Severe Alterations Research Articles

Protective effect of Panax ginseng extract on cisplatin-induced AKI via downregulating cell death associated genes

This study is designed to assess the effect of root extract of P. ginseng on kidney tissue injury attributed to cisplatin and its molecular mechanism involved in this process in the AKI rat model. Twenty-four male Wistar rats were randomly allocated into 4 experimental groups including: the control group, the cisplatin group, the extract 100 mg/kg group, and the extract 200 mg/kg group. The duration of the investigation was 7 days, and all rats except the control group received a single dose of 10 mg/kg cisplatin on the 4th day. Our findings exhibited a significant reduction in blood concentration of creatinine in extract groups compared to the cisplatin group. In the cisplatin group, severe renal histopathological alterations were observed compared to the control group. In extract groups, significantly less tissue damage was observed than in the cisplatin group. Ginseng extract 200 showed minimal tissue damage as compared to extract 100. The expression of p21, p27, p53, TIMP2, IGFBP7, and NF-κB decreased significantly in extract groups compared to the cisplatin group. Our findings displayed amelioration of cisplatin-induced AKI and dose-dependent decrease of the NF-κB gene expression and cell death-inducing genes by administration of P. ginseng extract.

Moringa oleifera Docking to Estrogen Receptor α Ameliorates Placental and Brain Damage in Stressed Rats

Background: Stress during pregnancy significantly impacts offspring early physiological programming. Herbal remedies are frequently used by pregnant women to enhance their wellbeing. Moringa oleifera Leaf Extract (MoLE) is believed to have both anti-stress and antioxidant properties which can act as a Selective Estrogen Receptor Modulator (SERM) that regulate activities of estrogen, and can have different effects on different tissues. Goal of this study is to compile information on molecular docking analysis of phytochemicals found in MoLE targeting Estrogen Receptor-alpha (ER-α) and assess effects of MoLE administration on dam's and fetal brain tissues and placenta, during gestational stress. Methods: Phytochemical study of MoLE was determined using Gas Chromatography-Mass Spectrometry. Molecular docking technique was employed to predict aspects of interaction and binding affinities energy of bioactive phytocompounds in protein site of ER-α using autodock tools. 30 apparently healthy pregnant Albino-Wistar rats were randomly placed into 6 groups of 5 rats per group and exposed to Chronic Unpredictable Stress (CUS) protocol for two weeks, as follows: Group I (water and normal rat chow ad libitum), Group II (CUS protocol only), Group III (5 mg/kg body weight/day of MoLE), Group IV (10 mg/kg body weight/day of MoLE), Group V (CUS protocol +5 mg/kg body weight/day of MoLE), Group VI (CUS protocol +10 mg/kg body weight/ day of MoLE). Results: This study found that 1-Propanol, 3,3'-oxy bis- and 1, 2, 3-Trimethyldiazir-idine are most potent ligands for ER-α among all 41 compounds. Photomicrograph examination of tissues from stressed rats showed mild to severe alterations in histology. Consumption of MoLE during chronic stress showed mild to moderate protective effects. Conclusion: These findings suggest that 1-Propanol, 3,3'-oxy bis- and 1, 2, 3-Trimethy-ldiaziridine can be further investigated for development of novel therapeutics.

Occurrence of Alternaria Toxins, Ochratoxin A and Aflatoxins B1 in Green Arabic Coffee (Coffea arabica) in Saudi Arabia: Risk Assessment on HepG-2 Cell Line and Male Albino Rats

