bluuebunny/crossref_metadata_2025 huggingface dataset:
Insights into the Genetics and Signaling Pathways in Maturity-Onset Diabetes of the Young
Authors: Sousa Madalena , Rego Teresa , Armas Jácome Bruges
Published: October 2022

Diabetes Mellitus (DM) is a complex disease with a significant impact in today’s world. Studies have emphasized the crucial role of genetics in DM, unraveling the distinction of monogenic diabetes from the most common types that have been recognized over the years, such as type 1 diabetes (T1DM) and type 2 diabetes (T2DM). A literature search was carried out to scrutinize the subtypes of maturity-onset diabetes of the young (MODY), as well as the connection between the recognized genetic and molecular mechanisms responsible for such phenotypes. Thus far, 14 subtypes of MODY have been identified. Here, the authors review the pathophysiological and molecular pathways in which monogenic diabetes genes are involved. Despite being estimated to affect approximately 2% of all T2DM patients in Europe, the exact prevalence of MODY is still unknown, enhancing the need for research focused on biomarkers. Due to its impact in personalized medicine, a follow-up of associated complications, and genetic implications for siblings and offspring of affected individuals, it is imperative to diagnose the monogenic forms of DM accurately. Currently, advances in the genetics field has allowed for the recognition of new DM subtypes, which until now were considered to be slight variations of the typical forms. New molecular insights can define therapeutic strategies, aiming for the prevention, correction, or at least delay of β-cell dysfunction. Thus, it is imperative to act in the close interaction between genetics and clinical manifestations to improve diagnosis and individualize treatment.
Variants of HCMV UL18 Sequenced Directly from Clinical Specimens Associate with Antibody and T-Cell Responses to HCMV
Authors: Waters Shelley , Lee Silvia , Ariyanto Ibnu , Leary Shay , Munyard Kylie , Gaudieri Silvana , Irish Ashley , Allcock Richard J. N. , Price Patricia
Published: October 2022

Around 80% of adults worldwide carry human cytomegaloviris (HCMV). The HCMV gene UL18 is a homolog of HLA class I genes and encodes a protein with high affinity for the NK and T-cell cytotoxicity inhibitor LIR-1. UL18 was deep sequenced from blood, saliva or urine from Indonesian people with HIV (PWH) (n = 28), Australian renal transplant recipients (RTR) (n = 21), healthy adults (n = 7) and neonates (n = 4). 95% of samples contained more than one variant of HCMV UL18, as defined by carriage of nonsynonymous variations. When aligned with immunological markers of the host’s burden of HCMV, the S318N variation associated with high levels of antibody reactive with HCMV lysate in PWH over 12 months on antiretroviral therapy. The A107T variation associated with HCMV antibody levels and inflammatory biomarkers in PWH at early timepoints. Variants D32G, D248N, V250A and E252D aligned with elevated HCMV antibody levels in RTR, while M191K, E196Q and F165L were associated with HCMV-reactive T-cells and proportions of Vδ2− γδ T-cells—populations linked with high burdens of HCMV. We conclude that UL18 is a highly variable gene, where variation may alter the persistent burden of HCMV and/or the host response to that burden.
Using Exogenous Melatonin, Glutathione, Proline, and Glycine Betaine Treatments to Combat Abiotic Stresses in Crops
Authors: Khalid Memoona , Rehman Hafiz Mamoon , Ahmed Nisar , Nawaz Sehar , Saleem Fozia , Ahmad Shakeel , Uzair Muhammad , Rana Iqrar Ahmad , Atif Rana Muhammad , Zaman Qamar U. , Lam Hon-Ming
Published: October 2022

Abiotic stresses, such as drought, salinity, heat, cold, and heavy metals, are associated with global climate change and hamper plant growth and development, affecting crop yields and quality. However, the negative effects of abiotic stresses can be mitigated through exogenous treatments using small biomolecules. For example, the foliar application of melatonin provides the following: it protects the photosynthetic apparatus; it increases the antioxidant defenses, osmoprotectant, and soluble sugar levels; it prevents tissue damage and reduces electrolyte leakage; it improves reactive oxygen species (ROS) scavenging; and it increases biomass, maintains the redox and ion homeostasis, and improves gaseous exchange. Glutathione spray upregulates the glyoxalase system, reduces methylglyoxal (MG) toxicity and oxidative stress, decreases hydrogen peroxide and malondialdehyde accumulation, improves the defense mechanisms, tissue repairs, and nitrogen fixation, and upregulates the phytochelatins. The exogenous application of proline enhances growth and other physiological characteristics, upregulates osmoprotection, protects the integrity of the plasma lemma, reduces lipid peroxidation, increases photosynthetic pigments, phenolic acids, flavonoids, and amino acids, and enhances stress tolerance, carbon fixation, and leaf nitrogen content. The foliar application of glycine betaine improves growth, upregulates osmoprotection and osmoregulation, increases relative water content, net photosynthetic rate, and catalase activity, decreases photorespiration, ion leakage, and lipid peroxidation, protects the oxygen-evolving complex, and prevents chlorosis. Chemical priming has various important advantages over transgenic technology as it is typically more affordable for farmers and safe for plants, people, and animals, while being considered environmentally acceptable. Chemical priming helps to improve the quality and quantity of the yield. This review summarizes and discusses how exogenous melatonin, glutathione, proline, and glycine betaine can help crops combat abiotic stresses.
Bi-Allelic Mutations in Zebrafish pank2 Gene Lead to Testicular Atrophy and Perturbed Behavior without Signs of Neurodegeneration
Authors: Mignani Luca , Zizioli Daniela , Khatri Deepak , Facchinello Nicola , Schiavone Marco , De Palma Giuseppe , Finazzi Dario
Published: October 2022

