bluuebunny/crossref_metadata_2025 huggingface dataset:
Preventing Disused Bone Loss through Inhibition of Advanced Glycation End Products
Authors: Liu Cong-Jin , Yang Xiao , Wang Shou-Hui , Wu Xin-Tong , Mao Yan , Shi Jing-Wen , Fan Yu-Bo , Sun Lian-Wen
Published: March 2023

Bone loss occurs in astronauts during long-term space flight, but the mechanisms are still unclear. We previously showed that advanced glycation end products (AGEs) were involved in microgravity-induced osteoporosis. Here, we investigated the improvement effects of blocking AGEs formation on microgravity-induced bone loss by using the AGEs formation inhibitor, irbesartan. To achieve this objective, we used a tail-suspended (TS) rat model to simulate microgravity and treated the TS rats with 50 mg/kg/day irbesartan, as well as the fluorochrome biomarkers injected into rats to label dynamic bone formation. To assess the accumulation of AGEs, pentosidine (PEN), non-enzymatic cross-links (NE−xLR), and fluorescent AGEs (fAGEs) were identified in the bone; 8-hydroxydeoxyguanosine (8-OHdG) was analyzed for the reactive oxygen species (ROS) level in the bone. Meanwhile, bone mechanical properties, bone microstructure, and dynamic bone histomorphometry were tested for bone quality assessment, and Osterix and TRAP were immunofluorescences stained for the activities of osteoblastic and osteoclastic cells. Results showed AGEs increased significantly and 8-OHdG expression in bone showed an upward trend in TS rat hindlimbs. The bone quality (bone microstructure and mechanical properties) and bone formation process (dynamic bone formation and osteoblastic cells activities) were inhibited after tail-suspension, and showed a correlation with AGEs, suggesting the elevated AGEs contributed to the disused bone loss. After being treated with irbesartan, the increased AGEs and 8-OHdG expression were significantly inhibited, suggesting irbesartan may reduce ROS to inhibit dicarbonyl compounds, thus suppressing AGEs production after tail-suspension. The inhibition of AGEs can partially alter the bone remodeling process and improve bone quality. Both AGEs accumulation and bone alterations almost occurred in trabecular bone but not in cortical bone, suggesting AGEs effects on bone remodeling under microgravity are dependent on the biological milieu.
Clostridium butyricum Prevents Dysbiosis and the Rise in Blood Pressure in Spontaneously Hypertensive Rats
Authors: Luo Xianshu , Han Zhuoyu , Kong Qing , Wang Yuming , Mou Haijin , Duan Xuefeng
Published: March 2023

Hypertension is accompanied by dysbiosis and a decrease in the relative abundance of short-chain fatty acid (SCFA)-producing bacteria. However, there is no report to examine the role of C. butyricum in blood pressure regulation. We hypothesized that a decrease in the relative abundance of SCFA-producing bacteria in the gut was the cause of spontaneously hypertensive rats (SHR)-induced hypertension. C. butyricum and captopril were used to treat adult SHR for six weeks. C. butyricum modulated SHR-induced dysbiosis and significantly reduced systolic blood pressure (SBP) in SHR (p < 0.01). A 16S rRNA analysis determined changes in the relative abundance of the mainly SCFA-producing bacteria Akkermansia muciniphila, Lactobacillus amylovorus, and Agthobacter rectalis, which increased significantly. Total SCFAs, and particularly butyrate concentrations, in the SHR cecum and plasma were reduced (p < 0.05), while C. butyricum prevented this effect. Likewise, we supplemented SHR with butyrate for six weeks. We analyzed the flora composition, cecum SCFA concentration, and inflammatory response. The results showed that butyrate prevented SHR-induced hypertension and inflammation, and the decline of cecum SCFA concentrations (p < 0.05). This research revealed that increasing cecum butyrate concentrations by probiotics, or direct butyrate supplementation, prevented the adverse effects of SHR on intestinal flora, vascular, and blood pressure.
CCR5∆32 and SDF1 3′A: Gene Variants, Expression and Influence on Biological Markers for the Clinical Progression to AIDS among HIV-1 Virus Controllers in a Mixed Population of the Amazon Region of Brazil
Authors: Lima Érica Ribeiro Gomes , Queiroz Maria Alice Freitas , Lima Sandra Souza , Machado Luiz Fernando Almeida , Cayres-Vallinoto Izaura Maria Vieira , Vallinoto Antonio Carlos Rosário , Figueiredo Fernanda Andreza de Pinho Lott , Guerreiro João Farias , Guimarães Ishak Marluísa de Oliveira , Ishak Ricardo
Published: March 2023

CCR5Δ32 and SDF1-3′A polymorphisms were investigated in a cohort of viremia controllers, without the use of therapy, along with their influence on CD4+ T lymphocytes (TLs), CD8+ TLs, and plasma viral load (VL). The samples were analyzed from 32 HIV-1-infected individuals classified as viremia controllers 1 and 2 and viremia non-controllers, from both sexes, mostly heterosexuals, paired with 300 individuals from a control group. CCR5∆32 polymorphism was identified by PCR amplification of a fragment of 189 bp for the wild-type allele and 157 bp for the allele with the ∆32 deletion. SDF1-3′A polymorphism was identified by PCR, followed by enzymatic digestion (restriction fragment length polymorphism) with the Msp I enzyme. The relative quantification of gene expression was performed by real-time PCR. The distribution of allele and genotype frequencies did not show significant differences between the groups. The gene expression of CCR5 and SDF1 was not different between the profiles of AIDS progression. There was no significant correlation between the progression markers (CD4+ TL/CD8+ TL and VL) and the CCR5∆32 polymorphism carrier status. The 3′A allele variant was associated with a marked loss of CD4+ TLs and a higher plasma VL. Neither CCR5∆32 nor SDF1-3′A was associated with viremia control or the controlling phenotype.
Role of Monomer/Tetramer Equilibrium of Rod Visual Arrestin in the Interaction with Phosphorylated Rhodopsin
Authors: Imamoto Yasushi , Kojima Keiichi , Maeda Ryo , Shichida Yoshinori , Oka Toshihiko
Published: March 2023

