAP, survivin and MCL-1, thereby rendering tumor cells more prone to apoptosis, a key tumor-lysis mechanism employed by T-cells and NK-cells. Moreover, MYC downregulation boosted T-cell activation and cytokine release in response to blinatumomab, revealing a MYC-mediated T-cell suppression mechanism. In conclusion, MYC overexpressing tumor cells mitigated the efficacy of therapeutic antibodies through several non-overlapping mechanisms. Given the challenges associated with direct MYC inhibition due to toxicity, successful modulation of MYC-mediated immune evasion mechanisms may improve the outcome of immunotherapeutic approaches in B-cell malignancies.
SERCA Modulators Reveal Distinct Signaling and Functional Roles of T Lymphocyte Ca2+ Stores
Authors: Uddin Md Nasim , Thomas David W.
Published: November 2024

The allosteric SERCA (Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPase) activator CDN1163 has been recently added to the group of pharmacological tools for probing SERCA function. We chose to investigate the effects of the compound on T lymphocyte Ca2+ stores, using the well-described Jurkat T lymphocyte as a reliable cell system for Ca2+ signaling pathways. Our study identified the lowest concentrations of the SERCA inhibitors thapsigargin (TG) and 2,5-di-(tert butyl)-1,4-benzohydroquinone (tBHQ) capable of releasing Ca2+, permitting the differentiation of the TG-sensitive SERCA 2b Ca2+ store from the tBHQ-sensitive SERCA 3 Ca2+ store. We proceeded to test the effects of CDN1163 on Ca2+ stores, examining specific actions on the SERCA 2b and SERCA 3 Ca2+ pools using our low-dose SERCA blocker regimen. In contrast to previous work, we find CDN1163 exerts complex time-sensitive and SERCA isoform-specific actions on Ca2+ stores. Surprisingly, short-term exposure (0–30 min) to CDN1163 perturbs T cell Ca2+ stores by suppressing Ca2+ uptake with diminished Ca2+ release from the SERCA 2b-controlled store. Concomitantly, we find evidence for a SERCA-activating effect of CDN1163 on the SERCA-3 regulated store, given the observation of increased Ca2+ release inducible by low-dose tBHQ. Intriguingly, longer-term (>12 h) CDN1163 exposure reversed this pattern, with increased Ca2+ release from SERCA 2b-regulated pools yet decreased Ca2+ release responses from the tBHQ-sensitive SERCA 3 pool. Indeed, this remodeling of SERCA 2b Ca2+ stores with longer-term CDN1163 exposure also translated into the compound’s ability to protect Jurkat T lymphocytes from TG but not tBHQ-induced growth suppression.
Renoprotective Effects of Brown-Strain Flammulina velutipes Singer in Chronic Kidney Disease-Induced Mice Through Modulation of Oxidative Stress and Inflammation and Regulation of Renal Transporters
Authors: Lee Min-Min , Chou Yun-Xuan , Huang Sheng-Hsiung , Cheng Hsu-Tang , Liu Chung-Hsiang , Huang Guan-Jhong
Published: November 2024

Cisplatin, widely used in chemotherapy, acts through mechanisms such as oxidative stress to damage the DNA and cause the apoptosis of cancer cells. Although effective, cisplatin treatment is associated with considerable side effects including chronic kidney disease (CKD). Studies on brown-strain Flammulina velutipes Singer (FVB) have shown its significant antioxidant and immunomodulatory effects. High-performance liquid chromatography (HPLC) confirmed that the FVB extract contained gallic acid and quercetin. This study investigated whether FVB extract can improve and protect against cisplatin-induced CKD in mice. C57BL/6 mice were used as an animal model, and CKD was induced through intraperitoneal cisplatin injection. FVB was orally administered to the mice for 14 consecutive days. N-acetylcysteine (NAC) was administered in the positive control group. Organ pathology and serum biochemical analyses were conducted after the mice were sacrificed. Significant dose-dependent differences were discovered in body mass, kidney mass, histopathology, renal function, inflammatory factors, and antioxidant functions among the different groups. FVB extract reduced the severity of cisplatin-induced CKD in pathways related to inflammation, autophagy, apoptosis, fibrosis, oxidative stress, and organic ion transport proteins; FVB extract, thus, displays protective physiological activity in kidney cells. Additionally, orally administered high doses of the FVB extract resulted in significantly superior renal function, inflammatory factors, antioxidative activity, and fibrotic pathways. This study establishes a strategy for future clinical adjunctive therapy using edible-mushroom-derived FVB extract to protect kidney function.
Nanopore-Based Sequencing of the Full-Length Transcriptome of Male and Female Cleavage-Stage Embryos of the Chinese Mitten Crab (Eriocheir sinensis)
Authors: Han Rui , Ni Mengqi , Lu Wentao , Zhu Dandan , Feng Tianyi , Yang Yanan , Cui Zhaoxia
Published: November 2024