Arabica coffee (Coffee arabica L.) is among the most popular and widely consumed drinks globally today. The current study aimed to detect and quantify of potential mycotoxins in coffee beans and to investigate their potential risk on HepG-2 human liver cancer cells and male albino rats. Eighteen fully matured coffee beans samples were collected from different geographical locations in Saudi Arabia. Mycotoxins detected and quantified utilizing high-performance liquid chromatography (HPLC). Cytotoxicity of the detected toxins was investigated utilizing the MTT assay method toward HepG-2 cells and male albino rats. Cytotoxic properties of the detected mycotoxins were investigated at doses of 31.25, 62.50, 125, 250 and 500 µg/ml following exposure durations of 24 and 48 h in comparison with control. HPLC analysis revealed the detection of four Alternaria toxins (ALT-Ts) namely Altenuene (ALT), Tenuazonic acid (TA), Alternariol (AOH), and Altenuisol being AOH reported as the frequently detected mycotoxin in 18 coffee beans samples representing 75 % with quantity ranged 0.98 to 8.97 μg/g. OTA was frequently detected (10 samples, 55.5%) in concentrations varied from 0.75 to 9.87 μg/g. In addition, Aflatoxin B1 was also detected with low quantity ranged 0.89 to 3.22 μg/g. Treatment of HepG-2 cell line with combined Alternaria toxins (ALT, TeA, AOH, and Altenuisol), Aflatoxin B1 (AFB1) and Ochratoxin A (OTA) as well as their combination triggered a decline in cell viability that was proportional to the dose administered. The elevated doses (62.50, 125, 250 and 500 µg/ml) notably reduced cell viability and induced cellular damages when contrasted with the lowest dose (31.25 µg/ml) and control. The IC50 for the tested mycotoxins registered for ALT-Ts, AFB1 and OTA as well as their combination were 115.95, 56.68, 59.86 and 31.05 µg/ml after 48 h of exposure. Secreting inflammatory markers (Interleukin-6 (IL-6), interleukin-1β (IL-1β) and COX-2), and oxidative markers (total antioxidant capacity (TAC), glutathione (GSH) and nitrite (NO) were downregulated by all mycotoxins with the highest decrease induced by their mixture. Malonaldehydes (MDA) and TAC were significantly increased by all toxins in treated rats. Hematological results revealed that AFB1, OTA and ALT-Ts-treated rats exhibited a notable decline in hemoglobin (Hb), red blood cells (RBCs), white blood cells (WBCs), and packed cell volume % (PCV). However, single and double dose-treated rats with OTA, Mix1 and Mix2 exhibited a marked increase in WBCs. The results demonstrated a notable decline in liver and kidney functions in all mycotoxins-treated rats. The studied organs (liver, kidney and spleen) exhibited significant damage, with the most severe alterations observed in the Mix1 and Mix2-treated group in comparison with the groups receiving individual treatment. This indicates that the mixture of AFB1, ALT-Ts and OTA had an enhanced toxic consequence against treated HepG-2 cell line and rats. Our results indicated the synergistic effect of the combined different mycotoxins against HepG-2 human liver cancer cells and male albino rats. This work could help fill in data gaps and enhance risk assessment for human health by addressing some of the possible risks associated with Alternaria toxins

Strain Energy and Biomechanical Constituent Models in Blood Vessel Tissues

Objective: To show the analysis of mechanical constitutive models in blood vessel tissues with a continuous media approach based on strain energy, which serve as a reference for new mathematical modeling proposals in them. Theoretical Framework: The mechanics of blood vessels, describes the structural and functional behavior of blood vessels and can characterize various cardiovascular diseases. Harmful changes that alter the mechanical response of the walls of blood vessels produce severe alterations in the health of the circulatory system. Predicting the mechanical behavior of blood vessels based on physiological status using biomechanical models is paramount for diagnosis. Therefore, in the present work, an analysis of the constitutive models is carried out with a continuous media approach based on strain energy. Method: Bibliographic review that identifies, analyzes and synthesizes the existing scientific proposals on blood vessel tissue modeling based on the deformation energy theory. Results and Discussion: A bibliographic study of the biomechanical constitutive models of blood vessel walls, generated over time, is presented. The behavior of the vascular wall is analyzed from the deformation energy approach. The benefits, limitations and potentialities of the models are also exposed: a) Strain energy with a transversely isotropic and homogeneous matrix; b) Strain energy with axis-symmetric fiber constants; c) Strain energy with collagen fibers subject to dispersion; d) Strain energy of four families of fibers without dispersion; and e) Strain energy of two families of fibers with anisotropic elastin and fiber recruitment. Implications of the research: The conclusions and analyzes presented serve as a basis for future research and mathematical modeling of the phenomenon of degradation and deformation of blood vessels, which will facilitate the understanding of the phenomenon and the subsequent strengthening of alternative treatment strategies that combat the clinical conditions derived from the transformations of mechanical properties in the same blood vessels. Originality/Value: This study contributes by giving order to the multiple bibliographic information related to the subject. The relevance of this research is evidenced in the conclusions issued when analyzing models based on the theory of continuous media as a function of strain energy.

