Therapeutic Effect Research Articles

Extraordinary therapeutic effect of PSMA radioligand therapy in treatment-refractory progressive metastatic prostate cancer with the transketolase inhibitor benfo-oxythiamine as a radiosensitizer—A case report

Herein we report, for the first time, the therapeutic response of a prostate cancer patient with the thiamine antagonist benfo-oxythiamine (B-OT) added to prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (PRLT). The patient was initially diagnosed as pT3b pN0 (0/7) M0 L0 V0 R0 G3, Gleason score 5 + 5 = 10, with an initial prostate-specific antigen (PSA) level of 4.05 ng/ml. Shortly after radical prostatectomy, 68Ga-PSMA positron emission tomography/computed tomography (PET/CT) revealed PSMA-positive lymph node metastases. Despite treatment with androgen deprivation therapy, external beam radiation therapy, palliative chemotherapy, and five cycles of PRLT (177Lu-PRLT or TANDEM-PRLT, respectively), the patient experienced progression in PSA levels as well as in PSMA PET/CT. Due to the intense PSMA expression, 177Lu-PRLT with 177Lu-PSMA-I&T was resumed for another 4 cycles (cycles 6th to 9th) and the patient was additionally treated with the thiamine antagonist benfo-oxythiamine. It was hypothesized that B-OT acts as a radiosensitizer by interfering with the repair of damaged DNA. B-OT-PRLT was well-tolerated and no substantial changes in laboratory results were observed. Additionally, the patient reported significant improvement in clinical symptoms. Post-treatment 177Lu-PSMA single-photon computed tomography (SPECT)/CT after the 7th cycle (and after 2 cycles of B-OT-PRLT) revealed regression of metastases compared to the post-treatment SPECT/CT after the 6th cycle. Before the 8th cycle, PSMA PET/CT showed a mixed response following prior uncontrollable cancer progression. Moreover, the PSA level showed a significant decline after one cycle of B-OT-PRLT. Although the patient had experienced massive progression before the first cycle of B-OT-PRLT, he survived for an additional 12 months. This case supports the hypothesis that B-OT-PRLT could overcome radiation resistance in prostate cancer patients who do not initially respond to 177Lu- or 225Ac-PRLT.

HDAC inhibitor SAHA enhances antitumor immunity via the HDAC1/JAK1/FGL1 axis in lung adenocarcinoma

BackgroundHistone deacetylase (HDAC), a kind of protease that regulates gene expression by modifying protein acetylation levels, is usually aberrantly activated in tumors. The approved pan-HDAC inhibitors (HDACi) have exhibited clinical...

Exaggerated postnatal surge of orexin neurons and the effects of elimination of excess orexin on blood pressure and exaggerated chemoreflex in spontaneously hypertensive rats

An overactive orexin (OX) system is associated with neurogenic hypertension and an exaggerated chemoreflex in spontaneously hypertensive rats (SHRs). However, the chronology and mechanism of this association is unclear. We hypothesized that increased postnatal neurogenesis of OX neurons in SHRs precedes and contributes to the aberrant increase in mean arterial blood pressure (MAP) and the exaggerated response to hypercapnia during postnatal development. Using immunohistochemical methods and bromodeoxyuridine, we mapped the timeline of orexin neuron neurogenesis and maturation during early postnatal development. We then used whole-body plethysmography with EEG and EMG to map the development of mean arterial pressure (MAP) and state regulation. Finally, we used OX-targeted saporin toxin to determine the effects of eliminating excess OX neurons on the elevated MAP and exaggerated chemoreflex in adult SHRs. We found that both SHRs and Wistar–Kyoto (WKY) rats experienced postnatal increases in OX neurons. However, SHRs experienced a greater increase than WKY rats before P15, which led to significantly more OX neurons in SHRs than age-matched WKY controls by P15–16 (3,720 ± 780 vs. 2,406 ± 363, p = 0.005). We found that neurogenesis, as evidenced by BrdU staining in OX-positive neurons, was the primary contributor to the excess OX neurons in SHRs during early postnatal development. While SHRs develop more OX neurons by P15–16, SHRs and normotensive WKY control rats have similar MAP during postnatal development until P25 in wakefulness (81.6 ± 6.6 vs. 67.5 ± 6.8 mmHg, p = 0.006) and sleep (79.3 ± 6.1 vs. 66.6 ± 6.5, p = 0.009), about 10 days after the surge of OX neurons. By selectively eliminating excess (∼30%) OX neurons in SHRs, we saw a significantly lowered MAP and hypercapnic ventilatory chemoreflex compared to non–lesioned SHRs at P40. Additionally, we found unique signatures in state indicative of the attention defecit phenotype commonly associated with this model. We suggest that the postnatal increase of OX neurons, primarily attributed to exaggerated postnatal OX neurogenesis, may be necessary for the development of higher MAP and exaggerated chemoreflex in SHRs, and modulation of the overactive OX system may have a potential therapeutic effect during the pre-hypertensive period.