Coenzyme A (CoA) is an essential cofactor in all living organisms, being involved in a large number of chemical reactions. Sequence variations in pantothenate kinase 2 (PANK2), the first enzyme of CoA biosynthesis, are found in patients affected by Pantothenate Kinase Associated Neurodegeneration (PKAN), one of the most common forms of neurodegeneration, with brain iron accumulation. Knowledge about the biochemical and molecular features of this disorder has increased a lot in recent years. Nonetheless, the main culprit of the pathology is not well defined, and no treatment option is available yet. In order to contribute to the understanding of this disease and facilitate the search for therapies, we explored the potential of the zebrafish animal model and generated lines carrying biallelic mutations in the pank2 gene. The phenotypic characterization of pank2-mutant embryos revealed anomalies in the development of venous vascular structures and germ cells. Adult fish showed testicular atrophy and altered behavioral response in an anxiety test but no evident signs of neurodegeneration. The study suggests that selected cell and tissue types show a higher vulnerability to pank2 deficiency in zebrafish. Deciphering the biological basis of this phenomenon could provide relevant clues for better understanding and treating PKAN.
Nanorings to Probe Mechanical Stress of Single-Stranded DNA Mediated by the DNA Duplex
Authors: Zagorski Karen , Stormberg Tommy , Hashemi Mohtadin , Kolomeisky Anatoly B. , Lyubchenko Yuri L.
Published: October 2022

The interplay between the mechanical properties of double-stranded and single-stranded DNA is a phenomenon that contributes to various genetic processes in which both types of DNA structures coexist. Highly stiff DNA duplexes can stretch single-stranded DNA (ssDNA) segments between the duplexes in a topologically constrained domain. To evaluate such an effect, we designed short DNA nanorings in which a DNA duplex with 160 bp is connected by a 30 nt single-stranded DNA segment. The stretching effect of the duplex in such a DNA construct can lead to the elongation of ssDNA, and this effect can be measured directly using atomic force microscopy (AFM) imaging. In AFM images of the nanorings, the ssDNA regions were identified, and the end-to-end distance of ssDNA was measured. The data revealed a stretching of the ssDNA segment with a median end-to-end distance which was 16% higher compared with the control. These data are in line with theoretical estimates of the stretching of ssDNA by the rigid DNA duplex holding the ssDNA segment within the nanoring construct. Time-lapse AFM data revealed substantial dynamics of the DNA rings, allowing for the formation of transient crossed nanoring formations with end-to-end distances as much as 30% larger than those of the longer-lived morphologies. The generated nanorings are an attractive model system for investigation of the effects of mechanical stretching of ssDNA on its biochemical properties, including interaction with proteins.
Exploring Next Generation Probiotics for Metabolic and Microbiota Dysbiosis Linked to Xenobiotic Exposure: Holistic Approach
Authors: Torres-Sánchez Alfonso , Ruiz-Rodríguez Alicia , Ortiz Pilar , Moreno María Alejandra , Ampatzoglou Antonis , Gruszecka-Kosowska Agnieszka , Monteoliva-Sánchez Mercedes , Aguilera Margarita
Published: October 2022

Variation of gut microbiota in metabolic diseases seems to be related to dysbiosis induced by exposure to multiple substances called Microbiota Disrupting Chemicals (MDCs), which are present as environmental and dietary contaminants. Some recent studies have focused on elucidating the alterations of gut microbiota taxa and their metabolites as a consequence of xenobiotic exposures to find possible key targets involved in the severity of the host disease triggered. Compilation of data supporting the triad of xenobiotic-microbiota-metabolic diseases would subsequently allow such health misbalances to be prevented or treated by identifying beneficial microbe taxa that could be Next Generation Probiotics (NGPs) with metabolic enzymes for MDC neutralisation and mitigation strategies. In this review, we aim to compile the available information and reports focused on variations of the main gut microbiota taxa in metabolic diseases associated with xenobiotic exposure and related microbial metabolite profiles impacting the host health status. We performed an extensive literature search using SCOPUS, Web of Science, and PubMed databases. The data retrieval and thorough analyses highlight the need for more combined metagenomic and metabolomic studies revealing signatures for xenobiotics and triggered metabolic diseases. Moreover, metabolome and microbiome compositional taxa analyses allow further exploration of how to target beneficial NGP candidates according to their alleged variability abundance and potential therapeutic significance. Furthermore, this holistic approach has identified limitations and the need of future directions to expand and integrate key knowledge to design appropriate clinical and interventional studies with NGPs. Apart from human health, the beneficial microbes and metabolites identified could also be proposed for various applications under One Health, such as probiotics for animals, plants and environmental bioremediation.
Targeting Key Signaling Pathways in Glioblastoma Stem Cells for the Development of Efficient Chemo- and Immunotherapy
Authors: Helweg Laureen P. , Storm Jonathan , Witte Kaya E. , Schulten Wiebke , Wrachtrup Lennart , Janotte Till , Kitke Angelika , Greiner Johannes F. W. , Knabbe Cornelius , Kaltschmidt Barbara , Simon Matthias , Kaltschmidt Christian
Published: October 2022