Sarcoglycans are enriched at the neuromuscular junction in a nerve-dependent manner

Sarcoglycanopathies are heterogeneous proximo-distal diseases presenting severe muscle alterations. Although there are 6 different sarcoglycan isoforms, sarcoglycanopathies are caused exclusively by mutations in genes coding for one of the four sarcoglycan transmembrane proteins (alpha, beta, gamma and delta) forming the sarcoglycan complex (SGC) in skeletal and cardiac muscle. Little is known about the different roles of the SGC beyond the dystrophin glycoprotein complex (DGC) structural role. Here, we show that SGC proteins are enriched at the post-synaptic membrane of neuromuscular junctions (NMJs). Using a mouse model lacking the beta-sarcoglycan subunit, we describe for the first time that the loss of the SGC in the NMJ area results in alterations of pre- and postsynaptic membrane, as well as a significant reduction of membrane potential. Moreover, using different denervated wild-type mouse models, we demonstrate that nerve presence precedes the sarcoglycan enrichment at NMJ, suggesting a nerve-dependent sarcoglycan expression. Altogether, our findings suggest that pathological decline should no longer be understood only in terms of sarcolemma damage but also in terms of sarcoglycans’ participation in the NMJ. Henceforth, our work paves the way for the identification of new mechanisms involving sarcoglycans and new approaches for the treatment of sarcoglycanopathies.

Oral supplementation of curcumin-encapsulated chitosan nanoconjugates as an innovative strategy for mitigating nickel-mediated hepatorenal toxicity in rats.

Nickel pollution adversely affects human health and causes various disorders, mainly hepatic and renal dysfunction. The present work focused on a comparative evaluation of the pure form of curcumin (CU) with curcumin-encapsulated chitosan nanoconjugates (CS/CU NCs), on mitigation of the delirious effects of Ni on hepatorenal tissue. Forty-two male rats were allocated into 6 groups (n = 7 for each) as follows: (1) control, (2) CU, (3) CS/CU NCs, (4) Ni, (5) Ni + CU, (6) Ni + CS/CU NCs. After 30days, blood and tissue (liver and kidneys) were collected to measure hepatorenal biomarkers, oxidant/antioxidant balance, inflammatory gene expression, liver and kidney histopathology, and immunohistochemistry. Results revealed disruption of hepatorenal functions, oxidative stress, and inflammatory markers at biochemical and molecular levels associated with severe hepatorenal histopathological alterations and abnormal immunohistochemical tissue expression for caspase-3 and cyclooxygenase-2. On the contrary, the treatment of Ni-intoxicated rats with CS/CU NCs markedly mitigated the adverse effect of Ni on hepatorenal tissue via regulation of oxidative stress, inflammatory, and apoptotic markers. The present study provides a novel nanoformulation for curcumin using CS NPs encapsulation that selectively targets the injured cells and improves the beneficial effect of CU via enhancing the antioxidant activity and regulating both inflammatory and apoptotic markers.

Comparison of mechanical properties and shaping performance of ProGlider and ProTaper ultimate slider

BackgroundThis study aims to compare design, phase transformation behavior, and torsional resistance of the ProGlider (PG) and ProTaper ultimate slider (PUS) and to compare the performance of two files in the glide-path preparation of a double-curved artificial canal.MethodsScanning electron microscopy, micro-computed tomography, and differential scanning calorimetry were used to characterize the samples. A torsional resistance test was performed to obtain ultimate strength and distortion angle. Simulated glide-path preparation was conducted with a double-curved resin canal, and both PG and PUS were operated on by 300 and 400 rpms. Maximum screw-in force, torque generated during canal shaping, number of pecking strokes to reach the apex were compared between groups. After canal shaping centering ratio and alteration of files were assessed. Statistical analyses were performed using the Mann-Whitney U test, and the Kruskal-Wallis test with Bonferroni correction. A p value less than 0.05 was considered significant.ResultsWhile the PG had a square cross-section, the PUS had variable square and rhomboid cross-sections and alternating cutting-edge. PG and PUS have austenitic transformation starting and finishing temperatures of 24–25℃, and 57–59℃, respectively. Ultimate strength of PUS are superior to that of PG, whereas the distortion angle of PG is greater than that of PUS (p < 0.05). The maximum screw-in force and clockwise torque generated during glide-path preparation were highest in the PUS group rotated at 300 rpm (p < 0.05). Shaping with the PG at 300 rpm and shaping with the PUS at 400 rpm exhibited comparable maximum screw-in forces. There were no significant differences in the number of pecking strokes to reach the apex and centering ability among groups shaped with PG and PUS at both rotation speeds. PG shaped at 400 rpm demonstrated severe alteration on its surface, while PUS shaped at 300 and 400 rpms exhibited comparable surface alterations.ConclusionsPG has a constant square cross-section, while PUS has a variable cross-section and alternating cutting-edge. Using PUS at recommended speed of 400 rpm ensures safe use with minimal screw-in force and surface alteration. At recommended speeds, both PG and PUS perform comparably and are safe for double-curved canals.