The phototransduction cascade in vertebrate rod visual cells is initiated by the photoactivation of rhodopsin, which enables the activation of the visual G protein transducin. It is terminated by the phosphorylation of rhodopsin, followed by the binding of arrestin. Here we measured the solution X-ray scattering of nanodiscs containing rhodopsin in the presence of rod arrestin to directly observe the formation of the rhodopsin/arrestin complex. Although arrestin self-associates to form a tetramer at physiological concentrations, it was found that arrestin binds to phosphorylated and photoactivated rhodopsin at 1:1 stoichiometry. In contrast, no complex formation was observed for unphosphorylated rhodopsin upon photoactivation, even at physiological arrestin concentrations, suggesting that the constitutive activity of rod arrestin is sufficiently low. UV-visible spectroscopy demonstrated that the rate of the formation of the rhodopsin/arrestin complex well correlates with the concentration of arrestin monomer rather than the tetramer. These findings indicate that arrestin monomer, whose concentration is almost constant due to the equilibrium with the tetramer, binds to phosphorylated rhodopsin. The arrestin tetramer would act as a reservoir of monomer to compensate for the large changes in arrestin concentration in rod cells caused by intense light or adaptation.
Relevance of HBx for Hepatitis B Virus-Associated Pathogenesis
Authors: Schollmeier Anja , Glitscher Mirco , Hildt Eberhard
Published: March 2023

The hepatitis B virus (HBV) counts as a major global health problem, as it presents a significant causative factor for liver-related morbidity and mortality. The development of hepatocellular carcinomas (HCC) as a characteristic of a persistent, chronic infection could be caused, among others, by the pleiotropic function of the viral regulatory protein HBx. The latter is known to modulate an onset of cellular and viral signaling processes with emerging influence in liver pathogenesis. However, the flexible and multifunctional nature of HBx impedes the fundamental understanding of related mechanisms and the development of associated diseases, and has even led to partial controversial results in the past. Based on the cellular distribution of HBx—nuclear-, cytoplasmic- or mitochondria-associated—this review encompasses the current knowledge and previous investigations of HBx in context of cellular signaling pathways and HBV-associated pathogenesis. In addition, particular focus is set on the clinical relevance and potential novel therapeutic applications in the context of HBx.
6-Shogaol as a Novel Thioredoxin Reductase Inhibitor Induces Oxidative-Stress-Mediated Apoptosis in HeLa Cells
Authors: Peng Shoujiao , Yu Shaopeng , Zhang Junmin , Zhang Jiange
Published: March 2023

Inhibition of thioredoxin reductase (TrxR) is a crucial strategy for the discovery of antineoplastic drugs. 6-Shogaol (6-S), a primary bioactive compound in ginger, has high anticancer activity. However, its potential mechanism of action has not been thoroughly investigated. In this study, we demonstrated for the first time that 6-S, a novel TrxR inhibitor, promoted oxidative-stress-mediated apoptosis in HeLa cells. The other two constituents of ginger, 6-gingerol (6-G) and 6-dehydrogingerduone (6-DG), have a similar structure to 6-S but fail to kill HeLa cells at low concentrations. 6-Shogaol specifically inhibits purified TrxR1 activity by targeting selenocysteine residues. It also induced apoptosis and was more cytotoxic to HeLa cells than normal cells. The molecular mechanism of 6-S-mediated apoptosis involves TrxR inhibition, followed by an outburst of reactive oxygen species (ROS) production. Furthermore, TrxR knockdown enhanced the cytotoxic sensitivity of 6-S cells, highlighting the physiological significance of targeting TrxR by 6-S. Our findings show that targeting TrxR by 6-S reveals a new mechanism underlying the biological activity of 6-S and provides meaningful insights into its action in cancer therapeutics.
Deferiprone and Iron–Maltol: Forty Years since Their Discovery and Insights into Their Drug Design, Development, Clinical Use and Future Prospects
Authors: Kontoghiorghes George J.
Published: March 2023

The historical insights and background of the discovery, development and clinical use of deferiprone (L1) and the maltol–iron complex, which were discovered over 40 years ago, highlight the difficulties, complexities and efforts in general orphan drug development programs originating from academic centers. Deferiprone is widely used for the removal of excess iron in the treatment of iron overload diseases, but also in many other diseases associated with iron toxicity, as well as the modulation of iron metabolism pathways. The maltol–iron complex is a recently approved drug used for increasing iron intake in the treatment of iron deficiency anemia, a condition affecting one-third to one-quarter of the world’s population. Detailed insights into different aspects of drug development associated with L1 and the maltol–iron complex are revealed, including theoretical concepts of invention; drug discovery; new chemical synthesis; in vitro, in vivo and clinical screening; toxicology; pharmacology; and the optimization of dose protocols. The prospects of the application of these two drugs in many other diseases are discussed under the light of competing drugs from other academic and commercial centers and also different regulatory authorities. The underlying scientific and other strategies, as well as the many limitations in the present global scene of pharmaceuticals, are also highlighted, with an emphasis on the priorities for orphan drug and emergency medicine development, including the roles of the academic scientific community, pharmaceutical companies and patient organizations.
Fluorescence Analysis of Biocide Efficiency in Antifouling Coatings against Cyanobacteria
Authors: Orzechowska Aleksandra , Czaderna-Lekka Anna , Trtílek Martin , Rusiniak Piotr
Published: March 2023