The cleavage stage plays a crucial role in embryo development, characterized by a swift surge in cell proliferation alongside the accurate genetic material transmission to offspring. To delve into the characteristics of sex development during the cleavage stage of embryos, we generated the full-length transcriptome of Eriocheir sinensis male and female cleavage-stage embryos using Oxford Nanopore Technologies (ONT). Notably, this investigation represents the first sequencing effort distinguishing between genders in E. sinensis embryos. In the transcriptome structure analysis, male and female cleavage-stage embryos, while not clustered, exhibited a comparable frequency of alternative splicing (AS) occurrences. We also successfully identified 2875 transcription factors (TFs). The quantitative analysis showed the top 150 genes, in which the highly expressed genes in male embryos predominantly related to protein synthesis and metabolism. Further investigation unveiled 500 differentially expressed genes (DEGs), of which 7 male-biased ribosomal protein genes (RPGs) were particularly noteworthy and further confirmed. These analyses suggest that there may be a more active protein synthesis process in male E. sinensis cleavage-stage embryos. Furthermore, among the 2875 identified TFs, we predicted that 18 TFs could regulate the differentially expressed RPGs, with most TFs belonging to the zf-C2H2 and Homeobox families, which are crucial for embryonic development. During the cleavage stage of E. sinensis, the differential RPGs between genders were intricately linked to energy metabolism. We proposed that these RPGs exert regulatory effects on gene expression in E. sinensis, thereby regulating the difference of development between male and females. Our research sheds light on the developmental mechanisms of E. sinensis during the embryo stage and establishes a groundwork for a deeper understanding of sex development in E. sinensis. The results also provide comprehensive full-length transcriptome data for future gene expression and genetic studies in E. sinensis.
Integration of mRNA and miRNA Analysis Sheds New Light on the Muscle Response to Heat Stress in Spotted Sea Bass (Lateolabrax maculatus)
Authors: Liu Cong , Wen Haishen , Zheng Yuan , Zhang Chong , Zhang Yonghang , Wang Lingyu , Sun Donglei , Zhang Kaiqiang , Qi Xin , Li Yun
Published: November 2024

Temperature is a crucial environmental factor for fish. Elevated temperatures trigger various physiological and molecular responses designed to maintain internal environmental homeostasis and ensure the proper functioning of the organism. In this study, we measured biochemical parameters and performed mRNA–miRNA integrated transcriptomic analysis to characterize changes in gene expression profiles in the muscle tissue of spotted sea bass (Lateolabrax maculatus) under heat stress. The measurement of biochemical parameters revealed that the activities of nine biochemical enzymes (ALP, γ-GT, AST, GLU, CK, ALT, TG, LDH and TC) were significantly affected to varying degrees by elevated temperatures. A total of 1940 overlapping differentially expressed genes (DEGs) were identified among the five comparisons in the muscle tissue after heat stress. Protein–protein interaction (PPI) analysis of DEGs indicated that heat shock protein genes (HSPs) were deeply involved in the response to heat stress. In addition, we detected 462 differential alternative splicing (DAS) events and 618 DAS genes, which are closely associated with sarcomere assembly in muscle, highlighting the role of alternative splicing in thermal response regulation. Moreover, 32 differentially expressed miRNAs (DEMs) were identified in response to heat stress, and 599 DEGs were predicted as potential target genes of those DEMs, generating 846 DEG–DEM negative regulatory pairs potentially associated with thermal response. Function enrichment analysis of the target genes suggested that lipid metabolism-related pathways and genes were regulated by miRNAs. By analyzing PPIs of target genes, we identified 28 key negative regulatory pairs, including 13 miRNAs (such as lma-miR-122, lma-miR-200b-5p and novel-miR-444) and 15 target genes (such as hspa13, dnaja1, and dnajb1a). This study elucidates the molecular mechanisms of response to high-temperature stress and offers valuable information for the selection and breeding of heat-tolerant strains of spotted sea bass.
Investigating the Effects of Gossypetin on Cardiovascular Function in Diet-Induced Pre-Diabetic Male Sprague Dawley Rats
Authors: Naidoo Karishma , Khathi Andile
Published: November 2024