Glioblastoma multiforme (GBM) is the most aggressive and most common malignant brain tumor with poor patient survival despite therapeutic intervention. On the cellular level, GBM comprises a rare population of glioblastoma stem cells (GSCs), driving therapeutic resistance, invasion, and recurrence. GSCs have thus come into the focus of therapeutic strategies, although their targeting remains challenging. In the present study, we took advantage of three GSCs-populations recently established in our lab to investigate key signaling pathways and subsequent therapeutic strategies targeting GSCs. We observed that NF-κB, a crucial transcription factor in GBM progression, was expressed in all CD44+/CD133+/Nestin+-GSC-populations. Exposure to TNFα led to activation of NF-κB-RELA and/or NF-κB-c-REL, depending on the GBM type. GSCs further expressed the proto-oncogene MYC family, with MYChigh GSCs being predominantly located in the tumor spheres (“GROW”-state) while NF-κB-RELAhigh GSCs were migrating out of the sphere (“GO”-state). We efficiently targeted GSCs by the pharmacologic inhibition of NF-κB using PTDC/Bortezomib or inhibition of MYC by KJ-Pyr-9, which significantly reduced GSC-viability, even in comparison to the standard chemotherapeutic drug temozolomide. As an additional cell-therapeutic strategy, we showed that NK cells could kill GSCs. Our findings offer new perspectives for developing efficient patient-specific chemo- and immunotherapy against GBM.
Dual Oxidase 2 (DUOX2) as a Proteomic Biomarker for Predicting Treatment Response to Chemoradiation Therapy for Locally Advanced Rectal Cancer: Using High-Throughput Proteomic Analysis and Machine Learning Algorithm
Authors: Lee Hyebin , Ryu Han Suk , Park Hee Chul , Yu Jeong Il , Yoo Gyu Sang , Choi Changhoon , Nam Heerim , Lee Jason Joon Bock , Do In-Gu , Han Dohyun , Ha Sang Yun
Published: October 2022

High-throughput mass-spectrometry-based quantitative proteomic analysis was performed using formalin-fixed, paraffin-embedded (FFPE) biopsy samples obtained before treatment from 13 patients with locally advanced rectal cancer (LARC), who were treated with concurrent chemoradiation therapy (CCRT) followed by surgery. Patients were divided into complete responder (CR) and non-complete responder (nCR) groups. Immunohistochemical (IHC) staining of 79 independent FFPE tissue samples was performed to validate the predictive ability of proteomic biomarker candidates. A total of 3637 proteins were identified, and the expression of 498 proteins was confirmed at significantly different levels (differentially expressed proteins—DEPs) between two groups. In Gene Ontology enrichment analyses, DEPs enriched in biological processes in the CR group included proteins linked to cytoskeletal organization, immune response processes, and vesicle-associated protein transport processes, whereas DEPs in the nCR group were associated with biosynthesis, transcription, and translation processes. Dual oxidase 2 (DUOX2) was selected as the most predictive biomarker in machine learning algorithm analysis. Further IHC validation ultimately confirmed DUOX2 as a potential biomarker for predicting the response of nCR to CCRT. In conclusion, this study suggests that the treatment response to RT may be affected by the pre-treatment tumor microenvironment. DUOX2 is a potential biomarker for the early prediction of nCR after CCRT.
Amyloid Beta in Aging and Alzheimer’s Disease
Authors: Sehar Ujala , Rawat Priyanka , Reddy Arubala P. , Kopel Jonathan , Reddy P. Hemachandra
Published: October 2022

Alzheimer’s disease (AD), is a progressive neurodegenerative disease that affects behavior, thinking, learning, and memory in elderly individuals. AD occurs in two forms, early onset familial and late-onset sporadic; genetic mutations in PS1, PS2, and APP genes cause early onset familial AD, and a combination of lifestyle, environment and genetic factors causes the late-onset sporadic form of the disease. However, accelerated disease progression is noticed in patients with familial AD. Disease-causing pathological changes are synaptic damage, and mitochondrial structural and functional changes, in addition to increased production and accumulation of phosphorylated tau (p-tau), and amyloid beta (Aβ) in the affected brain regions in AD patients. Aβ is a peptide derived from amyloid precursor protein (APP) by proteolytic cleavage of beta and gamma secretases. APP is a glycoprotein that plays a significant role in maintaining neuronal homeostasis like signaling, neuronal development, and intracellular transport. Aβ is reported to have both protective and toxic effects in neurons. The purpose of our article is to summarize recent developments of Aβ and its association with synapses, mitochondria, microglia, astrocytes, and its interaction with p-tau. Our article also covers the therapeutic strategies that reduce Aβ toxicities in disease progression and discusses the reasons for the failures of Aβ therapeutics.
Fumonisin B1 as a Tool to Explore Sphingolipid Roles in Arabidopsis Primary Root Development
Authors: Zhao Yanxue , Liu Zhongjie , Wang Lei , Liu Hao
Published: October 2022

Fumonisin B1 is a mycotoxin that is structurally analogous to sphinganine and sphingosine and inhibits the biosynthesis of complex sphingolipids by repressing ceramide synthase. Based on the connection between FB1 and sphingolipid metabolism, FB1 has been widely used as a tool to explore the multiple functions of sphingolipids in mammalian and plant cells. The aim of this work was to determine the effect of sphingolipids on primary root development by exposing Arabidopsis (Arabidopsis thaliana) seedlings to FB1. We show that FB1 decreases the expression levels of several PIN-FORMED (PIN) genes and the key stem cell niche (SCN)-defining transcription factor genes WUSCHEL-LIKE HOMEOBOX5 (WOX5) and PLETHORAs (PLTs), resulting in the loss of quiescent center (QC) identity and SCN maintenance, as well as stunted root growth. In addition, FB1 induces cell death at the root apical meristem in a non-cell-type-specific manner. We propose that sphingolipids play a key role in primary root growth through the maintenance of the root SCN and the amelioration of cell death in Arabidopsis.
Glymphatic System Dysfunction and Sleep Disturbance May Contribute to the Pathogenesis and Progression of Parkinson’s Disease
Authors: Massey Andie , Boag Matthew , Magnier Annie , Bispo Dharah , Khoo Tien , Pountney Dean
Published: October 2022