This study focused on the antifouling effect of copper oxide (Cu2O)- and zineb-based coatings against Cyanothece sp. ATCC 51142 by analysing photosynthetic activity using chlorophyll fluorescence. The photoautotrophically grown cyanobacterium was exposed to toxic coatings over a short-term period of 32 h. The study showed that Cyanothece cultures are particularly sensitive to biocides (i) released from antifouling paints and (ii) exhibited by contact with the coated surfaces. Changes in the maximum quantum yield of photosystem II (FV/FM) were observed within the first 12 h of exposure to the coatings. Partial recovery of FV/FM in Cyanothece was revealed 24 h post exposure to a copper- and zineb-free coating. In this research, we proposed an analysis of the evaluation of fluorescence data to study the initial response of cyanobacterial cells to copper- and non-copper-based antifouling coatings formulated with zineb. We evaluated the dynamics of coating toxicity by determining the characteristic time constants of changes in the FV/FM. Within the most toxic paints studied, those formulated with the highest concentration of Cu2O and zineb, the estimated time constants were 3.9 times lower compared to the copper- and zineb-free paint. The use of zineb in copper-based antifouling coatings enhanced the toxic effect of paints and contributed to a faster decline in photosystem II activity in Cyanothece cells. The analysis we proposed, along with the fluorescence screening results, may be useful in evaluating the initial antifouling dynamic action against photosynthetic aquacultures.
Advances in Boron Neutron Capture Therapy (BNCT) for Recurrent Intracranial Meningioma
Authors: Lan Tien-Li , Lin Chun-Fu , Lee Yi-Yen , Lin Ko-Han , Chang Feng-Chi , Lin Shih-Chieh , Lee Jia-Cheng , Chou Fong-In , Peir Jinn-Jer , Liu Hong-Ming , Mu Pei-Fan , Chen Yi-Wei
Published: March 2023

Meningiomas are the most frequently diagnosed primary intracranial tumors in adults. Surgical resection is preferred if the meningioma is accessible; for those that are not suitable for surgical resection, radiotherapy should be considered to improve local tumor control. However, recurrent meningiomas are challenging to treat, as the recurrent tumor might be located in the previously irradiated area. Boron Neutron Capture Therapy (BNCT) is a highly selective radiotherapy modality in which the cytotoxic effect focuses mainly on cells with increased uptake of boron-containing drugs. In this article, we describe four patients with recurrent meningiomas treated with BNCT in Taiwan. The mean boron-containing drug tumor-to-normal tissue uptake ratio was 4.125, and the tumor mean dose was 29.414 GyE, received via BNCT. The treatment response showed two stable diseases, one partial response, and one complete response. We also introduce and support the effectiveness and safety of BNCT as an alternative salvage treatment for recurrent meningiomas.
Therapeutic Effects of Cornuside on Particulate Matter–Induced Lung Injury
Authors: Kim Go Oun , Park Eui Kyun , Park Dong Ho , Song Gyu Yong , Bae Jong-Sup
Published: March 2023

Particulate matter (PM) is a mixture comprising both organic and inorganic particles, both of which are hazardous to health. The inhalation of airborne PM with a diameter of ≤2.5 μm (PM2.5) can cause considerable lung damage. Cornuside (CN), a natural bisiridoid glucoside derived from the fruit of Cornus officinalis Sieb, exerts protective properties against tissue damage via controlling the immunological response and reducing inflammation. However, information regarding the therapeutic potential of CN in patients with PM2.5-induced lung injury is limited. Thus, herein, we examined the protective properties of CN against PM2.5-induced lung damage. Mice were categorized into eight groups (n = 10): a mock control group, a CN control group (0.8 mg/kg mouse body weight), four PM2.5+CN groups (0.2, 0.4, 0.6, and 0.8 mg/kg mouse body weight), and a PM2.5+CN group (0.2, 0.4, 0.6, and 0.8 mg/kg mouse body weight). The mice were administered with CN 30 min following intratracheal tail vein injection of PM2.5. In mice exposed to PM2.5, different parameters including changes in lung tissue wet/dry (W/D) lung weight ratio, total protein/total cell ratio, lymphocyte counts, inflammatory cytokine levels in the bronchoalveolar lavage fluid (BALF), vascular permeability, and histology were examined. Our findings revealed that CN reduced lung damage, the W/D weight ratio, and hyperpermeability caused by PM2.5. Moreover, CN reduced the plasma levels of inflammatory cytokines produced because of PM2.5 exposure, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and nitric oxide, as well as the total protein concentration in the BALF, and successfully attenuated PM2.5-associated lymphocytosis. In addition, CN substantially reduced the expression levels of Toll-like receptors 4 (TLR4), MyD88, and autophagy-related proteins LC3 II and Beclin 1, and increased protein phosphorylation of the mammalian target of rapamycin (mTOR). Thus, the anti-inflammatory property of CN renders it a potential therapeutic agent for treating PM2.5-induced lung injury by controlling the TLR4–MyD88 and mTOR–autophagy pathways.
Preparation of a Mussel-Inspired Supramolecular Polymer Coating Containing Graphene Oxide on Magnesium Alloys with Anti-Corrosion and Self-Healing Properties
Authors: Zhang Meiling , Yu Xiaoming , Sheng Mengyi , Chen Hua , Chen Bailin
Published: March 2023

