Search Results (103)

Osteoarthritis (OA) is a debilitating joint disorder characterized by cartilage degradation and disruption of chondrocyte homeostasis. Although retinoic acid (RA) has been used in OA models, its precise targets are not clear. A translational framework was employed, integrating RNA-sequencing results, network pharmacology prediction, computational ligand-receptor molecular docking, and biological experimental validation, to systematically elucidate RA’s disease-modifying targets in OA pathogenesis. RNA-sequencing of RA-treated chondrocytes revealed 656 differentially expressed genes (DEGs). Protein–protein interaction (PPI) network analysis and functional enrichment [Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG)] highlighted key pathways, including extracellular matrix (ECM) reorganization and PI3K-Akt-mediated mechanotransduction and others. Network pharmacology analysis identified 42 shared targets between RA and OA. PPI analysis and functional enrichment (GO/KEGG) highlighted pathways including the renin–angiotensin system and the neuroactive ligand–receptor interaction, among others. Molecular docking ranked candidate targets by binding affinity of RA in descending order as MAPK14 (p38α), PTGER3 (PGE2 receptor), CA2 (CA2), and others. Five intersecting targets CA2, ACE, PTGS1 (COX-1), PGR, and EDNRA (ETAR) were identified by integrating RNA-sequencing (RNA-seq) results and network pharmacology predictions. These interactions were experimentally validated via western blot, RT-qPCR and immunofluorescence. RA increased the expression of MMP13, CA2 and ACE, and decreased the expression of COL2A1 in chondrocytes. siRNA-mediated knockdown of both CA2 (human CA2 homolog) and ACE (human ACE homolog) inhibit cartilage degradation through downregulating MMP13 and upregulating COL2A1. This study not only elucidates potential molecular mechanisms by which RA modulates chondrocyte catabolism but also offers a valuable reference for the development of novel OA therapeutics. Full article

There is an escalating need to comprehend the long-term impacts of nuclear radiation exposure since the permeation of ionizing radiation has been frequent in our current societal framework. A system evaluation of the microbes that reside inside a host’s colon could meet this knowledge gap since the microbes play major roles in a host’s response to stress. Indeed, our past study suggested that these microbes might break their symbiotic association with moribund hosts to form a pro-survival condition exclusive to themselves. In this study, we undertook metagenomics and metabolomics assays regarding the descending colon content (DCC) of adult mice. DCCs were collected 1 month and 6 months after 7 Gy or 7.5 Gy total body irradiation (TBI). The assessment of the metagenomic diversity profile in DCC found a significant sex bias caused by TBI. Six months after 7.5 Gy TBI, decreased Bacteroidetes were replaced by increased Firmicutes in males, and these alterations were reflected in the functional analysis. For instance, a larger number of networks linked to small chain fatty acid (SCFA) synthesis and metabolism were inhibited in males than in females. Additionally, bioenergy networks showed regression dynamics in females at 6 months post-TBI. Increased accumulation of glucose and pyruvate, which are typical precursors of beneficial SCFAs coupled with the activated networks linked to the production of reactive oxygen species, suggest a cross-sex energy-deprived state. Overall, there was a major chronic adverse implication in male mice that supported the previous literature in suggesting females are more radioresistant than males. The sex-biased chronic effects of TBI should be taken into consideration in designing the pertinent therapeutics. Full article