Fermented Ofada rice (A Nigerian recipe) attenuates renal and hepatic dysfunction induced by crude oil poisoning in Wistar Rats

Objectives: This work examined the antioxidative capacity of Ofada rice Koji (ORK) to ameliorate toxicity emanating from Bonny Light Crude Oil (BLCO) on xenobiotic targeted tissues (liver and kidney) in rats. Methods: Twenty Wistar rats were divided into 4groups (ABCD). Short-term crude oil toxicity was conducted for seven days. Groups A (positive control) were exempted and devoid of the toxicant while B (negative control) to D were administered 4ml BLCO/kg bwt. Group C was fed with 40g of standard rat feed mixed with 60g of fermented ORK powder (60% w/w) while group D animals were given 95g of standard rat feed mixed with 5g of ascorbic acid (ASC) (5g w/w) by composition. ORK and ASC diets were given for 14 days. Results: ORK intake reduced Malondialdehyde (MDA) formation in the kidney and liver by 46% and 61% respectively. Assessment of Catalase (CAT), Superoxide dismutase (SOD), and Glutathione (GSH), when compared with untreated control rats, were increased by 28%, 45% and 24% respectively (for kidney) and 19%, 34% and 38% respectively (for liver). ORK maintained these enzyme levels by 17%, 4% and 14% respectively (for kidney) and 7%, 14% and 17% respectively (for liver). Renal creatinine and urea were elevated by BLCO treatment but were normalized by ORK intake. The severe alteration in renal and hepatic morphology as observed with BLCO intubation was almost regularized by ORK intake. Conclusion: Data from this experimental research expresses the ameliorative capacity of ORK in BLCO toxicity.

Reading comprehension evaluation by means of the neuropsi assessment tool in patients attending “alcoholics anonymous” due to alcohol consumption

Alcohol drinking negatively affects the reading skill. The article addresses the prevalence of reading difficulties in alcohol rehabilitation patients by applying the neuropsychological assessment tool NEUROPSI. Methodology: non-experimental, exploratory, and observational study based on the Neuropsychological assessment tool NEUROPSI in Spanish (brief version). Findings: In a sample of 20 participants, the results indicate that only 40% fall within the normal values, whilst 60% exhibit low scores in reading comprehension, concentration, and attention. Lastly, 60% of the participants presented alterations in neurocognitive functions, with 25% indicating moderate alterations, 20% revealing severe alterations, and 15% exhibiting mild alterations.

Protective effects of adipose-derived stem cells against testicular injury induced after ischemia-reperfusion by regulating autophagy.

The damaged organ may experience severe pathological alterations as a result of tissue ischemia-reperfusion (I/R). The study of stem cell-based repair therapies is actively being conducted, and the outcomes and therapeutic potential of these cells are both promising. Autophagy checks protein homeostasis by breaking down huge damaged proteins or organelles. The study's objective was to assess how ADSCs impact the autophagic process after testicular ischemia/reperfusion. In our investigation, 30 male rats were divided into five groups: control, ADSC, ischemia, I/R, and I/R + ADSC (n = 6). Hematoxylin-eosin (HE) was used to stain the testes, and histological changes were assessed. The immunoexpression of androgen receptor (AR), Beclin1, protein light chain 3B (LC3B), and p62 were examined. The seminiferous epithelium in the testis from the ischemia and I/R groups revealed significant degeneration with disorganized morphology, damaged spermatogenic cells, and interstitial space congestion, according to HE stain results. Johnsen's score were significantly better in I/R + ADSC group than in ischemia and I/R groups. We demonstrated that in rat testes from the I/R groups, immunostaining of Beclin 1 (p = 0.042) and LC3B (p = 0.011) were raised, and p62 (p = 0.047) and AR (p = 0.049) were decreased. Ischemia and I/R promoted testicular autophagy, therefore we can conclude that ADSCs prevent excessive autophagy. Additionally, these results show that the use of ADSCs cures testicular injury and dysfunction associated with I/R injury in rats even a little.