Herein, we present a mussel-inspired supramolecular polymer coating to improve the an-ti-corrosion and self-healing properties of an AZ31B magnesium alloy. A self-assembled coating of polyethyleneimine (PEI) and polyacrylic acid (PAA) is a supramolecular aggregate that takes advantage of the weak interaction of non-covalent bonds between molecules. The cerium-based conversion layers overcome the corrosion problem between the coating and the substrate. Catechol mimics mussel proteins to form adherent polymer coatings. Chains of PEI and PAA interact electrostatically at high density, forming a dynamic binding that causes strand entanglement, enabling the rapid self-healing properties of a supramolecular polymer. The addition of graphene oxide (GO) as an anti-corrosive filler gives the supramolecular polymer coating a superior barrier and impermeability properties. The results of EIS revealed that a direct coating of PEI and PAA accelerates the corrosion of magnesium alloys; the impedance modulus of a PEI and PAA coating is only 7.4 × 103 Ω·cm2, and the corrosion current of a 72 h immersion in a 3.5 wt% NaCl solution is 1.401 × 10−6 Ω·cm2. The impedance modulus of the addition of a catechol and graphene oxide supramolecular polymer coating is up to 3.4 × 104 Ω·cm2, outperforming the substrate by a factor of two. After soaking in a 3.5 wt% NaCl solution for 72 h, the corrosion current is 0.942 × 10−6 A/cm2, which is superior to other coatings in this work. Furthermore, it was found that 10-micron scratches were completely healed in all coatings within 20 min, in the presence of water. The supramolecular polymer offers a new technique for the prevention of metal corrosion.
Molecular Insights into IQSEC2 Disease
Authors: Levy Nina S. , Borisov Veronika , Lache Orit , Levy Andrew P.
Published: March 2023

Recent insights into IQSEC2 disease are summarized in this review as follows: (1) Exome sequencing of IQSEC2 patient DNA has led to the identification of numerous missense mutations that delineate at least six and possibly seven essential functional domains present in the IQSEC2 gene. (2) Experiments using IQSEC2 transgenic and knockout (KO) mouse models have recapitulated the presence of autistic-like behavior and epileptic seizures in affected animals; however, seizure severity and etiology appear to vary considerably between models. (3) Studies in IQSEC2 KO mice reveal that IQSEC2 is involved in inhibitory as well as stimulatory neurotransmission. The overall picture appears to be that mutated or absent IQSEC2 arrests neuronal development, resulting in immature neuronal networks. Subsequent maturation is aberrant, leading to increased inhibition and reduced neuronal transmission. (4) The levels of Arf6-GTP remain constitutively high in IQSEC2 knockout mice despite the absence of IQSEC2 protein, indicating impaired regulation of the Arf6 guanine nucleotide exchange cycle. (5) A new therapy that has been shown to reduce the seizure burden for the IQSEC2 A350V mutation is heat treatment. Induction of the heat shock response may be responsible for this therapeutic effect.
Chromogranin A: An Endocrine Factor of Pregnancy
Authors: Bralewska Michalina , Pietrucha Tadeusz , Sakowicz Agata
Published: March 2023

Pregnancy is a state of physiological and hormonal changes. One of the endocrine factors involved in these processes is chromogranin A, an acidic protein produced, among others, by the placenta. Although it has been previously linked to pregnancy, no existing articles have ever managed to clarify the role of this protein regarding this subject. Therefore, the aim of the present study is to gather knowledge of chromogranin A’s function with reference to gestation and parturition, clarify elusive information, and, most importantly, to formulate hypotheses for the future studies to verify.
Resveratrol Modulates Chemosensitisation to 5-FU via β1-Integrin/HIF-1α Axis in CRC Tumor Microenvironment
Authors: Brockmueller Aranka , Girisa Sosmitha , Kunnumakkara Ajaikumar B. , Shakibaei Mehdi
Published: March 2023

Frequent development of resistance to chemotherapeutic agents such as 5-flourouracil (5-FU) complicates the treatment of advanced colorectal cancer (CRC). Resveratrol is able to utilize β1-integrin receptors, strongly expressed in CRC cells, to transmit and exert anti-carcinogenic signals, but whether it can also utilize these receptors to overcome 5-FU chemoresistance in CRC cells has not yet been investigated. Effects of β1-integrin knockdown on anti-cancer capabilities of resveratrol and 5-FU were investigated in HCT-116 and 5-FU-resistant HCT-116R CRC tumor microenvironment (TME) with 3D-alginate as well as monolayer cultures. Resveratrol increased CRC cell sensitivity to 5-FU by reducing TME-promoted vitality, proliferation, colony formation, invasion tendency and mesenchymal phenotype including pro-migration pseudopodia. Furthermore, resveratrol impaired CRC cells in favor of more effective utilization of 5-FU by down-regulating TME-induced inflammation (NF-kB), vascularisation (VEGF, HIF-1α) and cancer stem cell production (CD44, CD133, ALDH1), while up-regulating apoptosis (caspase-3) that was previously inhibited by TME. These anti-cancer mechanisms of resveratrol were largely abolished by antisense oligonucleotides against β1-integrin (β1-ASO) in both CRC cell lines, indicating the particular importance of β1-integrin receptors for the 5-FU-chemosensitising effect of resveratrol. Lastly, co-immunoprecipitation tests showed that resveratrol targets and modulates the TME-associated β1-integrin/HIF-1α signaling axis in CRC cells. Our results suggest for the first time the utility of the β1-integrin/HIF-1α signaling axis related to chemosensitization and overcoming chemoresistance to 5-FU in CRC cells by resveratrol, underlining its potential supportive applications in CRC treatment.
Pharmacological Agents Used in the Prevention and Treatment of Actinic Keratosis: A Review
Authors: Arcuri Domenico , Ramchatesingh Brandon , Lagacé François , Iannattone Lisa , Netchiporouk Elena , Lefrançois Philippe , Litvinov Ivan V.
Published: March 2023