Parkinson’s disease (PD) is a multisystem alpha-synucleinopathic neurodegenerative disease and the most prevalent neurodegenerative disorder after Alzheimer’s disease with a high incidence rate in the elderly population. PD is highly multifactorial in etiology and has complex and wide-ranging pathogenic mechanisms. Environmental exposures and genetic predisposition are prominent risk factors. However, current evidence suggests that an intimate link may exist between the risk factor of sleep disturbance and PD pathogenesis. PD is characterized by the pathological hallmarks of alpha-synuclein aggregations and dopaminergic neuron degeneration in the substantia nigra. The loss of dopamine-producing neurons results in both motor and non-motor symptoms, most commonly, bradykinesia, tremor, rigidity, psychiatric disorders, sleep disorders and gastrointestinal problems. Factors that may exacerbate alpha-synuclein accumulation and dopamine neuron loss include neuroinflammation and glymphatic system impairment. Extracellular alpha-synuclein can induce an inflammatory response which can lead to neural cell death and inhibition of neurogenesis. The glymphatic system functions most optimally to remove extracellular brain solutes during sleep and therefore sleep disruption may be a crucial progression factor as well as a risk factor. This literature review interprets and analyses data from experimental and epidemiological studies to determine the recent advances in establishing a relationship between glymphatic system dysfunction, sleep disturbance, and PD pathogenesis and progression. This review addresses current limitations surrounding the ability to affirm a causal link between improved glymphatic clearance by increased sleep quality in PD prevention and management. Furthermore, this review proposes potential therapeutic approaches that could utilize the protective mechanism of sleep, to promote glymphatic clearance that therefore may reduce disease progression as well as symptom severity in PD patients.
Preeclampsia Correlates with an Increase in Cannabinoid Receptor 1 Levels Leading to Macromolecular Alterations in Chorionic Villi of Term Placenta
Authors: Lombó Marta , Giommi Christian , Paolucci Michela , Notarstefano Valentina , Montik Nina , Delli Carpini Giovanni , Ciavattini Andrea , Ragusa Antonio , Maradonna Francesca , Giorgini Elisabetta , Carnevali Oliana
Published: October 2022

Preeclampsia is a human pregnancy-specific disease characterized by abnormal placentation that usually presents with maternal hypertension and proteinuria. The main hallmark of preeclampsia, impaired trophoblast migration, and the subsequent disruption of uterine arteries remodeling lead to several molecular alterations in the placental compartments with those occurring in the chorionic villi being of the utmost importance. Given the essential role of the endocannabinoid system during preimplantation and trophoblast migration, we have combined the histological and hyperspectral imaging analyses to shed light on the involvement of two cannabinoid receptors in the macromolecular alterations related to preeclampsia. The results obtained by immunohistochemistry showed a significant increase in the protein levels of cannabinoid receptor 1 (CB1) in the preeclamptic chorionic villi. However, no changes were reported regarding transient receptor potential vanilloid 1 (TRPV-1) levels either in the bulk placental samples or chorionic villi when comparing control and preeclamptic patients. Histological analysis and Fourier-transform infrared spectroscopy (FTIRI) showed an increase in collagen deposition together with higher levels of lipid peroxidation and phosphorylated compounds in the pathological villi. Since CB1 enhancement has been described as promoting fibrosis and oxidative stress in several tissues, we proposed that the higher receptor abundance in preeclampsia could be triggering similar molecular effects in preeclamptic term placentas.
Genes Whose Gain or Loss of Function Changes Type 1, 2A, 2X, or 2B Muscle Fibre Proportions in Mice—A Systematic Review
Authors: Kuhnen Gabryela , Guedes Russomanno Tiago , Murgia Marta , Pillon Nicolas J. , Schönfelder Martin , Wackerhage Henning
Published: October 2022

Adult skeletal muscle fibres are classified as type 1, 2A, 2X, and 2B. These classifications are based on the expression of the dominant myosin heavy chain isoform. Muscle fibre-specific gene expression and proportions of muscle fibre types change during development and in response to exercise, chronic electrical stimulation, or inactivity. To identify genes whose gain or loss-of-function alters type 1, 2A, 2X, or 2B muscle fibre proportions in mice, we conducted a systematic review of transgenic mouse studies. The systematic review was conducted in accordance with the 2009 PRISMA guidelines and the PICO framework. We identified 25 “muscle fibre genes” (Akirin1, Bdkrb2, Bdnf, Camk4, Ccnd3, Cpt1a, Epas1, Esrrg, Foxj3, Foxo1, Il15, Mapk12, Mstn, Myod1, Ncor1, Nfatc1, Nol3, Ppargc1a, Ppargc1b, Sirt1, Sirt3, Thra, Thrb, Trib3, and Vgll2) whose gain or loss-of-function significantly changes type 1, 2A, 2X or 2B muscle fibre proportions in mice. The fact that 15 of the 25 muscle fibre genes are transcriptional regulators suggests that muscle fibre-specific gene expression is primarily regulated transcriptionally. A reanalysis of existing datasets revealed that the expression of Ppargc1a and Vgll2 increases and Mstn decreases after exercise, respectively. This suggests that these genes help to regulate the muscle fibre adaptation to exercise. Finally, there are many known DNA sequence variants of muscle fibre genes. It seems likely that such DNA sequence variants contribute to the large variation of muscle fibre type proportions in the human population.
Contribution of Microhomology to Genome Instability: Connection between DNA Repair and Replication Stress
Authors: Jiang Yuning
Published: October 2022