Modulatory effects of traditional Chinese medicines on gut microbiota and the microbiota-gut-x axis

The gut microbiota offers numerous benefits to the human body, including the promotion of nutrient absorption, participation in metabolic processes, and enhancement of immune function. Recent studies have introduced the concept of the gut-organ axis, which encompasses interactions such as the gut-brain axis, gut-liver axis, and gut-lung axis. This concept underscores the complex interplay between gut microbiota and various organs and tissues, including the brain, heart, lungs, liver, kidneys, muscles, and bones. Growing evidence indicates that gut microbiota can influence the onset and progression of multi-organ system diseases through their effects on the gut-organ axis. Traditional Chinese medicine has demonstrated significant efficacy in regulating the gastrointestinal system, leveraging its unique advantages. Considerable advancements have been made in understanding the role of gut microbiota and the gut-organ axis within the mechanisms of action of traditional Chinese medicine. This review aims to elucidate the roles of gut microbiota and the gut-organ axis in human health, explore the potential connections between traditional Chinese medicine and gut microbiota, and examine the therapeutic effects of traditional Chinese medicine on the microbiota-gut-organ axis. Furthermore, the review addresses the limitations and challenges present in current research while proposing potential directions for future investigations in this area.

Transient increase of flicker electroretinograms after combined cataract surgery and vitrectomy for idiopathic epiretinal membrane

To determine the characteristics of the changes in the amplitude of the flicker electroretinograms (ERGs) after combined cataract surgery and vitrectomy for an idiopathic epiretinal membrane (ERM). To accomplish this, we conducted a prospective study on 20 patients. Flicker ERGs and central macular thickness (CMT) were measured before the surgery (baseline), and at 1 week, 1 month, 3 months, and 6 months postoperatively. The mean amplitude of the flicker ERGs increased significantly by 63.5% at 1 week after surgery (P < 0.001) and then gradually decreased. The amplitude at 6 months was not significantly different from the baseline amplitude. This transient increase in the flicker ERG amplitudes after ERM surgery suggests that electrophysiologic evaluations of the therapeutic effects of vitrectomy should be performed 6 months postoperatively. The mean CMT decreased significantly at 1 week postoperatively (P < 0.001) and continued to decrease progressively over six months. The relative increase of amplitude at 1 week was significantly associated with the relative decrease of CMT at 6 months, and evaluation of retinal functional changes at 1 week may be able to predict the postoperative course of the ERM.

Single-Cell Transcriptomics Reveals a Pivotal Role of DOCK2 in Sjögren Disease.

Sjögren disease (SjD) is an autoimmune condition characterized by the dysfunction of the salivary and lacrimal glands. The study aimed to decipher the pathogenic cell populations and their immunologic pathways in the salivary glands. We further determined the therapeutic effect of inhibiting dedicator of cytokinesis 2 (DOCK2) shared by novel clusters of CD8+ T cells in an SjD mouse model. This study employed single-cell RNA sequencing to examine the composition and dynamics of immune cells in the salivary glands of SjD mice. By analyzing the transcriptomic data and employing clustering analysis, a specific target was identified, leading to the treatment of mice with a targeted inhibitor. The results showed diverse immune cell types, including B cells, CD4+ T cells, CD8+ T cells, macrophages, and natural killer cells. We identified specific clusters possessing phenotypic characteristics of immune cell subpopulations, thereby showing specific genes/pathways associated with the disease. The most striking finding was the elevated expression of DOCK2 in CD8+ T cells in the SjD model. This discovery is significant because subsequent treatment with a DOCK2 inhibitor 4-[3-(2-Chlorophenyl)-2-propen-1-ylidene]-1-phenyl-3,5-pyrazolidinedione (CPYPP) led to a marked amelioration of SjD signs. The effectiveness of DOCK2 inhibition in alleviating SjD signs highlights the potential of DOCK2 as a therapeutic target, opening new avenues for treatment strategies that could modulate the immune response more effectively in SjD.

AAV-mediated combination gene therapy of inducible Caspase 9 and miR-199a-5p is therapeutic in hepatocellular carcinoma.