Actinic keratosis (AK) is among the most commonly diagnosed skin diseases with potentially life-threatening repercussions if left untreated. Usage of pharmacologic agents represents one of many therapeutic strategies that can be used to help manage these lesions. Ongoing research into these compounds continues to change our clinical understanding as to which agents most benefit particular patient populations. Indeed, factors such as past personal medical history, lesion location and tolerability of therapy only represent a few considerations that clinicians must account for when prescribing appropriate treatment. This review focuses on specific drugs used in either the prevention or treatment of AKs. Nicotinamide, acitretin and topical 5-fluorouracil (5-FU) continue to be used with fidelity in the chemoprevention of actinic keratosis, although some uncertainty persists in regard to which agents should be used in immunocompetent vs. immunodeficient/immunosuppressed patients. Topical 5-FU, including combination formulations with either calcipotriol or salicylic acid, as well as imiquimod, diclofenac and photodynamic light therapy are all accepted treatment strategies employed to target and eliminate AKs. Five percent of 5-FU is regarded as the most effective therapy in the condition, although the literature has conflictingly shown that lower concentrations of the drug might also be as effective. Topical diclofenac (3%) appears to be less efficacious than 5% 5-FU, 3.75–5% imiquimod and photodynamic light therapy despite its favorable side effect profile. Finally, traditional photodynamic light therapy, while painful, appears to be of higher efficacy in comparison to its more tolerable counterpart, daylight phototherapy.
Dual Role of Mitogen-Activated Protein Kinase 8 Interacting Protein-1 in Inflammasome and Pancreatic β-Cell Function
Authors: Saeed Rania , Mohammed Abdul Khader , Saleh Sarra E. , Aboulwafa Mohammad M. , Aboshanab Khaled M. , Taneera Jalal
Published: March 2023

Inflammasomes have been implicated in the pathogenesis of type 2 diabetes (T2D). However, their expression and functional importance in pancreatic β-cells remain largely unknown. Mitogen-activated protein kinase 8 interacting protein-1 (MAPK8IP1) is a scaffold protein that regulates JNK signaling and is involved in various cellular processes. The precise role of MAPK8IP1 in inflammasome activation in β-cells has not been defined. To address this gap in knowledge, we performed a set of bioinformatics, molecular, and functional experiments in human islets and INS-1 (832/13) cells. Using RNA-seq expression data, we mapped the expression pattern of proinflammatory and inflammasome-related genes (IRGs) in human pancreatic islets. Expression of MAPK8IP1 in human islets was found to correlate positively with key IRGs, including the NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3), Gasdermin D (GSDMD) and Apoptosis-associated speck-like protein containing a CARD (ASC), but correlate inversely with Nuclear factor kappa β1 (NF-κβ1), Caspase-1 (CASP-1), Interleukin-18 (IL-18), Interleukin-1β (IL-1β) and Interleukin 6 (IL-6). Ablation of Mapk8ip1 by siRNA in INS-1 cells down-regulated the basal expression levels of Nlrp3, NLR family CARD domain containing 4 (Nlrc4), NLR family CARD domain containing 1 (Nlrp1), Casp1, Gsdmd, Il-1β, Il-18, Il-6, Asc, and Nf-κβ1 at the mRNA and/or protein level and decreased palmitic acid (PA)-induced inflammasome activation. Furthermore, Mapk8ip1-silened cells substantially reduced reactive oxygen species (ROS) generation and apoptosis in palmitic acid-stressed INS-1 cells. Nonetheless, silencing of Mapk8ip1 failed to preserve β-cell function against inflammasome response. Taken together, these findings suggest that MAPK8IP1 is involved in regulating β-cells by multiple pathways.
MicroRNA-200c-5p Regulates Migration and Differentiation of Myoblasts via Targeting Adamts5 in Skeletal Muscle Regeneration and Myogenesis
Authors: Liu Yanwen , Yao Yilong , Zhang Yongsheng , Yan Chao , Yang Mingsha , Wang Zishuai , Li Wangzhang , Li Fanqinyu , Wang Wei , Yang Yalan , Li Xinyun , Tang Zhonglin
Published: March 2023

Skeletal muscle, as a regenerative organization, plays a vital role in physiological characteristics and homeostasis. However, the regulation mechanism of skeletal muscle regeneration is not entirely clear. miRNAs, as one of the regulatory factors, exert profound effects on regulating skeletal muscle regeneration and myogenesis. This study aimed to discover the regulatory function of important miRNA miR-200c-5p in skeletal muscle regeneration. In our study, miR-200c-5p increased at the early stage and peaked at first day during mouse skeletal muscle regeneration, which was also highly expressed in skeletal muscle of mouse tissue profile. Further, overexpression of miR-200c-5p promoted migration and inhibited differentiation of C2C12 myoblast, whereas inhibition of miR-200c-5p had the opposite effect. Bioinformatic analysis predicted that Adamts5 has potential binding sites for miR-200c-5p at 3’UTR region. Dual-luciferase and RIP assays further proved that Adamts5 is a target gene of miR-200c-5p. The expression patterns of miR-200c-5p and Adamts5 were opposite during the skeletal muscle regeneration. Moreover, miR-200c-5p can rescue the effects of Adamts5 in the C2C12 myoblast. In conclusion, miR-200c-5p might play a considerable function during skeletal muscle regeneration and myogenesis. These findings will provide a promising gene for promoting muscle health and candidate therapeutic target for skeletal muscle repair.
Microbiota-Derived Natural Products Targeting Cancer Stem Cells: Inside the Gut Pharma Factory
Authors: Artusa Valentina , Calabrone Luana , Mortara Lorenzo , Peri Francesco , Bruno Antonino
Published: March 2023

Cancer stem cells (CSCs) have drawn much attention as important tumour-initiating cells that may also be crucial for recurrence after chemotherapy. Although the activity of CSCs in various forms of cancer is complex and yet to be fully elucidated, opportunities for therapies targeting CSCs exist. CSCs are molecularly distinct from bulk tumour cells, so they can be targeted by exploiting their signature molecular pathways. Inhibiting stemness has the potential to reduce the risk posed by CSCs by limiting or eliminating their capacity for tumorigenesis, proliferation, metastasis, and recurrence. Here, we briefly described the role of CSCs in tumour biology, the mechanisms involved in CSC therapy resistance, and the role of the gut microbiota in cancer development and treatment, to then review and discuss the current advances in the discovery of microbiota-derived natural compounds targeting CSCs. Collectively, our overview suggests that dietary intervention, toward the production of those identified microbial metabolites capable of suppressing CSC properties, is a promising approach to support standard chemotherapy.
New Insights into Cardiac Ion Channel Regulation 2.0
Authors: Delisle Brian P. , Aromolaran Ademuyiwa S.
Published: March 2023