Microhomology-mediated end joining (MMEJ) is a highly mutagenic pathway to repair double-strand breaks (DSBs). MMEJ was thought to be a backup pathway of homologous recombination (HR) and canonical nonhomologous end joining (C-NHEJ). However, it attracts more attention in cancer research due to its special function of microhomology in many different aspects of cancer. In particular, it is initiated with DNA end resection and upregulated in homologous recombination-deficient cancers. In this review, I summarize the following: (1) the recent findings and contributions of MMEJ to genome instability, including phenotypes relevant to MMEJ; (2) the interaction between MMEJ and other DNA repair pathways; (3) the proposed mechanistic model of MMEJ in DNA DSB repair and a new connection with microhomology-mediated break-induced replication (MMBIR); and (4) the potential clinical application by targeting MMEJ based on synthetic lethality for cancer therapy.
A New Manganese Superoxide Dismutase Mimetic Improves Oxaliplatin-Induced Neuropathy and Global Tolerance in Mice
Authors: Prieux-Klotz Caroline , Chédotal Henri , Zoumpoulaki Martha , Chouzenoux Sandrine , Chêne Charlotte , Lopez-Sanchez Alvaro , Thomas Marine , Ranjan Sahoo Priya , Policar Clotilde , Batteux Frédéric , Bertrand Hélène C. , Nicco Carole , Coriat Romain
Published: October 2022

Reactive oxygen species (ROS) are produced by every aerobic cell during mitochondrial oxidative metabolism as well as in cellular response to xenobiotics, cytokines, and bacterial invasion. Superoxide Dismutases (SOD) are antioxidant proteins that convert superoxide anions (O2•−) to hydrogen peroxide (H2O2) and dioxygen. Using the differential in the level of oxidative stress between normal and cancer cells, SOD mimetics can show an antitumoral effect and prevent oxaliplatin-induced peripheral neuropathy. New Pt(IV) conjugate prodrugs (OxPt-x-Mn1C1A (x = 1, 1-OH, 2)), combining oxaliplatin and a Mn SOD mimic (MnSODm Mn1C1A) with a covalent link, were designed. Their stability in buffer and in the presence of sodium ascorbate was studied. In vitro, their antitumoral activity was assessed by the viability and ROS production of tumor cell lines (CT16, HCT 116, KC) and fibroblasts (primary culture and NIH 3T3). In vivo, a murine model of colorectal cancer was created with subcutaneous injection of CT26 cells in Balb/c mice. Tumor size and volume were measured weekly in four groups: vehicle, oxaliplatin, and oxaliplatin associated with MnSODm Mn1C1A and the bis-conjugate OxPt-2-Mn1C1A. Oxaliplatin-induced peripheral neuropathy (OIPN) was assessed using a Von Frey test reflecting chronic hypoalgesia. Tolerance to treatment was assessed with a clinical score including four items: weight loss, weariness, alopecia, and diarrhea. In vitro, Mn1C1A associated with oxaliplatin and Pt(IV) conjugates treatment induced significantly higher production of H2O2 in all cell lines and showed a significant improvement of the antitumoral efficacy compared to oxaliplatin alone. In vivo, the association of Mn1C1A to oxaliplatin did not decrease its antitumoral activity, while OxPt-2-Mn1C1A had lower antitumoral activity than oxaliplatin alone. Mn1C1A associated with oxaliplatin significantly decreased OIPN and also improved global clinical tolerance of oxaliplatin. A neuroprotective effect was observed, associated with a significantly improved tolerance to oxaliplatin without impairing its antitumoral activity.
Biosynthesis and Characterization of Gold Nanoparticles Produced Using Rhodococcus Actinobacteria at Elevated Chloroauric Acid Concentrations
Authors: Kuyukina Maria S. , Makarova Marina V. , Ivshina Irena B. , Kazymov Konstantin P. , Osovetsky Boris M.
Published: October 2022

The growing industrial and medical use of gold nanoparticles (AuNPs) requires environmentally friendly methods for their production using microbial biosynthesis. The ability of actinobacteria of the genus Rhodococcus to synthesize AuNPs in the presence of chloroauric acid (HAuCl4) was studied. The effect of elevated (0.8–3.2 mM) concentrations of HAuCl4 on bacterial viability, morphology, and intracellular accumulation of AuNPs by different Rhodococcus species was shown. An increase in surface roughness, a shift of the zeta potential to the positive region, and the formation of cell aggregates of R. erythropolis IEGM 766 and R. ruber IEGM 1135 during nanoparticle synthesis were revealed as bacterial adaptations to toxic effects of HAuCl4. The possibility to biosynthesize AuNPs at a five times higher concentration of chloroauric acid compared to chemical synthesis, for example, using the citrate method, suggests greater efficiency of the biological process using Rhodococcus species. The main parameters of biosynthesized AuNPs (size, shape, surface roughness, and surface charge) were characterized using atomic force microscopy, dynamic and electrophoretic light scattering, and also scanning electron microscopy in combination with energy-dispersive spectrometry. Synthesized by R. erythropolis spherical AuNPs have smaller (30–120 nm) dimensions and are positively (12 mV) charged, unlike AuNPs isolated from R. ruber cells (40–200 nm and −22 mV, respectively). Such differences in AuNPs size and surface charge are due to different biomolecules, which originated from Rhodococcus cells and served as capping agents for nanoparticles. Biosynthesized AuNPs showed antimicrobial activity against Gram-positive (Micrococcus luteus) and Gram-negative (Escherichia coli) bacteria. Due to the positive charge and high dispersion, the synthesized by R. erythropolis AuNPs are promising for biomedicine, whereas the AuNPs formed by R. ruber IEGM 1135 are prone to aggregation and can be used for biotechnological enrichment of gold-bearing ores.
Molecular Mechanisms of Ischaemia-Reperfusion Injury and Regeneration in the Liver-Shock and Surgery-Associated Changes
Authors: Pretzsch Elise , Nieß Hanno , Khaled Najib Ben , Bösch Florian , Guba Markus , Werner Jens , Angele Martin , Chaudry Irshad H.
Published: October 2022