Background: Heart failure (HF), the terminal stage of cardiovascular disease with high morbidity and mortality, remains poorly managed by current therapies. Ventricular remodeling in HF is fundamentally characterized by myocardial fibrosis. While ginsenoside Rb₁ has demonstrated anti-fibrotic effects in HF, the underlying mechanism remains unclear. Twist1, an upstream regulator of energy metabolism factors PGC-1α and PPARα, may attenuate fibrosis by preserving systemic energy homeostasis, suggesting its pivotal role in HF pathogenesis. This study explores ginsenoside Rb₁′s anti-HF mechanisms through the regulation of ginsenoside Rb₁ on these metabolic regulators. Methods: Sprague Dawley rats were subjected to a ligation of the left anterior descending coronary artery to induce an HF model, followed by ginsenoside Rb₁ treatment for 6 weeks. Therapeutic effects were evaluated through cardiac function assessment, myocardial histopathological staining (HE, Masson, immunofluorescence, immunohistochemistry), mitochondrial morphology observation (transmission electron microscopy), energy metabolism analysis (electron transport chain efficiency, mitochondrial membrane potential, ATP content), and protein expression profiling (Twist1, PGC-1α, PPARα, GLUT4, PPARγ). Additionally, H9c2 cells induced with endothelin-1 to model HF were employed as an in vitro model to further investigate ginsenoside Rb₁′s regulatory effects on the Twist1/PGC-1α/PPARα signaling pathway. Results: Ginsenoside Rb₁ can restore cardiac function in HF rats, improve mitochondrial function, alleviate energy metabolism disorders, and inhibit ventricular remodeling. By modulating the Twist1/PGC-1α/PPARα signaling pathway, ginsenoside Rb₁ suppressed the abnormal overexpression of Twist1 and maintained normal expression of downstream PGC-1α and PPARα. In vitro experiments further demonstrated that ginsenoside Rb₁ significantly inhibited Twist1 expression in H9c2 cardiomyocytes with HF while promoting PGC-1α and PPARα expression, thereby restoring myocardial energy metabolism and mitigating ventricular remodeling in HF. Conclusions: Ginsenoside Rb₁ can inhibit the upregulation of Twist1 and activate the expression of its downstream PGC-1α and PPARα expression, by modulating the Twist1/PGC-1α/PPARα signaling pathway, alleviating ventricular remodeling in HF patients and improving myocardial energy metabolism dysfunction. Twist1 may be a key target for the treatment of HF. This study not only elucidates the mechanism by which ginsenoside Rb₁ alleviates HF, but also provides new insights into the clinical treatment of HF. Full article

Inhibition of HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) causes the stabilization of hypoxia-inducible factor-1α and -2α (HIF-1α and HIF-2α) to regulate various cell signaling pathways. Hypoxia-inducible factor (HIF) is crucial in regulating signal responses mediated by hypoxia. HIF regulates the transcription of many genes involved in the response to hypoxia and ischemic insult. Our current work investigates the protective effects of PHD1 knockout in mice against myocardial infarction. Study Design: Myocardial infarction (MI) was induced by left anterior descending coronary artery (LAD) ligation (8–12-week-old mice) in both wild-type (WT) and PHD1 knockout (PHD1^−/−) mice. WT sham (S) and PHD1^−/−S group mice underwent surgery without LAD ligation. Thirty days post-surgery, cardiac functions were measured by echocardiogram. Mice in all the groups were euthanized at various time points for tissue collection post-MI 8 h (gel shift and microarray analysis), 4 days (Western blot analysis), 7 days (blood vessel density), or 30 days (histological analysis). For microarray analysis, WTMI and PHD1^−/−MI group mices’ heart tissue was used for RNA isolation, then hybridization to a GeneChip™ Mouse Gene 1.0 ST Array as per the manufacturer’s instructions. Bioinformatic analysis was performed using the transcriptome analysis console (TAC) to generate a list of differentially regulated genes, followed by ingenuity pathway analysis. Results: The study findings revealed a significant increase in vessel density (capillary and arteriolar density) in the PHD1^−/−MI mice compared to those with WTMI. The echocardiographic examination demonstrated that the PHD1^−/−MI mice group had an increased ejection fraction and fractional shortening than the WT mice 30 days post-MI. HIF-1α DNA binding activity was higher in PHD1^−/−MI mice than in WTMI. The Western blot analysis showed a significant increase in the expression of HSPA12B in the PHD1^−/−MI compared to WTMI mice. Bioinformatic analysis using TAC software, Version 4.0.2.15 (1.5 fold, p < 0.05) showed 174 differentially regulated genes. Conclusions: In conclusion, our study showed PHD1 knockout activates several important molecules and signaling pathways, resulting in increased angiogenesis and cardioprotection against myocardial infarction. Full article