Sudden cardiac death (SCD) and arrhythmias represent a global public health problem, accounting for 15–20% of all deaths [...]
An Immunological Perspective on the Mechanism of Drug Induced Liver Injury: Focused on Drugs for Treatment of Hepatocellular Carcinoma and Liver Transplantation
Authors: Lee Soon Kyu , Choi Jong Young , Jung Eun Sun , Kwon Jung Hyun , Jang Jeong Won , Bae Si Hyun , Yoon Seung Kew
Published: March 2023

The liver is frequently exposed to potentially toxic materials, and it is the primary site of clearance of foreign agents, along with many innate and adaptive immune cells. Subsequently, drug induced liver injury (DILI), which is caused by medications, herbs, and dietary supplements, often occurs and has become an important issue in liver diseases. Reactive metabolites or drug–protein complexes induce DILI via the activation of various innate and adaptive immune cells. There has been a revolutionary development of treatment drugs for hepatocellular carcinoma (HCC) and liver transplantation (LT), including immune checkpoint inhibitors (ICIs), that show high efficacy in patients with advanced HCC. Along with the high efficacy of novel drugs, DILI has become a pivotal issue in the use of new drugs, including ICIs. This review demonstrates the immunological mechanism of DILI, including the innate and adaptive immune systems. Moreover, it aims to provide drug treatment targets, describe the mechanisms of DILI, and detail the management of DILI caused by drugs for HCC and LT.
Pathophysiology and Management of Fatigue in Neuromuscular Diseases
Authors: Torri Francesca , Lopriore Piervito , Montano Vincenzo , Siciliano Gabriele , Mancuso Michelangelo , Ricci Giulia
Published: March 2023

Fatigue is a major determinant of quality of life and motor function in patients affected by several neuromuscular diseases, each of them characterized by a peculiar physiopathology and the involvement of numerous interplaying factors. This narrative review aims to provide an overview on the pathophysiology of fatigue at a biochemical and molecular level with regard to muscular dystrophies, metabolic myopathies, and primary mitochondrial disorders with a focus on mitochondrial myopathies and spinal muscular atrophy, which, although fulfilling the definition of rare diseases, as a group represent a representative ensemble of neuromuscular disorders that the neurologist may encounter in clinical practice. The current use of clinical and instrumental tools for fatigue assessment, and their significance, is discussed. A summary of therapeutic approaches to address fatigue, encompassing pharmacological treatment and physical exercise, is also overviewed.
Autoimmune Regulator Gene Polymorphisms and the Risk of Primary Immune Thrombocytopenic Purpura: A Case-Control Study
Authors: Abdel Ghafar Muhammad T. , Elshora Ola A. , Allam Alzahraa A. , Mashaal Raghda Gabr , Hamous Shereen Awny Abdelsalam , Abd El-Khalik Sarah Ragab , Abd-Ellatif Rania Nagi , Mariah Reham A. , Eissa Radwa , Mwafy Mai , Shalaby Rasha E. , Nasif Elham , Elkholy Rasha A.
Published: March 2023

This study aimed to assess the possible association between two single nucleotide polymorphisms (SNPs) of the autoimmune regulator (AIRE) gene (rs2075876 G/A and rs760426 A/G) with the risk of primary immune thrombocytopenia (ITP), as well as AIRE serum levels, in the Egyptian population. In this case-control study, 96 cases with primary ITP and 100 healthy subjects were included. Two SNPs of the AIRE gene (rs2075876 G/A and rs760426 A/G) were genotyped via Taqman allele discrimination real-time polymerase chain reaction (PCR). Additionally, serum AIRE levels were measured using the enzyme-linked immunosorbent assay (ELISA) technique. After adjusting for age, gender, and family history of ITP, the AIRE rs2075876 AA genotype and A allele were associated with increased ITP risk (adjusted odds ratio (aOR): 4.299, p = 0.008; aOR: 1.847, p = 0.004, respectively). Furthermore, there was no significant association between AIRE rs760426 A/G different genetic models and ITP risk. A linkage disequilibrium revealed that A-A haplotypes were associated with an increased ITP risk (aOR: 1.821, p = 0.020). Serum AIRE levels were found to be significantly lower in the ITP group, positively correlated with platelet counts, and were even lower in the AIRE rs2075876 AA genotype and A allele, as well as A-G and A-A haplotype carriers (all p < 0.001). The AIRE rs2075876 genetic variants (AA genotype and A allele) and A-A haplotype are associated with an increased ITP risk in the Egyptian population and lower serum AIRE levels, whereas the SNP rs760426 A/G is not.
Aquatic Bacteria Rheinheimera tangshanensis New Ability for Mercury Pollution Removal
Authors: Zhao Mengmeng , Zheng Gege , Kang Xiuyun , Zhang Xiaoyan , Guo Junming , Wang Shaomei , Chen Yiping , Xue Lingui
Published: March 2023