Gossypetin (GTIN) is a naturally occurring flavonoid recognised for its pharmacological properties. This study examined the effects of GTIN on cardiovascular function in a diet-induced pre-diabetic rat model, which has not been previously studied. Pre-diabetes was induced using a high-fat high-carbohydrate (HFHC) diet supplemented with 15% fructose water for 20 weeks. Thereafter, the pre-diabetic animals were sub-divided into five groups (n = 6), where they were either orally treated with GTIN (15 mg/kg) or metformin (MET) (500 mg/kg), both in the presence and absence of dietary intervention for 12 weeks. The results demonstrated that the pre-diabetic (PD) control group exhibited significantly higher plasma triglyceride, total cholesterol, low-density lipoprotein and very low-density lipoprotein levels, along with decreased high-density lipoprotein (HDL) levels in comparison to the non-pre-diabetic (NPD) group. This was accompanied by significantly higher mean arterial pressure (MAP), body mass index (BMI), waist circumference (WC) and plasma endothelial nitric oxide (eNOS) levels in PD control. Additionally, there were increased heart malondialdehyde levels, reduced heart superoxide dismutase and glutathione peroxidase activity as well as increased plasma interleukin-6, tumour necrosis factor alpha and c-reactive protein levels present in the PD control group. Notably, both GTIN-treated groups showed significantly reduced plasma lipid levels and increased HDL, as well as decreases in MAP, BMI, WC and eNOS levels in comparison to PD control. Additionally, GTIN significantly decreased heart lipid peroxidation, enhanced antioxidant activity and decreased plasma inflammation markers. These findings may suggest that GTIN administration in both the presence and absence of dietary intervention may offer therapeutic potential in ameliorating cardiovascular disturbances associated with the PD state. However, future studies are needed to determine the physiological mechanisms by which GTIN improves cardiovascular function in the PD state.
Loss of Brcc3 in Zebrafish Embryos Increases Their Susceptibility to DNA Damage Stress
Authors: Wang Zhengyang , Wang Caixia , Zhai Yanpeng , Bai Yan , Wang Hongying , Rong Xiaozhi
Published: November 2024

DNA double-strand breaks (DSBs) represent one of the most severe forms of genetic damage in organisms, yet vertebrate models capable of monitoring DSBs in real-time remain scarce. BRCA1/BRCA2-containing complex subunit 3 (BRCC3), also known as BRCC36, functions within various multiprotein complexes to mediate diverse biological processes. However, the physiological role of BRCC3 in vertebrates, as well as the underlying mechanisms that govern its activity, are not well understood. To explore these questions, we generated brcc3-knockout zebrafish using CRISPR/Cas9 gene-editing technology. While brcc3 mutant zebrafish appear phenotypically normal and remain fertile, they exhibit significantly increased rates of mortality and deformity following exposure to DNA damage. Furthermore, embryos lacking Brcc3 display heightened p53 signaling, elevated γ-H2AX levels, and increased apoptosis in response to DNA-damaging agents such as ultraviolet (UV) light and Etoposide (ETO). Notably, genetic inactivation of p53 or pharmacological inhibition of Ataxia-telangiectasia mutated (ATM) activity rescues the hypersensitivity to UV and ETO observed in Brcc3-deficient embryos. These findings suggest that Brcc3 plays a critical role in DNA damage response (DDR), promoting cell survival during embryogenesis. Additionally, brcc3-null mutant zebrafish offer a promising vertebrate model for real-time monitoring of DSBs.
Over Expression of Mango MiGA2ox12 in Tobacco Reduced Plant Height by Reducing GA1 and GA4 Content
Authors: Zhang Yu , Zhang Ji , Huang Guodi , Tan Yiwei , Ning Lei , Li Mu , Mo Yonglong
Published: November 2024