Hepatic ischemia-reperfusion injury (IRI) represents a major challenge during liver surgery, liver preservation for transplantation, and can cause hemorrhagic shock with severe hypoxemia and trauma. The reduction of blood supply with a concomitant deficit in oxygen delivery initiates various molecular mechanisms involving the innate and adaptive immune response, alterations in gene transcription, induction of cell death programs, and changes in metabolic state and vascular function. Hepatic IRI is a major cause of morbidity and mortality, and is associated with an increased risk for tumor growth and recurrence after oncologic surgery for primary and secondary hepatobiliary malignancies. Therapeutic strategies to prevent or treat hepatic IRI have been investigated in animal models but, for the most part, have failed to provide a protective effect in a clinical setting. This review focuses on the molecular mechanisms underlying hepatic IRI and regeneration, as well as its clinical implications. A better understanding of this complex and highly dynamic process may allow for the development of innovative therapeutic approaches and optimize patient outcomes.
Nanosecond PEF Induces Oxidative Stress and Apoptosis via Proteasomal Activity Inhibition in Gastric Adenocarcinoma Cells with Drug Resistance
Authors: Kulbacka Julita , Rembiałkowska Nina , Szewczyk Anna , Rossowska Joanna , Drąg-Zalesińska Małgorzata , Kulbacki Marek , Choromańska Anna
Published: October 2022

Nanosecond (ns) pulsed electric field (PEF) is a technology in which the application of ultra-short electrical pulses can be used to disrupt the barrier function of cell plasma and internal membranes. Disruptions of the membrane integrity cause a substantial imbalance in cell homeostasis in which oxidative stress is a principal component. In the present study, nsPEF-induced oxidative stress was investigated in two gastric adenocarcinoma cell lines (EPG85-257P and EPG85-257RDB) which differ by their sensitivity to daunorubicin. Cells were exposed to 200 pulses of 10 ns duration, with the amplitude and pulse repetition frequency at 1 kHz, with electric field intensity varying from 12.5 to 50 kV/cm. The electroporation buffer contained either 1 mM or 2 mM calcium chloride. CellMask DeepRed visualized cell plasma permeabilization, Fluo-4 was used to visualize internal calcium ions content, and F-actin was labeled with AlexaFluor®488 for the cytoskeleton. The cellular viability was determined by MTT assay. An alkaline and neutral comet assay was employed to detect apoptotic and necrotic cell death. The luminescent method estimated the modifications in GSSG/GSH redox potential and the imbalance of proteasomal activity (chymotrypsin-, trypsin- and caspase-like). The reactive oxygen species (ROS) level was measured by flow cytometry using dihydroethidium (DHE) dye. Morphological visualization indicated cell shrinkage, affected cell membranes (characteristic bubbles and changed cell shape), and the reorganization of actin fibers with sites of its dense concentration; the effect was more intense with the increasing electric field strength. The most significant decrease in cell viability and GSSG/GSH redox potential was noted at the highest amplitude of 50 kV/cm, and calcium ions amplified this effect. nsPEF, particularly with calcium ions, inhibited proteasomal activities, resulting in increased protein degradation. nsPEF increased the percentage of apoptotic cells and ROS levels. The EPG85-257 RDB cell line, which is resistant to standard chemotherapy, was more sensitive to applied nsPEF protocols. The applied nsPEF method disrupted the metabolism of cancer cells and induced apoptotic cell death. The nsPEF ability to cause apoptosis, oxidative stress, and protein degradation make the nsPEF methodology a suitable alternative to current anticancer pharmacological methods.
Coapplication of Magnesium Supplementation and Vibration Modulate Macrophage Polarization to Attenuate Sarcopenic Muscle Atrophy through PI3K/Akt/mTOR Signaling Pathway
Authors: Cui Can , Bao Zhengyuan , Chow Simon Kwoon-Ho , Wong Ronald Man Yeung , Welch Ailsa , Qin Ling , Cheung Wing Hoi
Published: October 2022

Sarcopenia is an age-related geriatric syndrome characterized by the gradual loss of muscle mass and function. Low-magnitude high-frequency vibration (LMHFV) was shown to be beneficial to structural and functional outcomes of skeletal muscles, while magnesium (Mg) is a cofactor associated with better indices of skeletal muscle mass and strength. We hypothesized that LMHFV, Mg and their combinations could suppress inflammation and sarcopenic atrophy, promote myogenesis via PI3k/Akt/mTOR pathway in senescence-accelerated mouse P8 (SAMP8) mice and C2C12 myoblasts. Results showed that Mg treatment and LMHFV could significantly decrease inflammatory expression (C/EBPα and LYVE1) and modulate a CD206-positive M2 macrophage population at month four. Mg treatment also showed significant inhibitory effects on FOXO3, MuRF1 and MAFbx mRNA expression. Coapplication showed a synergistic effect on suppression of type I fiber atrophy, with significantly higher IGF-1, MyoD, MyoG mRNA (p < 0.05) and pAkt protein expression (p < 0.0001) during sarcopenia. In vitro inhibition of PI3K/Akt and mTOR abolished the enhancement effects on myotube formation and inhibited MRF mRNA and p85, Akt, pAkt and mTOR protein expressions. The present study demonstrated that the PI3K/Akt/mTOR pathway is the predominant regulatory mechanism through which LMHFV and Mg enhanced muscle regeneration and suppressed atrogene upregulation.
In Silico and In Vitro Studies of Benzothiazole-Isothioureas Derivatives as a Multitarget Compound for Alzheimer’s Disease
Authors: Rosales Hernández Martha Cecilia , Fragoso Morales Leticia Guadalupe , Correa Basurto José , Olvera Valdez Marycruz , García Báez Efrén Venancio , Román Vázquez Dania Guadalupe , Anaya García Ana Paola , Cruz Alejandro
Published: October 2022