To explore the strong tolerance of bacteria to Hg pollution, aquatic Rheinheimera tangshanensis (RTS-4) was separated from industrial sewage, with a maximum Hg(II) tolerant concentration of 120 mg/L and a maximum Hg(II) removal rate of 86.72 ± 2.11%, in 48 h under optimum culture conditions. The Hg(II) bioremediation mechanisms of RTS-4 bacteria are as follows: (1) the reduction of Hg(II) through Hg reductase encoded by the mer operon; (2) the adsorption of Hg(II) through the production of extracellular polymeric substances (EPSs); and (3) the adsorption of Hg(II) using dead bacterial biomass (DBB). At low concentrations [Hg(II) ≤ 10 mg/L], RTS-4 bacteria employed Hg(II) reduction and DBB adsorption to remove Hg(II), and the removal percentages were 54.57 ± 0.36% and 45.43 ± 0.19% of the total removal efficiency, respectively. At moderate concentrations [10 mg/L < Hg(II) ≤ 50 mg/L], all three mechanisms listed above coexisted, with the percentages being 0.26 ± 0.01%, 81.70 ± 2.31%, and 18.04 ± 0.62% of the total removal rate, respectively. At high concentrations [Hg(II) > 50 mg/L], the bacteria primary employed EPS and DBB adsorption to remove Hg(II), where the percentages were 19.09 ± 0.04% and 80.91 ± 2.41% of the total removal rate, respectively. When all three mechanisms coexisted, the reduction of Hg(II) occurred within 8 h, the adsorption of Hg(II) by EPSs and DBB occurred within 8–20 h and after 20 h, respectively. This study provides an efficient and unused bacterium for the biological treatment of Hg pollution.
CaSPDS, a Spermidine Synthase Gene from Pepper (Capsicum annuum L.), Plays an Important Role in Response to Cold Stress
Authors: Zhang Jianwei , Xie Minghui , Yu Guofeng , Wang Dong , Xu Zeping , Liang Le , Xiao Jiachang , Xie Yongdong , Tang Yi , Sun Guochao , Sun Bo , Huang Zhi , Lai Yunsong , Li Huanxiu
Published: March 2023

Spermidine synthase (SPDS) is a key enzyme in the polyamine anabolic pathway. SPDS genes help regulate plant response to environmental stresses, but their roles in pepper remain unclear. In this study, we identified and cloned a SPDS gene from pepper (Capsicum annuum L.), named CaSPDS (LOC107847831). Bioinformatics analysis indicated that CaSPDS contains two highly conserved domains: an SPDS tetramerisation domain and a spermine/SPDS domain. Quantitative reverse-transcription polymerase chain reaction results showed that CaSPDS was highly expressed in the stems, flowers, and mature fruits of pepper and was rapidly induced by cold stress. The function of CaSPDS in cold stress response was studied by silencing and overexpressing it in pepper and Arabidopsis, respectively. Cold injury was more serious and reactive oxygen species levels were greater in the CaSPDS-silenced seedlings than in the wild-type (WT) seedlings after cold treatment. Compared with the WT plants, the CaSPDS-overexpression Arabidopsis plants were more tolerant to cold stress and showed higher antioxidant enzyme activities, spermidine content, and cold-responsive gene (AtCOR15A, AtRD29A, AtCOR47, and AtKIN1) expression. These results indicate that CaSPDS plays important roles in cold stress response and is valuable in molecular breeding to enhance the cold tolerance of pepper.
Function and Evolution of the Loop Extrusion Machinery in Animals
Authors: Kabirova Evelyn , Nurislamov Artem , Shadskiy Artem , Smirnov Alexander , Popov Andrey , Salnikov Pavel , Battulin Nariman , Fishman Veniamin
Published: March 2023

Structural maintenance of chromosomes (SMC) complexes are essential proteins found in genomes of all cellular organisms. Essential functions of these proteins, such as mitotic chromosome formation and sister chromatid cohesion, were discovered a long time ago. Recent advances in chromatin biology showed that SMC proteins are involved in many other genomic processes, acting as active motors extruding DNA, which leads to the formation of chromatin loops. Some loops formed by SMC proteins are highly cell type and developmental stage specific, such as SMC-mediated DNA loops required for VDJ recombination in B-cell progenitors, or dosage compensation in Caenorhabditis elegans and X-chromosome inactivation in mice. In this review, we focus on the extrusion-based mechanisms that are common for multiple cell types and species. We will first describe an anatomy of SMC complexes and their accessory proteins. Next, we provide biochemical details of the extrusion process. We follow this by the sections describing the role of SMC complexes in gene regulation, DNA repair, and chromatin topology.
Fibrosis of Peritoneal Membrane, Molecular Indicators of Aging and Frailty Unveil Vulnerable Patients in Long-Term Peritoneal Dialysis
Authors: Branco Patrícia , Calça Rita , Martins Ana Rita , Mateus Catarina , Jervis Maria João , Gomes Daniel Pinto , Azeredo-Lopes Sofia , De Melo Junior Antonio Ferreira , Sousa Cátia , Civantos Ester , Mas-Fontao Sebastian , Gaspar Augusta , Ramos Sância , Morello Judit , Nolasco Fernando , Rodrigues Anabela , Pereira Sofia Azeredo
Published: March 2023

Peritoneal membrane status, clinical data and aging-related molecules were investigated as predictors of long-term peritoneal dialysis (PD) outcomes. A 5-year prospective study was conducted with the following endpoints: (a) PD failure and time until PD failure, (b) major cardiovascular event (MACE) and time until MACE. A total of 58 incident patients with peritoneal biopsy at study baseline were included. Peritoneal membrane histomorphology and aging-related indicators were assessed before the start of PD and investigated as predictors of study endpoints. Fibrosis of the peritoneal membrane was associated with MACE occurrence and earlier MACE, but not with the patient or membrane survival. Serum α-Klotho bellow 742 pg/mL was related to the submesothelial thickness of the peritoneal membrane. This cutoff stratified the patients according to the risk of MACE and time until MACE. Uremic levels of galectin-3 were associated with PD failure and time until PD failure. This work unveils peritoneal membrane fibrosis as a window to the vulnerability of the cardiovascular system, whose mechanisms and links to biological aging need to be better investigated. Galectin-3 and α-Klotho are putative tools to tailor patient management in this home-based renal replacement therapy.
Characterization of Ly108-H1 Signaling Reveals Ly108-3 Expression and Additional Strain-Specific Differences in Lupus Prone Mice
Authors: Rietdijk Svend , Keszei Marton , Castro Wilson , Terhorst Cox , Abadía-Molina Ana C.
Published: March 2023