The regulation of gibberellic acid 2-oxidase (GA2ox) gene expression represents a critical mechanism in the modulation of endogenous gibberellic acids (GAs) levels, thereby exerting an influence on plant height. In this context, we conducted a comprehensive genome-wide analysis of the GA2ox gene family in mango (Mangifera indica L.), a species of significant economic importance, with the aim of identifying potential candidate genes for mango dwarf breeding. Our findings delineated the presence of at least 14 members within the MiGA2ox gene family in the mango genome, which were further categorized into three subfamilies: C19-GA2ox-I, C19-GA2ox-II, and C20-GA2ox-I. Notably, MiGA2ox12, a member of the C19-GA2ox-II subfamily, exhibited substantial expression across various tissues, including roots, bark, leaves, and flowers. Through overexpression of the MiGA2ox12 gene in tobacco, a distinct dwarf phenotype was observed alongside reduced levels of GA1 and GA4, while the knockout line exhibited contrasting traits. This provides evidence suggesting that MiGA2ox12 may exert control over plant height by modulating GA content. Consequently, the MiGA2ox12 gene emerges as a promising candidate for facilitating advancements in mango dwarfing techniques.
The Catheter Flushing Method Shows a Similar Diagnostic Yield to the Conventional Method in Brushing Cytology for Biliary Strictures
Authors: Jang Sung Ill , Nahm Ji Hae , Lee See Young , Jeong Seok , Lee Tae Hoon , Kim Dong Uk , Kwon Chang-Il , Cho Jae Hee , Sung Min Je
Published: November 2024

Background/Objectives: Endobiliary brushing is usually performed in the diagnosis of indeterminate biliary strictures; however, in this setting, brush cytology is limited by a low diagnostic yield and sensitivity. Here, we compared the catheter flushing method (CFM) with the conventional cytologic method (CCM) in terms of cellularity and diagnostic performance. Methods: Endobiliary brushings were obtained during endoscopic retrograde cholangiopancreatography (ERCP) from patients with biliary strictures enrolled at six tertiary hospitals. Additionally, the CFM was performed after brushing. Using liquid-based cytologic preparations of samples, we assessed the diagnostic performance of the CCM using Pap staining and the CFM using methionyl-transfer RNA synthetase 1 (MARS1) immunofluorescence staining. Results: From a total of 399 patients (malignant, 253; benign, 146), 374 CCM samples and 361 CFM samples contained adequate cells, with no significant difference in diagnostic yield (93.7% vs. 90.5%, respectively; p = 0.088). The sensitivity of the CFM (90.3%) was significantly higher than that of the CCM (75.1%; p < 0.001), with no significant difference in accuracy between methods (81.2% vs. 82.6%, respectively; p = 0.608). Conclusions: The diagnostic yield of the CFM was comparable to that of the CCM. Additionally, the diagnostic performance of the CFM was comparable to that of the CCM. These findings indicate that the CFM could be an additional brush cytology method for sample collection in patients with indeterminate biliary strictures. Incorporating both the CCM and CFM might be expected to improve the diagnostic yield of brush cytology in the biliary strictures. Further prospective comparative studies between the CCM and CFM using the same staining method are needed to validate these findings.
Exercise in Postural Orthostatic Tachycardia Syndrome: Focus on Individualized Exercise Approach
Authors: Trimble Kristine Zeznick , Switzer Jennifer N. , Blitshteyn Svetlana
Published: November 2024