Association between microcephaly and hearing disorders in children exposed or suspected of exposure to the Zika virus during the intrauterine period.

This study aimed to evaluate the association between microcephaly and hearing disorders in children with exposed or suspected exposure to Zika virus (ZIKV) during the intrauterine period. In this cross-sectional study, we enrolled children exposed or suspected of being exposed to ZIKV during intrauterine period, admitted to the hospital between April 2016 and July 2018, and followed up until September 2021. All children underwent at least one automated auditory brainstem response (AABR) test. For analysis, the patients were divided into four groups: those with microcephaly, without microcephaly, suspected ZIKV infection, and controls. Other causes of microcephaly were excluded. Hearing impairment was assessed using the AABR to determine associations with microcephaly or central nervous system (CNS) abnormalities. Of the 134 children included, 34 (25.4%) were diagnosed with congenital Zika syndrome (CZS), of whom 28 (82.4%) had microcephaly, and the remaining six (17.6%) without microcephaly. Among the 28 children with microcephaly, 3 (10.7%) had abnormal AABR. Among CZS children without microcephaly (n = 6), 1 (16.7%) had abnormal AABR (Fisher's exact test p = 0.56).Conclusion: In our study population, that hearing impairment assessed using the AABR test was not associated with microcephaly or severe CNS alterations.

Astrocytic Alterations and Dysfunction in Down Syndrome: Focus on Neurogenesis, Synaptogenesis, and Neural Circuits Formation.

Down syndrome (DS) is characterized by severe neurodevelopmental alterations that ultimately lead to the typical hallmark of DS: intellectual disability. In the DS brain, since the prenatal life stages, the number of astrocytes is disproportional compared to the healthy brain. This increase is due to a shift from neuron to astrocyte differentiation during brain development. Astrocytes are involved in numerous functions during brain development, including balancing pro-neurogenic and pro-gliogenic stimuli, sustaining synapse formation, regulating excitatory/inhibitory signal equilibrium, and supporting the maintenance and integration of functional neural circuits. The enhanced number of astrocytes in the brain of DS individuals leads to detrimental consequences for brain development. This review summarizes the mechanisms underlying astrocytic dysfunction in DS, and particularly the dysregulation of key signaling pathways, which promote astrogliogenesis at the expense of neurogenesis. It further examines the implications of astrocytic alterations on dendritic branching, spinogenesis and synaptogenesis, and the impact of the abnormal astrocytic number in neural excitability and in the maintenance of the inhibitory/excitatory balance. Identifying deregulated pathways and the consequences of astrocytic alterations in early DS brain development may help in identifying new therapeutic targets, with the ultimate aim of ameliorating the cognitive disability that affects individuals with DS.

Morphological Alterations and Oxidative Stress Induction in Danio rerio Liver After Short-Term Exposure to the Strobilurin Fungicide Dimoxystrobin

Unlike many other fungicides, strobilurins are applied several times during the growing season for prophylactic purposes, thus heightening the risk of environmental contamination. In the EU, the dimoxystrobin approval period lasted for 17 years. It has been classified as moderately toxic to birds and highly toxic to earthworms, and it is suspected to be carcinogenic to humans. However, it is still commercialized in several countries. The effects of dimoxystrobin are still largely underexplored, with only three studies reporting sublethal alterations in fish. Here, we evaluated for the first time the effects of dimoxystrobin on zebrafish liver after short-term exposure (96 h) to two sublethal and environmentally relevant concentrations (6.56 and 13.13 μg/L), providing evidence of morphological, functional, and ultrastructural modifications. We revealed severe alterations encompassing three reaction patterns: circulatory disturbance, regressive and progressive changes, which also showed a dose-dependent trend. Furthermore, we revealed that dimoxystrobin induced a significant increase in lipid content, a decrease in glycogen granules and affected the defensive response against oxidative stress through a significant downregulation of SOD and CAT. The information presented here demonstrates that the hazardous properties of dimoxystrobin may result from several pathological events involving multiple targets. Our results also emphasize the importance of the combined use of morphological, ultrastructural and functional investigation in ecotoxicological studies.

Myeloid cell-specific loss of NPC1 in mice recapitulates microgliosis and neurodegeneration in patients with Niemann-Pick type C disease.