Botulinum neurotoxins are synthetized by anaerobic, spore-forming bacteria that inhibit acetylcholine release at the level of the neuromuscular and autonomic cholinergic junctions, thus inducing a series of symptoms, the most relevant of which is flaccid paralysis. At least seven serotypes and over 40 subtypes are known, and they are among the most poisonous natural substances. There are different forms of botulism according to the route of contamination, but the clinical manifestation of descending symmetric flaccid paralysis is consistent, regardless of the route of contamination. It is very severe and potentially lethal. The induced paralysis lasts as long as the toxin is active, with variable length, according to the serotype of the toxin. This transient activity, as well as the precise mechanism of action, are the basis for the rationale behind use of the toxin in therapy for several clinical conditions, particularly, spastic conditions, as well as chronic migraine and axillary hyperhidrosis. The toxin has also been approved for the reduction in facial wrinkles; all these clinical applications, coupled with the toxin’s risks, have earned botulinum the title of a two-faced Janus protein. No approved vaccines are currently available, andthe only approved antidotes are the human specific intravenous immunoglobulins for infant botulism and the heptavalent equine immunoglobulins/(F(ab’)² for adults. Nanobodies, which show great promise, may penetrate neuronal cells to inactivate the toxin within the cytoplasm, and Ebselen, a non-toxic, economic, small-molecule inhibitor, has the characteristic of inhibiting the toxin irrespective of the serotype. Full article

Impaired contractility after myocardial infarction (MI) causes cardiogenic shock. MARK4 activity impairs contractility post-MI by increasing α-tubulin detyrosination. We assessed the impact of naringenin, a small-molecule MARK4 inhibitor, on contractility post-MI. Naringenin (Nar) was encapsulated in PEG-PCL to augment bioavailability. Wistar rats were randomized to receive either MI + micellized naringenin (0.3 mg/kg) [MI-NarMic], MI + naringenin (0.3 mg/kg) in 1% DMSO [MI-NarDMSO], MI + empty micelle [MI-Mic], MI alone [MI-Untreated], or no MI [Sham]. MI was induced via left anterior descending artery ligation. Invasive hemodynamics with pressure–volume catheterization, cardiomyocyte contractility, and ventricular protein abundance were assessed one day post-MI. A total of 45 rats underwent hemodynamic assessment. MI-NarMic rats demonstrated decreased α-tubulin detyrosination relative to MI-Untreated rats (p < 0.05). Myocytes isolated from peri-infarct tissue had increased contraction and relaxation velocities in MI-NarMic versus MI-Untreated rats (both p < 0.0001). MI-NarMic rats had higher ejection fractions than MI-Mic and MI-Untreated rats (63 ± 3% v. 48 ± 5% vs. 39 ± 4%, p < 0.05) and similar levels to Sham (61 ± 1%, p = 0.97) and MI-NarDMSO (54 ± 5%) rats (p > 0.05). MI-Nar rats had greater stroke work and lower end-diastolic pressure and tau than MI-Untreated rats (all p < 0.05). Micellized naringenin is a translatable agent with the potential to rescue hemodynamics post-MI by inhibiting MARK4 and mitigating myocardial α-tubulin detyrosination. Full article

The insular cortex (IC) is a brain region that both receives relevant sensory information and is responsible for emotional and cognitive processes, allowing the perception of sensory information. The IC has connections with multiple sites of the pain matrix, including cortico-cortical interactions with the anterior cingulate cortex (ACC) and top-down connections with sites of descending pain inhibition. We explored the changes in the extracellular release of serotonin (5HT) and its major metabolite, 5-hydroxyindoleacetic acid (5HIAA), after inflammation was induced by carrageenan injection. Additionally, we explored the role of 5HT receptors (the 5HT1A, 5HT2A, and 5HT3 receptors) in the IC after inflammatory insult. The results showed an increase in the extracellular levels of 5HT and 5-HIAA during the inflammatory process compared to physiological levels. Additionally, the 5HT1A receptor was overexpressed. Finally, the 5HT1A, 5HT2A, and 5HT3 receptor blockade in the IC had antinociceptive effects. Our results highlight the role of serotonergic neurotransmission in long-lasting inflammatory nociception within the IC. Full article