Exercise is a vital component of health and is commonly utilized as a non-pharmacologic therapy for many disorders, including postural orthostatic tachycardia syndrome (POTS). However, exercise intolerance is a key feature of POTS and other autonomic disorders and, therefore, presents a major barrier for many patients. Despite exercise being uniformly recommended as a therapeutic intervention, a majority of patients with POTS, especially those with severe orthostatic intolerance and fatigue, are unable to complete or sustain rigorous exercise programs or successfully integrate them into their daily routine. In this narrative review, we discuss the current literature on exercise and POTS and our clinical experience with a home-based exercise approach developed at the Dysautonomia Clinic. We conclude that individualized exercise programs that are delivered remotely by a certified physical therapist may be convenient, easily accessible, and safe for patients with POTS, especially those with severe symptoms who may be home- or bedbound. Future randomized controlled studies are needed to quantify and characterize the benefits of home-based exercise programs delivered remotely compared to standard therapy.
Management of Complex Root Fractures in Young Patients—Case Series and a Literature Review
Authors: Sobczak-Zagalska Hanna , Ogonowska-Paul Dorota , Bartmański Michał , Adamska Paulina
Published: November 2024

Background: Root fractures are defined as injuries involving dentine, cementum, and the pulp. They are rare, and they account for 0.5–7% of the dental injuries in the permanent teeth. Root fractures may be the result of direct trauma to the teeth or indirect trauma to the oral cavity. Their incidence is highest in the group of adolescent patients aged 11 to 20 years. The purpose of the paper is to review the literature supported by a case series with three different types of root fractures with various healing patterns, though all with successful long-term treatment outcomes. Case series: All presented patients were boys aged 10 to 11 years. Root fractures occurred as a result of direct impact with the teeth by an object. Only one boy had his root-fractured teeth endodontically treated. However, one of the teeth was misdiagnosed with pulp necrosis, and the other became non-vital after additional trauma. Conclusions: Root fractures in young patients have good healing potential. Appropriate and early diagnostic and therapeutic procedures for treating root-fractured teeth are necessary to achieve favorable healing and a good long-term prognosis. Regardless of the pattern of healing of fractured roots and the treatment provided, patients require long-term follow-up and the need to plan a management strategy in case complications occur. Failure of the healing of fractured root is a worst-case scenario, especially in patients of developmental age. In such cases, the primary goal of treatment is to preserve the alveolar ridge until growth is complete.
Biomarkers: Promising Tools Towards the Diagnosis, Prognosis, and Treatment of Myopia
Authors: Ruamviboonsuk Varis , Lanca Carla , Grzybowski Andrzej
Published: November 2024

The prevalence of myopia, especially high myopia, continues to increase in several parts of the world. Thus, the use of biomarkers for early myopia detection would be highly valuable for clinical practice aiding in the prevention and myopia control management. The identification of biomarkers that can predict the risk of myopia development, severity of myopia, and treatment response are of paramount significance. In this review, we present the current state of research on biomarkers and myopia, highlighting the challenges and opportunities in biomarkers research for myopia. Although myopia biomarkers may have a role as early indicators of myopia or treatment response, the adoption of biomarkers into myopia clinical practice may only be done when tests have high accuracy, are easily measurable, minimally invasive, and acceptable to parents, children, and eye care professionals. Large consortia studies are necessary to validate biomarkers and translate evidence into clinical practice.
Neuropathological Heterogeneity of Dementia Due to Combined Pathology in Aged Patients: Clinicopathological Findings in the Vallecas Alzheimer’s Reina Sofía Cohort
Authors: Burgueño-García Iván , López-Martínez María José , Uceda-Heras Alicia , García-Carracedo Lucía , Zea-Sevilla María Ascensión , Rodrigo-Lara Héctor , Rego-García Iago , Saiz-Aúz Laura , Ruiz-Valderrey Paloma , López-González Francisco J. , Guerra-Martín Virginia , Rábano Alberto
Published: November 2024