Niemann-Pick type C (NPC) disease is an inherited lysosomal storage disorder mainly driven by mutations in the NPC1 gene, causing lipid accumulation within late endosomes/lysosomes and resulting in progressive neurodegeneration. Although microglial activation precedes neuronal loss, it remains elusive whether loss of the membrane protein NPC1 in microglia actively contributes to NPC pathology. In a mouse model with depletion of NPC1 in myeloid cells, we report severe alterations in microglial lipidomic profiles, including the enrichment of bis(monoacylglycero)phosphate, increased cholesterol, and a decrease in cholesteryl esters. Lipid dyshomeostasis was associated with microglial hyperactivity, marked by an increase in translocator protein 18 kDa (TSPO). These hyperactive microglia initiated a pathological cascade resembling NPC-like phenotypes, including a shortened life span, motor impairments, astrogliosis, neuroaxonal pathology, and increased neurofilament light chain (NF-L), a neuronal injury biomarker. As observed in the mouse model, patients with NPC showed increased NF-L in the blood and microglial hyperactivity, as visualized by TSPO-PET imaging. Reduced TSPO expression in blood-derived macrophages of patients with NPC was measured after N-acetyl-l-leucine treatment, which has been recently shown to have beneficial effects in patients with NPC, suggesting that TSPO is a potential marker to monitor therapeutic interventions for NPC. Conclusively, these results demonstrate that myeloid dysfunction, driven by the loss of NPC1, contributes to NPC disease and should be further investigated for therapeutic targeting and disease monitoring.

Therapeutic potency of kaempferol against Naja haje venom induced neurotoxicity, inflammation, biological activities, and antioxidant system damage: a pre-clinical antivenom evaluation.

Naja haje envenoming manifests organ system disorders leading to severe fatalities due to the venom's toxins. The neutralizing capacity of kaempferol has been reported against some medically significant snake venoms with exception of N. haje venom (NhV). This current study assessed the neutralizing profile of kaempferol against toxicities induced by NhV using in vitro and in vivo methods. In in vitro, NhV induced wide spectrum of toxic biological activities with substantial increase in hemorrhagic, anticoagulating, and hemolytic effects. Likewise in the in vivo study, the venom caused hematological disorders by inducing acute anemia, thrombocytopenia, and leucopenia in envenomed rats. Also, the venom caused detrimental effect on the antioxidant defense system of the brain through significant (P < 0.05) elevation of malondialdehyde (MDA), nitrite (NIT), and suppression of reduce glutathione (GSH) antioxidant, superoxide dismutase (SOD), catalase (CAT), and glutathione transferase (GST) enzymes. Additionally, the levels of neurotoxicity biomarkers, monoamine oxidase (MAO) and acetylcholinesterase (AChE), and pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), were significantly (P < 0.0.5) enhanced by NhV in the brain of envenomed rats. Severe pathohistological effects were observed in brain tissues of the envenomed rats. However, kaempferol substantially (P < 0.05) inhibited the NhV-induced biological activities, normalized the hematological disorders, enhanced antioxidants system functions, and significantly (P < 0.05) suppressed the levels of neurotoxicity biomarkers and pro-inflammatory cytokines. Severe structural alterations observed in the brain tissues were ameliorated after kaempferol treatment. Further exploration of kaempferol could lead to the development of an alternative therapy for treatment of N. haje envenoming.

DNMT aberration-incurred GPX4 suppression prompts osteoblast ferroptosis and osteoporosis