Patients with unstable angina present clinical characteristics of atherosclerotic plaque vulnerability, contrary to chronic coronary syndrome patients. The process of athersclerotic plaque destabilization is also regulated by microRNA particles. In this study, the investigation on expression levels of microRNAs inhibiting the expression of proteins that protect from atherosclerotic plaque progression (miR-92a inhibiting KLF2, miR-10b inhibiting KLF4, miR-126 inhibiting MerTK, miR-98 inhibiting IL-10, miR-29b inhibiting TGFβ1) was undertaken. A number of 62 individuals were enrolled—unstable angina (UA, n = 14), chronic coronary syndrome (CCS, n = 38), and healthy volunteers (HV, n = 10). Plasma samples were taken, and microRNAs expression levels were assessed by qRT-PCR. As a result, the UA patients presented significantly increased miR-10b levels compared to CCS patients (0.097 vs. 0.058, p = 0.033). Moreover, in additional analysis when UA patients were grouped together with stable patients with significant plaque in left main or proximal left anterior descending (“UA and LM/proxLAD” group, n = 29 patients) and compared to CCS patients with atherosclerotic lesions in other regions of coronary circulation (“CCS other” group, n = 25 patients) the expression levels of both miR-10b (0.104 vs. 0.046; p = 0.0032) and miR-92a (92.64 vs. 54.74; p = 0.0129) were significantly elevated. In conclusion, the study revealed significantly increased expression levels of miR-10b and miR-92a, a regulator of endothelial protective KLF factors (KLF4 and KLF2, respectively) in patients with more vulnerable plaque phenotypes. Full article

Microorganisms that colonize in or on a host play significant roles in regulating the host’s immunological fitness and bioenergy production, thus controlling the host’s stress responses. Radiation elicits a pro-inflammatory and bioenergy-expensive state, which could influence the gut microbial compositions and, therefore, the host–microbe bidirectional relationship. To test this hypothesis, young adult mice were exposed to total body irradiation (TBI) at doses of 9.5 Gy and 11 Gy, respectively. The irradiated mice were euthanized on days 1, 3, and 9 post TBI, and their descending colon contents (DCCs) were collected. The 16S ribosomal RNAs from the DCCs were screened to find the differentially enriched bacterial taxa due to TBI. Subsequently, these data were analyzed to identify the metagenome-specific biofunctions. The bacterial community of the DCCs showed increased levels of diversity as time progressed following TBI. The abundance profile was the most divergent at day 9 post 11 Gy TBI. For instance, an anti-inflammatory and energy-harvesting bacterium, namely, Firmicutes, became highly abundant and co-expressed in the DCC with pro-inflammatory Deferribacteres at day 9 post 11 Gy TBI. A systems evaluation found a diverging trend in the regulation profiles of the functional networks that were linked to the bacteria and metabolites of the DCCs, respectively. Additionally, the network clusters associated with lipid metabolism and bioenergy synthesis were found to be activated in the DCC bacteria but inhibited in the metabolite space at day 9 post 11 Gy. Taking these results together, the present analysis indicated a disrupted mouse–bacteria symbiotic relationship as time progressed after lethal irradiation. This information can help develop precise interventions to ameliorate the symptoms triggered by TBI. Full article

This study evaluated push-out bond test (POBT), surface roughness, and antimicrobial properties against Enterococcus faecalis of bioceramic sealers supplemented with silver nanoparticles (AgNPs). The sealers tested were CeraSeal^®, EndoSequence^® BC Sealer^TM, and Bio-C^® Sealer. The POBT was measured with a Universal Testing Machine, and the type of failure was evaluated with a stereomicroscope. The roughness average (Sa) and peak–valley height (Sy) values were evaluated by atomic force microscopy. The bacterial growth inhibition was evaluated using a disk diffusion test, and antimicrobial activity was determined with the plate microdilution method. The POBT showed no significant difference between sealers with and those without NPs in cervical and apical thirds (p > 0.05). In the middle third, the adhesion force was significant for Endosequence BC Sealer^® (p < 0.05). The results showed that the Sa and Sy parameters, when AgNPs were added, did not show a statistically significant difference compared to the groups without nanoparticles (p > 0.05). All tested sealers showed bacterial growth inhibition, but no significant difference was found. Their efficacy, in descending order of antibacterial activity when AgNPs were added, is as follows: EndoSequence^® BC Sealer^TM > Bio-C^® Sealer > CeraSeal^®. The incorporation of AgNPs into bioceramics improves antimicrobial activity without affecting mechanical properties. Full article