Background/Objectives: Clinicopathological research in late-life dementia has focused recently on combined neurodegenerative and vascular conditions underlying the high phenotypic heterogeneity of patients. The Vallecas Alzheimer’s Reina Sofía (VARS) cohort (n > 550), and particularly the series of associated brain donations (VARSpath cohort) are presented here. The aim of this study is to contribute to research in dementia with a well-characterized cohort from a single center. Methods: A total of 167 patients with complete neuropathological work-ups were analyzed here. The cohort is characterized by a high female predominance (79%), advanced age at death (88 yrs.), and a high frequency of ApoE-e4 haplotype (43%). Results: The main neuropathological diagnosis was Alzheimer’s disease (79.6%), followed by vascular dementia (10.2%) and Lewy body dementia (6%). Overall, intermediate-to-high cerebrovascular disease was observed in 38.9%, Lewy body pathology in 57.5%, LATE (TDP-43 pathology) in 70.7%, ARTAG in 53%, and argyrophilic grain disease in 12% of the patients. More than one pathology with a clinically relevant burden of disease was present in 71.1% of the brains, and a selection of premortem neuropsychological and functional scores showed significant correlation with the number of co-pathologies identified in postmortem brains. Conclusions: The VARS cohort, with thorough clinical follow-up, regular blood sampling, 3-Tesla MR, and a high rate of postmortem brain donation, can provide essential multidisciplinary data in the rising age of modifying therapies and biomarkers for Alzheimer’s disease and related dementias.
Symptomatic Acetabular Erosion After Hip Hemiarthroplasty: Is It a Major Concern? A Retrospective Analysis of 2477 Hemiarthroplasty Cases
Authors: Mahmoud Ahmed Nageeb , Suk Michael , Horwitz Daniel S.
Published: November 2024

Background/Objectives: Acetabular erosion is a postoperative condition that can occur after hip hemiarthroplasty (HA), potentially leading to pain and requiring conversion to total hip arthroplasty (THA). Given the discrepancy in its incidence and impact in the literature, this study aims to report the incidence of symptomatic acetabular erosion and the subsequent conversion to THA in all HA cases performed in a single health system. Methods: A total of 2477 HA cases had their clinical notes and serial radiographs examined for this retrospective study. Outcome measures included any records of hip or groin pain and conversion to THA that were attributed to acetabular erosion as documented in the clinical notes. Results: Two thousand four hundred and seventy-seven HA cases were reviewed in this study. The mean age for all patients in the study was 81.5 years and the mean follow up was 3.7 years. Out of the 2477 HA cases, only 12 HA cases (0.48%) in 12 patients had data records of chronic hip pain, attributable to acetabular wear in the clinical notes, of variable severity and presentations. The mean duration until the clinical documentation of acetabular wear-induced pain was 25.6 months (range, 1.4–146.4 months), with most symptomatic hip erosion cases presented within the first year (50% presented within the first 6 months) after the index HA surgery. Despite that, only five cases underwent conversion to THA (0.2%) while seven patients received conservative management. Conclusions: In patients older than 65 years of age who are candidates for HA, the incidence of symptomatic hip erosion and the subsequent conversion to THA is low and hence HA remains a viable treatment option. Based on the duration until clinical presentation of acetabular erosion, this study suggests that the state of acetabular cartilage during surgery may influence the development of early acetabular wear in most symptomatic patients. On the other hand, hip hemiarthroplasty is a rare treatment option for displaced femoral neck fractures in patients younger than 65 years of age, and its use in this patient subset depends on conditional and patient-related factors such as the activity level, cognitive function, and medical comorbidities.
Mandibular Advancement Devices in Obstructive Sleep Apnea and Its Effects on the Cardiovascular System: A Comprehensive Literature Review
Authors: Polecka Agnieszka , Nawrocki Jakub , Pulido Maria Alejandra , Olszewska Ewa
Published: November 2024