Osteoporosis (OP) is a common and fracture-prone skeletal disease characterized by deteriorated trabecular microstructure and pathologically involving various forms of regulated bone cell death. However, the exact role, cellular nature and regulatory mechanisms of ferroptosis in OP are not fully understood. Here, we reported that OP femurs from ovariectomized (Ovx) mice exhibited pronounced iron deposition, ferroptosis, and transcriptional suppression of a key anti-ferroptotic factor GPX4 (glutathione peroxidase 4). GPX4 suppression was accompanied by hypermethylation of the Gpx4 promoter and an increase in DNA methyltransferases DNMT1/3a/3b and was transcriptionally promoted by repressive KLF5 and the transcriptional corepressors NCoR and SnoN. Conversely, DNMT inhibition with SGI-1027 reversed promoter hypermethylation, GPX4 suppression and ferroptotic osteoporosis. In cultured primary bone cells, ferric ammonium citrate (FAC) mimicking iron loading similarly induced GPX4 suppression and ferroptosis in osteoblasts but not in osteoclasts, which were rescued by siRNA-mediated individual knockdown of DNMT 1/3a/3b. Intriguingly, SGI-1027 alleviated the ferroptotic changes caused by FAC, but not by a GPX4 inactivator RSL3. More importantly, we generated a strain of osteoblast-specific Gpx4 haplo-deficient mice Gpx4Ob+/− that developed spontaneous and more severe ferroptotic OP alterations after Ovx operation, and showed that GPX4 inactivation by RSL3 or semi-knockout in osteoblasts largely abolished the anti-ferroptotic and osteoprotective effects of SGI-1027. Taken together, our data suggest that GPX4 epigenetic suppression caused by DNMT aberration and the resulting osteoblastic ferroptosis contribute significantly to OP pathogenesis, and that the strategies preserving GPX4 by DNMT intervention are potentially effective to treat OP and related bone disorders.

Effect of dietary habits on Alzheimer’s disease progression

AbstractBackgroundResearch on the relationship between diet and dementia among Koreans are lacking. This study investigated the association between dietary habits and dementia progression over 3 years in patients with Alzheimer’s disease dementia (ADD).MethodThis study included 705 patients with mild‐to‐moderate ADD. Dietary habits were assessed using the Mini Dietary Assessment Index, comprising 10 questions. Outcome measures included the Clinical Dementia Rating scale‐Sum of Boxes (CDR‐SB), Seoul‐Instrumental Activities of Daily Living, Caregiver‐Administered Neuropsychiatric Inventory (CGA‐NPI), and neuropsychological test battery (NTB) z‐scores, which were evaluated annually over 3 years.ResultIn Q10 (eat all food evenly without being picky), the 3‐year mean differences in CDR‐SB (increases in scores represent worsening) compared to the “rarely” group were –1.86 (95% confidence interval [CI] = –3.64 ∼ –0.09, P = 0.039) for the “usually” group and –2.23 (95% CI = –4.40 ∼ –0.06, P = 0.044) for the “always” group. In Q7 (add salt or soy sauce to food, when eating), the 3‐year mean differences in CDR‐SB compared to the “always” group were –2.47 (95% CI = –4.70 ∼ –0.24, P = 0.030) for the “usually” group and –3.16 (95% CI = –5.36 ∼ –0.96, P = 0.005) for the “rarely” group. The “rarely” and “usually” groups in Q7 showed significantly less decline in NTB z‐score and CGA‐NPI compared to the “always” group.ConclusionEating a balanced diet and reducing salt intake were associated with a slower decline in dementia severity, cognition, and behavioral alterations in patients with ADD.

Therapeutic deep eutectic solvent with saponin, optimized through response surface methodology, exert potent in vivo antimicrobial effects against Pseudomonas aeruginosa

Therapeutic deep eutectic solvents (THEDES) are a type of deep eutectics that can be used as active pharmaceutical ingredients (APIs) by enhancing the drug bioavailability, by increasing the solubility of APIs in aqueous solutions or by increasing their permeability through biological barriers. In this study, we demonstrate the utility of designer THEDES, based on Quillaja Saponin (SAP), a triterpene natural product to unravel the antimicrobial potential of such THEDES. THEDES were prepared by gently mixing and heating five different α- hydroxy acids- malic, citric, tartaric, glycolic, lactic acids and SAP with water as a third component in the THEDES. The antimicrobial assays were performed with the as-prepared SAP-THEDES and among the panel of bacterial strains, saponin-malic acid THEDES [SMA-THEDES] displayed potent activity in disassembling PA biofilms, demonstrating that the SMA-THEDES can serve as therapeutic antibacterial biomaterials. To further optimize, a Box-Behnken- response surface methodology (RSM) experimental design was done and at the optimum conditions of SAP (1.014 m.mol), Malic acid (1.003 m.mol), Water (0.117 m.mol), SMA-THEDES exhibited maximum MIC of P. aeruginosa with the minimum absorbance at 590 nm of 0.105. The effectiveness of SMA-THEDES as antibiofilm agents on P. aeruginosa with the mechanism studies have been explored. The colony count from the in vivo infection zebrafish model in the treatment group showed a decline of > 2 fold for SMA-THEDES. Toxicity studies did not reveal any abnormality in liver and brain enzyme levels. Liver morphology images show no severe cytological alterations when treated with SMA-THEDES and were almost similar to the normal liver.