Ly108 (SLAMF6) is a homophilic cell surface molecule that binds SLAM-associated protein (SAP), an intracellular adapter protein that modulates humoral immune responses. Furthermore, Ly108 is crucial for the development of natural killer T (NKT) cells and CTL cytotoxicity. Significant attention has been paid towards expression and function of Ly108 since multiple isoforms were identified, i.e., Ly108-1, Ly108-2, Ly108-3, and Ly108-H1, some of which are differentially expressed in several mouse strains. Surprisingly, Ly108-H1 appeared to protect against disease in a congenic mouse model of Lupus. Here, we use cell lines to further define Ly108-H1 function in comparison with other isoforms. We show that Ly108-H1 inhibits IL-2 production while having little effect upon cell death. With a refined method, we could detect phosphorylation of Ly108-H1 and show that SAP binding is retained. We propose that Ly108-H1 may regulate signaling at two levels by retaining the capability to bind its extracellular as well as intracellular ligands, possibly inhibiting downstream pathways. In addition, we detected Ly108-3 in primary cells and show that this isoform is also differentially expressed between mouse strains. The presence of additional binding motifs and a non-synonymous SNP in Ly108-3 further extends the diversity between murine strains. This work highlights the importance of isoform awareness, as inherent homology can present a challenge when interpreting mRNA and protein expression data, especially as alternatively splicing potentially affects function.
Why Don’t the Mutant Cells That Evade DNA Repair Cause Cancer More Frequently? Importance of the Innate Immune System in the Tumor Microenvironment
Authors: Mohapatra Shubhasmita , Cafiero Jared , Kashfi Khosrow , Mehta Parag , Banerjee Probal
Published: March 2023

The standard of care for most malignant solid tumors still involves tumor resection followed by chemo- and radiation therapy, hoping to eliminate the residual tumor cells. This strategy has been successful in extending the life of many cancer patients. Still, for primary glioblastoma (GBM), it has not controlled recurrence or increased the life expectancies of patients. Amid such disappointment, attempts to design therapies using the cells in the tumor microenvironment (TME) have gained ground. Such “immunotherapies” have so far overwhelmingly used genetic modifications of Tc cells (Car-T cell therapy) or blocking of proteins (PD-1 or PD-L1) that inhibit Tc-cell-mediated cancer cell elimination. Despite such advances, GBM has remained a “Kiss of Death” for most patients. Although the use of innate immune cells, such as the microglia, macrophages, and natural killer (NK) cells, has been considered in designing therapies for cancers, such attempts have not reached the clinic yet. We have reported a series of preclinical studies highlighting strategies to “re-educate” GBM-associated microglia and macrophages (TAMs) so that they assume a tumoricidal status. Such cells then secrete chemokines to recruit activated, GBM-eliminating NK cells and cause the rescue of 50–60% GBM mice in a syngeneic model of GBM. This review discusses a more fundamental question that most biochemists harbor: “since we are generating mutant cells in our body all the time, why don’t we get cancer more often?” The review visits publications addressing this question and discusses some published strategies for re-educating the TAMs to take on the “sentry” role they initially maintained in the absence of cancer.
Correction: Bay et al. Functional Characterization of the Solute Carrier LAT-1 (SLC7A5/SLC3A2) in Human Brain Capillary Endothelial Cells with Rapid UPLC-MS/MS Quantification of Intracellular Isotopically Labelled L-Leucine. Int. J. Mol. Sci. 2022, 23, 3637
Authors: Bay Cindy , Bajraktari-Sylejmani Gzona , Haefeli Walter E. , Burhenne Jürgen , Weiss Johanna , Sauter Max
Published: March 2023

The authors would like to make the following corrections to the publication [...]
Neutrophil Extracellular Traps in Airway Diseases: Pathological Roles and Therapeutic Implications
Authors: Jo Ara , Kim Dae Woo
Published: March 2023

Neutrophils are important effector cells of the innate immune response that fight pathogens by phagocytosis and degranulation. Neutrophil extracellular traps (NETs) are released into the extracellular space to defend against invading pathogens. Although NETs play a defensive role against pathogens, excessive NETs can contribute to the pathogenesis of airway diseases. NETs are known to be directly cytotoxic to the lung epithelium and endothelium, highly involved in acute lung injury, and implicated in disease severity and exacerbation. This review describes the role of NET formation in airway diseases, including chronic rhinosinusitis, and suggests that targeting NETs could be a therapeutic strategy for airway diseases.
Role of Omega-Hydroxy Ceramides in Epidermis: Biosynthesis, Barrier Integrity and Analyzing Method
Authors: Ge Fei , Sun Keyan , Hu Zhenlin , Dong Xin
Published: March 2023

Attached to the outer surface of the corneocyte lipid envelope (CLE), omega-hydroxy ceramides (ω-OH-Cer) link to involucrin and function as lipid components of the stratum corneum (SC). The integrity of the skin barrier is highly dependent on the lipid components of SC, especially on ω-OH-Cer. Synthetic ω-OH-Cer supplementation has been utilized in clinical practice for epidermal barrier injury and related surgeries. However, the mechanism discussion and analyzing methods are not keeping pace with its clinical application. Though mass spectrometry (MS) is the primary choice for biomolecular analysis, method modifications for ω-OH-Cer identification are lacking in progress. Therefore, finding conclusions on ω-OH-Cer biological function, as well as on its identification, means it is vital to remind further researchers of how the following work should be done. This review summarizes the important role of ω-OH-Cer in epidermal barrier functions and the forming mechanism of ω-OH-Cer. Recent identification methods for ω-OH-Cer are also discussed, which could provide new inspirations for study on both ω-OH-Cer and skin care development.