Myocardial infarction (MI) is a leading cause of heart failure, characterized by adverse cardiac remodeling. This study evaluated the cardioprotective potential of Dohongsamul-tang (DHT), a traditional Korean herbal formula, in a rat model of MI-induced heart failure. Rats underwent left anterior descending (LAD) artery ligation and were treated with either 100 mg/kg or 200 mg/kg of DHT daily for 8 weeks. DHT treatment significantly improved cardiac function, as evidenced by increased ejection fraction (EF) from 62.1% to 70.1% (100 mg/kg) and fractional shortening (FS) from 32.3% to 39.4% (200 mg/kg) compared to the MI control group. Additionally, DHT reduced infarct size by approximately 63.3% (from 60.0% to 22.0%) and heart weight by approximately 16.7% (from 3.6 mg/g to 3.0 mg/g), and significantly decreased levels of heart failure biomarkers: LDH was reduced by 37.6% (from 1409.1 U/L to 879.1 U/L) and CK-MB by 47.6% (from 367.3 U/L to 192.5 U/L). Histological analysis revealed a reduction in left ventricle (LV) fibrosis by approximately 50% (from 24.0% to 12.0%). At the molecular level, DHT inhibited the expression of phospho-JAK by 75% (from 2-fold to 0.5-fold), phospho-STAT3 by 30.8% (from 1.3-fold to 0.9-fold), Bax/Bcl-2 by 56.3% (from 3.2-fold to 1.4-fold), and caspase-3 by 46.3% (from 1.23-fold to 0.66-fold). These results suggest that DHT exerts cardioprotective effects by modulating the JAK/STAT3 signaling pathway, highlighting its potential as a therapeutic option for heart failure. Full article

Safflower yellow is an extract of the famous Chinese medicine Carthamus tinctorious L, and safflower yellow injection (SYI) is widely used clinically to treat angina pectoris. However, there are few studies on the anti-myocardial ischemia/reperfusion (I/R) injury effect of SYI, and its mechanisms are unclear. In the present study, we aimed to investigate the protective effect of SYI on myocardial I/R injury and explore its underlying mechanisms. Male Sprague Dawley rats were randomly divided into a control group, sham group, model group, and SYI group (20 mg/kg, femoral vein injection 1 h before modeling). The left anterior descending coronary artery was ligated to establish a myocardial I/R model. H9c2 cells were exposed to oxygen–glucose deprivation/reoxygenation (OGD/R) after incubation with 80 μg/mL SYI for 24 h. In vivo, TsTC, HE, and TUNEL staining were performed to evaluate myocardial injury and apoptosis. A kit was used to detect superoxide dismutase (SOD) and malondialdehyde (MDA) to assess oxidative stress. In vitro, flow cytometry was used to detect the reactive oxygen species (ROS) content and apoptosis rate. Protein levels were determined via Western blotting. Pretreatment with SYI significantly reduced infarct size and pathological damage in rat hearts and suppressed cardiomyocyte apoptosis in vivo and in vitro. In addition, SYI inhibited oxidative stress by increasing SOD activity and decreasing MDA content and ROS production. Myocardial I/R and OGD/R activate endoplasmic reticulum (ER) stress, as evidenced by increased expression of activating transcription factor 6 (ATF6), glucose-regulated protein 78 (GRP78), cysteinyl aspartate-specific proteinase caspase-12, and C/EBP-homologous protein (CHOP), which were all inhibited by SYI. SYI ameliorated myocardial I/R injury by attenuating apoptosis, oxidative damage, and ER stress, which revealed new mechanistic insights into its application. Full article