Valence-dependent immune responses of earthworm coelomocytes: Toxicity pathways and molecular mechanisms of As (III) and As (V)-induced immunotoxicity

Epidemiological studies in inorganic arsenic (iAs) exposure populations have offered convincing evidence that exposure to arsenite (As (III)) and arsenate (As (V)) are linked to immune dysfunction and immunosuppression. However, the valence-dependent immunotoxicity mechanism of iAs has not been explored. In this work, we conducted a thorough investigation and comparison of lysosome dysfunction in As (III) and As (V) induced earthworm typical immune cells coelomocytes, and the binding reaction between As (III)/As (V) and immunoprotein lysozyme (LZM). Results indicated As (III) and As (V) induced severe alterations in NR uptake and caused serious damage to lysosomal membrane, particularly As (III). As (III) (21.24 %) had a stronger inhibitory effect on LZM activity in coelomocytes than As (V) (67.40 %), which showed a similar toxic trend as enzyme activity in vitro (As (III)-68.66 % and As (V)-78.50 %). LZM skeleton relaxation, secondary structural transformation, fluorescence sensitization and particle alteration provided evidence for As (III) trigger more grievous immunoprotein dysfunction. In conclusion, As (III) and As (V) triggered lysosomal membrane destruction in coelomocytes, as well as induced structural changes in LZM result in lysosomal hydrolase dysfunction in coelomocytes. Ultimately, cellular lysosome dysfunction and destruction, which leads to the normal immune system of the cells is disrupted. As (III) induced stronger immunosuppression through lysosome pathway than As (V). Our work reveals the degree of lysosome dysfunction triggered by As (III) and As (V) probably responsible for the valence-dependent immunosuppression patterns of iAs, and provide new insights for As toxicity assessment.

H 2 protects H9c2 cells from hypoxia/reoxygenation injury by inhibiting the Wnt/CX3CR1 signaling pathway.

Myocardial ischemia‒reperfusion injury is a severe cardiovascular disease, and its treatment and prevention are crucial for improving patient prognosis and reducing the economic burden. This study aimed to explore the impact of hydrogen (H 2 ) on hypoxia/reoxygenation (H/R) injury in H9c2 cells (derived from rat embryonic heart tissue) induced by hydrogen peroxide (H 2 O 2 ) and to elucidate its underlying mechanism. An H/R injury model was established in H9c2 cells via exposure to 15 μM H 2 O 2 for 3 hours, followed by incubation in a 5% CO 2 atmosphere at 37°C for 24 hours. Then, the cells were treated with H 2 (50%) for 6, 12 or 24 hours. The results demonstrated that H9c2 cells exposed to H 2 O 2 and subjected to H/R injury presented a marked decrease in the cell survival rate, accompanied by severe morphological alterations, such as curling and wrinkling, and elevated lactate dehydrogenase levels. Notably, H 2 mitigated H/R injury induced by H 2 O 2 in a time-dependent manner, improving the morphological damage observed in H9c2 cells and decreasing lactate dehydrogenase levels. Compared with the model group, treatment with H 2 increased the activities of antioxidant enzymes, including catalase, superoxide dismutase, and glutathione peroxidase, while concurrently reducing the level of malondialdehyde, an indicator of cellular damage. Furthermore, H 2 treatment downregulated the expression of inflammatory cytokines and inflammatory-related factors, specifically interleukin-6, high-mobility group box 1, tumor necrosis factor-alpha, and Toll-like receptor 4, in H9c2 cells post-H/R injury. Furthermore, H 2 treatment resulted in a marked decrease in the expression levels of proteins associated with the Wnt/C-X3-C-motif receptor 1 signaling pathway, such as β-catenin, glycogen synthase kinase-3 beta, adenomatous polyposis coli, and Wnt and C-X3-C-motif receptor 1. This observation suggests a potential mechanism for its protective effects against H/R injury. Therefore, H 2 exerts a protective effect against H/R injury in H9c2 cells induced by H 2 O 2 , potentially by inhibiting the activated Wnt/C-X3-C-motif receptor 1 signaling pathway. This inhibition, in turn, prevents the generation of oxidative stress, inflammatory cytokines, and inflammation-associated factors.