Background: Obstructive sleep apnea syndrome (OSA) is a chronic inflammatory disease characterized by endothelial dysfunction and cardiovascular complications. Continuous positive airway pressure (CPAP) is the standard treatment, hence poor adherence has prompted interest in mandibular advancement devices (MAD) as an alternative. This comprehensive review aimed to explore the effects of MAD therapy on oxidative stress, inflammation, endothelial function, and its impact on the cardiovascular risk in OSA patients. Results: MAD therapy significantly reduces the apnea-hypopnea index (AHI), improves serum nitric oxide (NOx) concentrations, reduces oxidative stress markers, and enhances endothelial function. Animal studies indicated that MAD reduces myocardial fibrosis and attenuates inflammatory markers. While both CPAP and MADs improve endothelial function and heart rate variability, CPAP is more effective in reducing OSA severity. Nevertheless, MAD has higher compliance, contributing to its positive impact on cardiovascular function. Moreover, CPAP and MADs have similar effectiveness in reducing cardiovascular risk. Conclusions: MAD therapy is an effective alternative to CPAP, particularly for patients with mild to moderate OSA as well as those intolerant to CPAP. It offers significant improvements in endothelial function and oxidative stress. Further studies are needed to assess MAD therapy in comprehensive OSA management.
Tunnel Technique and Subepithelial Connective Tissue Graft, With or Without Cross-Linked Hyaluronic Acid, in the Treatment of Multiple Gingival Recessions: Prognostic Parameters for Clinical Treatment Outcomes of Randomized Controlled Trial
Authors: Górski Bartłomiej , Skierska Izabela Maria , Nijakowski Kacper , Brodzikowska Aniela
Published: November 2024

Objectives: This study aimed to investigate factors that influence the 12-month outcomes after the treatment of multiple gingival recessions (GRs) with a modified coronally advanced tunnel (MCAT) and a subepithelial connective tissue graft (SCTG), with cross-linked hyaluronic acid (HA, tests) or without (controls). Materials and Methods: Twenty-four patients with 266 GRs were treated. A logistic regression model was set to identify the baseline parameters that could predict the 12-month outcomes. The study protocol was registered at ClinicalTrials.gov (ID No. NCT05045586). Results: The evaluated clinical and esthetic parameters showed marked improvement in both groups without any statistically significant differences between the groups, with the exception of the soft tissue texture (STT). The STT was in favor of the HA group (0.96 versus 0.73, p = 0.0091). The likelihood of an MRC > 85%, of achieving CRC, and of gaining an RES = 10 was the highest for the incisors (reference group) and the lowest for the molars (OR = 0.046, p = 0.005). With each 1 mm increase in the baseline clinical attachment level, the odds of failure (MRC < 85%, not achieving CRC) increased, whereas each 1 mm increase in the baseline keratinized tissue width (KTW) improved the chances of an MRC > 85%, of achieving CRC, and of gaining an RES = 10. The application of HA increased the likelihood of a perfect RES more than twofold (OR = 2.683, p = 0.001). Conclusions: The application of HA improved the 12-month esthetic outcomes after the treatment of GRs with the MCAT technique. The baseline CAL, KTW, and tooth type predicted the 12-month MRC, CRC, and RES. An evaluation of the baseline characteristics of the surgical area might help clinicians develop individualized treatment plans.
The Efficacy of Different Tenotomies in the Treatment of Lateral Epicondylitis: A Systematic Review
Authors: Ansari Ayub , Shoaib Dania , Tanbour Yazan , Marchese Charles R. , Pautler Benjamin J. , Baghdadi Abdullah , Sloan Sara , Dennis Jennifer F.
Published: November 2024

Background: Lateral epicondylitis impacts 1–3% of the population. It affects nearly half of all tennis players, primarily due to repetitive forearm muscle use leading to pain at the lateral elbow, particularly at the extensor carpi radialis brevis tendon. While conservative treatments resolve most cases, 4–11% of patients with persistent pain require surgery. Tenotomy is the gold standard for repair, but the research comparing the benefits of specific types of tenotomies (open, arthroscopic, percutaneous, ultrasonically assisted, and Tenex forms) is lacking. Methods: PubMed and Embase searches were conducted for articles focused on four tenotomy techniques. The inclusion criteria allowed for the use of randomized controlled trials (RCTs), prospective cohort studies, and comparative observational studies, while the exclusion criteria excluded meta-analyses. Following the PRISMA guidelines, the initial search resulted in 2327 articles. Once the inclusion and exclusion criteria were applied, 1702 articles underwent abstract screening. Finally, 232 articles proceeded to full-text screening, resulting in 37 articles undergoing data extraction. Results: The primary outcomes included functional improvement, pain relief, overall performance, and postoperative disability. The secondary outcomes included patient-reported satisfaction, return-to-work timeframes, and procedural complications. Conclusions: The tenotomy outcomes were similar, regardless of the method, indicating that discussions with patients about their specific outcome preferences may help guide tenotomy method selection.