Aeolian sand is distributed worldwide, exhibiting poor grading, low cohesion, and loose structure. Infrastructure construction in desert areas sometimes requires stabilization of the sand, with cement as the primary curing agent. This study first employed orthogonal experiments to evaluate critical factors, e.g., curing time, cement dosage, and water dosage, affecting the unconfined compressive strength (UCS) of the aeolian sand stabilized with cement (ASC). Each of the aforementioned factors were set at five levels, namely curing time (7, 14, 28, 60, and 90 days), cement dosage (3%, 5%, 7%, 9%, and 11%), and water dosage (3%, 6%, 9%, 12%, and 15%), respectively. The water and cement dosages were percentages of the mass of the natural aeolian sand. The results indicated that the sensitivity of the influencing factors on the UCS of ASC was cement dosage, curing time, and water dosage in descending order. The UCS of ASC positively correlated with curing time and cement dosage, while it first increased and then decreased with the water dosage increase. The optimal conditions were 90 days’ curing time, 11% cement dosage, and 9% water dosage. The microscopic analyses of ASC using optical microscopy, scanning electron microscopy (SEM), and X-ray diffraction (XRD) revealed that hydration products enhanced strength by bonding loose particles and filling pores, thereby improving compaction. The quantity and compactness of hydration products in the aeolian–cement reaction system increased with the increases in cement dosage and curing time, and low water dosage inhibited the hydration reaction. This study can provide insights into the stabilization mechanism of aeolian sand, aiding infrastructure development in desert regions. Full article

Following spinal cord injury (SCI), the regenerative capacity of the central nervous system (CNS) is severely limited by the failure of axonal regeneration. The regeneration of CNS axons has been shown to occur by grafting predegenerated peripheral nerves (PPNs) and to be promoted by the transplantation of neural precursor cells (NPCs). The introduction of a combinatorial treatment of PPNs and NPCs after SCI has to address the additional problem of glial scar formation, which prevents regenerating axons from leaving the implant and making functional connections. Previously, we discovered that the synthetic sulfoglycolipid Tol-51 inhibits astrogliosis. The objective was to evaluate axonal regeneration and locomotor function improvement after SCI in rats treated with a combination of PPN, NPC, and Tol-51. One month after SCI, the scar tissue was removed and replaced with segments of PPN or PPN+Tol-51; PPN+NPC+Tol-51. The transplantation of a PPN segment favors regenerative axonal growth; in combination with Tol-51 and NPC, 30% of the labeled descending corticospinal axons were able to grow through the PPN and penetrate the caudal spinal cord. The animals treated with PPN showed significantly better motor function. Our data demonstrate that PPN implants plus NPC and Tol-51 allow successful axonal regeneration in the CNS. Full article

Plants play a crucial role in soil fixation and enhancement of slope stability, and saline–alkaline stress is one of the main restrictions inhibiting plant growth and development. At present, there is a lack of research on the effects of saline–alkaline composite stress on the mechanical properties of the root system and the erosion resistance of the root–soil complex. In this study, three gradients of saline–alkaline composite stress treatments and a control of saline-free treatment was set up for Oenothera biennis, Perilla frutescens, Echinops sphaerocephalus, and Lychnis fulgens. The plant salt damage rate, osmotic index, antioxidant enzyme activity and plant root morphological indicators were measured. The biomechanical characteristics were determined by stretching tests, the resistance of the plant was measured by a whole-plant vertical uprooting test, and the anti-erosion capacity of the root soil composite was measured by scrubbing test. The results showed that, at 200 mM, the salt damage index and salt damage rate of the four plants, in descending order, were as follows: E. sphaerocephalus < L. fulgens < O. biennis < P. frutescens. Among them, SOD of Perilla frutescens did not play an obvious protective role, and the substantial changes in CAT and POD, as well as the content of soluble sugars, soluble proteins, and proline, showed its sensitivity to saline and alkaline stresses. Root growth was also significantly suppressed in all four plants, the 100- and 200-mM concentrations of saline solution significantly reduced the average tensile strength of O. biennis and P. frutescens, while the saline–alkali solution of 200 mM significantly reduced the elongation of E. sphaerocephalus and L. fulgens, and significantly elevated the soil detachment rate of the root–soil composite for E. sphaerocephalus. Additionally, all three concentrations of saline treatments significantly reduced the pullout resistance of all 4 plants. There was a negative power rate relationship between tensile resistance and root diameter in four plant species, while the relationship between tensile strength and root diameter showed a negative power law only for L. fulgens treated with 0–50 mM saline solution. There was no significant correlation between elongation and root diameter in the four plants. P. frutescens had the greatest tensile resistance and strength, as well as the lowest rate of elongation, while L. fulgens possessed the greatest pullout resistance, and both had comparable resistance to erosion of the root–soil complex. Therefore, compared to the other three plants, L. fulgens is more suitable for soil reinforcement applications on saline slopes. Full article