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Inhibiting acetylcholinesterase (AChE), amyloid beta (Aβ1-42) aggregation and avoiding the oxidative stress could prevent the progression of AD. Benzothiazole groups have shown neuroprotective activity whereas isothioureas groups act as AChE inhibitors and antioxidants. Therefore, 22 benzothiazole-isothiourea derivatives (3a–v) were evaluated by docking simulations as inhibitors of AChE and Aβ1-42 aggregation. In silico studies showed that 3f, 3r and 3t had a delta G (ΔG) value better than curcumin and galantamine on Aβ1-42 and AChE, respectively. The physicochemical and pharmacokinetics predictions showed that only 3t does not violate Lipinski’s rule of five, though it has moderated cytotoxicity activity. Then, 3f, 3r and 3t were synthetized and chemically characterized for their in vitro evaluation including their antioxidant activity and their cytotoxicity in PC12 cells. 3r was able to inhibit AChE, avoid Aβ1-42 aggregation and exhibit antioxidant activity; nevertheless, it showed cytotoxic against PC12 cells. Compound 3t showed the best anti-Aβ1-42 aggregation and inhibitory AChE activity and, despite that predictor, showed that it could be cytotoxic; in vitro with PC12 cell was negative. Therefore, 3t could be employed as a scaffold to develop new molecules with multitarget activity for AD and, due to physicochemical and pharmacokinetics predictions, it could be administered in vivo using liposomes due to is not able to cross the BBB.
Physiological and Molecular Mechanisms of Plant Responses to Copper Stress
Authors: Chen Guang , Li Jia , Han Huimin , Du Ruiying , Wang Xu
Published: October 2022

Copper (Cu) is an essential micronutrient for humans, animals, and plants, and it participates in various morphological, physiological, and biochemical processes. Cu is a cofactor for a variety of enzymes, and it plays an important role in photosynthesis, respiration, the antioxidant system, and signal transduction. Many studies have demonstrated the adverse effects of excess Cu on crop germination, growth, photosynthesis, and antioxidant activity. This review summarizes the biological functions of Cu, the toxicity of excess Cu to plant growth and development, the roles of Cu transport proteins and chaperone proteins, and the transport process of Cu in plants, as well as the mechanisms of detoxification and tolerance of Cu in plants. Future research directions are proposed, which provide guidelines for related research.
Role of Cannabidiol for Improvement of the Quality of Life in Cancer Patients: Potential and Challenges
Authors: Green Ryan , Khalil Roukiah , Mohapatra Shyam S. , Mohapatra Subhra
Published: October 2022

There is currently a growing interest in the use of cannabidiol (CBD) to alleviate the symptoms caused by cancer, including pain, sleep disruption, and anxiety. CBD is often self-administered as an over-the-counter supplement, and patients have reported benefits from its use. However, despite the progress made, the mechanisms underlying CBD’s anti-cancer activity remain divergent and unclear. Herein, we provide a comprehensive review of molecular mechanisms to determine convergent anti-cancer actions of CBD from pre-clinical and clinical studies. In vitro studies have begun to elucidate the molecular targets of CBD and provide evidence of CBD’s anti-tumor properties in cell and mouse models of cancer. Furthermore, several clinical trials have been completed testing CBD’s efficacy in treating cancer-related pain. However, most use a mixture of CBD and the psychoactive, tetrahydrocannabinol (THC), and/or use variable dosing that is not consistent between individual patients. Despite these limitations, significant reductions in pain and opioid use have been reported in cancer patients using CBD or CBD+THC. Additionally, significant improvements in quality-of-life measures and patients’ overall satisfaction with their treatment have been reported. Thus, there is growing evidence suggesting that CBD might be useful to improve the overall quality of life of cancer patients by both alleviating cancer symptoms and by synergizing with cancer therapies to improve their efficacy. However, many questions remain unanswered regarding the use of CBD in cancer treatment, including the optimal dose, effective combinations with other drugs, and which biomarkers/clinical presentation of symptoms may guide its use.
From Cyclo[18]carbon to the Novel Nanostructures—Theoretical Predictions
Authors: Brzyska Agnieszka , Panczyk Tomasz , Wolinski Krzysztof
Published: October 2022

In this paper, we present a number of novel pure-carbon structures generated from cyclo[18]carbon. Due to the very high reactivity of cyclo[18]carbon, it is possible to link these molecules together to form bigger molecular systems. In our studies, we generated new structures containing 18, 36 and 72 carbon atoms. They are of different shapes including ribbons, sheets and tubes. All these new structures were obtained in virtual reactions driven by external forces. For every reaction, the energy requirement was evaluated exactly when the corresponding transition state was found or it was estimated through our new approach. A small HOMO–LUMO gap in these nanostructures indicates easy excitations and the multiple bonds network indicates their high reactivity. Both of these factors suggest that some potential applications of the new nanostructures are as components of therapeutically active carbon quantum dots, terminal fragments of graphene or carbon nanotubes obtained after fracture or growing in situ in catalytic reactions leading to the formation of carbonaceous materials.
Nna1, Essential for Purkinje Cell Survival, Is also Associated with Emotion and Memory
Authors: Zhou Li , Konno Kohtarou , Yamazaki Maya , Abe Manabu , Natsume Rie , Watanabe Masahiko , Takebayashi Hirohide , Sakimura Kenji
Published: October 2022

Nna1/CCP1 is generally known as a causative gene for a spontaneous autosomal recessive mouse mutation, Purkinje cell degeneration (pcd). There is enough evidence that the cytosolic function of the zinc carboxypeptidase (CP) domain at the C-terminus of the Nna1 protein is associated with cell death. On the other hand, this molecule’s two nuclear localization signals (NLSs) suggest some other functions exist. We generated exon 3-deficient mice (Nna1N KO), which encode a portion of the N-terminal NLS. Despite the frameshift occurring in these mice, there was an expression of the Nna1 protein lacking the N-terminal side. Surprisingly, the pcd phenotype did not occur in the Nna1N KO mouse. Behavioral analysis revealed that they were less anxious when assessed by the elevated plus maze and the light/dark box tests compared to the control. Furthermore, they showed impairments in context-dependent and sound stimulus-dependent learning. Biochemical analysis of Nna1N KO mice revealed a reduced level of the AMPA-type glutamine receptor GluA2 in the hippocampal synaptosomal fraction. In addition, the motor protein kinesin-1, which transports GluA2 to dendrites, was also decreased. These results indicate that Nna1 is also involved in emotion and memory learning, presumably through the trafficking and expression of synaptic signaling molecules, besides a known role in cell survival.
Impact of High-Density Lipoproteins on Sepsis
Authors: De Geest Bart , Mishra Mudit
Published: October 2022

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Here, we review the impact of high-density lipoproteins (HDL) on sepsis from the perspective of biochemistry and pathophysiology, epidemiological research, and intervention studies in animals. Pathogen lipid moieties are major ligands for innate immunity receptors, such as toll-like receptors. The binding of pathogen-associated lipids to lipoproteins leads to sequestration, neutralization, and inactivation of their pro-inflammatory effects. Lipoproteins constitute an arm of the innate immune system. Pathogen-associated lipids can be removed from the body via the reverse lipopolysaccharide transport pathway in which HDL play a key role. Independent of the capacity for sequestration, the direct anti-inflammatory effects of HDL may counteract the development of sepsis. Mendelian randomization research using genetic variants associated with HDL cholesterol as an instrumental variable was consistent with a probable causal relationship between increased HDL cholesterol levels and decreased risk of infectious hospitalizations. Low HDL cholesterol independently predicts an adverse prognosis in sepsis both in observational epidemiology and in Mendelian randomization studies. Several HDL-associated enzymes, including phospholipid transfer protein (PLTP) and cholesterol ester transfer protein (CETP), undergo profound changes during sepsis. Potential HDL-directed interventions for treatment of sepsis include apolipoprotein A-I-based therapies, recombinant PLTP, and CETP inhibition.
Old and New Blood Markers in Human Colorectal Cancer
Authors: Wautier Jean-Luc , Wautier Marie-Paule
Published: October 2022

Cancer is a predominant cause of mortality all over the world. Lung, prostate, and colorectal cancer are the more frequent in men while breast and colorectal have a high incidence in women. Major progress aside, some cancers are still frequent and one major issue is improvements in detection methods. Imaging techniques have a major role, but inflammatory, tumoral markers and calculated scores may contribute to the assessment of prognosis. The erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and carcinoembryonic antigen cell adhesion molecule (CEACAM) have been used for decades and do not have a clear use for diagnosis or prognosis yet. The CEACAM family includes 12 human members, and some of them have a cluster differentiation (CD). CD66 may be an interesting indicator of disease severity. Beside interleukin-6 (IL-6), the high level of which is observed in patients with a high mortality rate, other cytokines IL-17A, IL-22, and transforming growth factor -β (TGF-β) are expressed at the tumor level. The detection of circulating tumor cells has been improved but is still of undetermined value. Circulating tumor DNA (ctDNA) was recently studied in CRC stage II patients and may be helpful for chemotherapy management.
Expression Profile of microRNAs during Development of the Hypopharyngeal Gland in Honey Bee, Apis mellifera
Authors: Qin Kaixin , Cheng Fuping , Pan Luxia , Wang Zilong
Published: October 2022

The hypopharyngeal gland is an important organ for honey bees to secrete royal jelly, and its secretory activity varies with the age of workers. However, by now, the regulation mechanism of hypopharyngeal gland development is still unclear. Here, the expression profiles of miRNAs in the hypopharyngeal gland of newly emerged workers, nurses, and foragers were investigated via small RNA sequencing. From these three stages, 81 known miRNAs and 135 novel miRNAs have been identified. A total of 85 miRNAs showed expression differences between different development stages, and their target genes were predicted to range from 1 to more than 10. Many of the differentially expressed miRNAs and target genes are related to growth and development or apoptosis. Moreover, dual-luciferase-reporter assays verified that novel-miR-11 directly targets the 3′-untranslated regions of LOC410685 (inactive tyrosine-protein kinase 7) and LOC725318 (uncharacterized protein). These results suggested that miRNAs were widely involved in the developmental regulation of the hypopharyngeal gland in honey bees.