Advanced-stage hepatocellular carcinoma (HCC) remains an untreatable disease with an overall survival of less than one year. One of the critical molecular mediators contributing to increased resistance to therapy and relapse, is increased hypoxia-inducible factor 1α (HIF-1α) levels, leading to metastasis of tumor cells. Several microRNAs are known to be dysregulated and impact HIF-1α expression in HCC. An in silico analysis demonstrated that hsa-miR-199a-5p is downregulated at various stages of HCC and is known to repress HIF-1α expression. Based on this analysis, we developed a combinatorial suicide gene therapy by employing hepatotropic Adeno-associated virus-based vectors encoding an inducible caspase 9 (iCasp9) and miR-199a. The overexpression of miR-199a-5p alone significantly decreased ( ~ 2-fold vs. Mock treated cells, p < 0.05) HIF-1α mRNA levels, with a concomitant increase in cancer cell cytotoxicity in Huh7 cells in vitro and in xenograft models in vivo. To further enhance the efficacy of gene therapy, we evaluated the synergistic therapeutic effect of AAV8-miR-199a and AAV6-iCasp9 in a xenograft model of HCC. Our data revealed that mice receiving combination suicide gene therapy exhibited reduced expression of HIF-1α ( ~ 4-fold vs. Mock, p < 0.001), with a significant reduction in tumor growth when compared to mock-treated animals. These findings underscore the therapeutic potential of downregulating HIF-1α during suicide gene therapy for HCC.

Exploring the significance and potential mechanisms of hippo pathway-associated genes in prognosis of glioma patients

PurposeDespite the efforts of countless researchers to develop glioma treatment strategies, the current therapeutic effect of glioma is still not ideal, and it is necessary to further explore the mechanism to guide treatment. Thus, this study aims to introduce a novel approach for predicting patient prognosis and guiding further treatment interventions.MethodsInitially, we conducted a differential gene expression analysis to identify Hippo pathway-associated genes overexpressed in tumors and determined genes correlated with prognosis. Subsequently, employing cluster analysis, we categorized samples into two groups and performed further analyses including prediction, immune cell infiltration abundance, and drug response rates. We utilized weighted gene co-expression analysis to reveal gene sets with high co-variation, delineate inter-sample gene correlation patterns, and conduct enrichment analysis. Prognostic models were built using ten machine learning algorithms combined in 101 different combinations, followed by evaluation and validation. Immune infiltration analysis, differential expression analysis of depleted T cell-related markers, drug sensitivity analysis, and exploration of pathway dysregulation were performed for different risk groups. Quality control and batch integration were performed, and single-cell data were analyzed using dimensionality reduction clustering algorithms and annotation tools to evaluate the activity of the prognostic model in malignant cells.ResultsWe conducted data filtering to identify genes overexpressed in tumors, intersecting these genes with Hippo pathway-related genes, identifying 62 genes correlated with prognosis, and performing cluster analysis to divide tumor tissues into two groups. Cluster 2 exhibited a poorer prognosis and demonstrated differences in immune cell infiltration. Utilizing weighted gene co-expression analysis on Cluster 2, we identified gene modules, conducted functional enrichment analysis, and delineated pathways. Employing a combined model based on ten machine learning algorithm combinations, we selected the optimal prognostic model system and validated the model’s predictive ability within the dataset. Through immune-related analysis and drug sensitivity analysis, we uncovered differences in immune infiltration and varying sensitivities to chemotherapy drugs. Additionally, the enrichment analysis of gene set revealed discrepancies in upregulation within relevant pathways between the high and low-risk groups. Finally, annotation and evaluation of malignant cells via single-cell analysis showed increased activity of the prognostic model and variations in distribution across different prognostic levels in malignant cells.ConclusionThis study introduces a novel approach utilizing the Hippo pathway and associated genes for glioma prognosis research, demonstrating the potential and significance of this method in evaluating the outcome for patients with glioma. These findings hold substantial clinical significance in guiding therapy and predicting outcomes for individuals diagnosed with glioma, offering significant clinical utility.

Investigating the Effect of Polypyrrole-Gelatin/Silk Fibroin Hydrogel Mediated Pulsed Electrical Stimulation for Skin Regeneration.

In clinical practice to treat complex injuries, the application of electrical stimulation (ES) directly to the skin complicates the wound. In this work, the effect of a conductive hydrogel mediated electric field on skin regeneration is investigated. Polypyrrole incorporated matrices of gelatin and silk fibroin were prepared by two-step interfacial polymerization. The maximum electrical conductivity of 10-4 S cm-1 was achieved when 200 mM polypyrrole was loaded. Mechanically stable and cytocompatible hydrogels were evidenced to have antioxidant and blood compatible characteristics. Human dermal fibroblast cells responded to pulsed stimulation of 100 or 300 mV mm-1 as observed from the increased expressions of TGFβ1, αSMA, and COLIAI genes. Further, the increase in the αSMA protein expression with the magnitude of electrical stimulation also suggested transdifferentiation of the fibroblast to myofibroblast. Moreover, Raman spectroscopy identified two fingerprint regions (collagen and lipid) to differentiate ES treated and nontreated samples. Therefore, the combination of hydrogels and electrical stimulation has potential therapeutic effects for accelerating the rate of skin regeneration.

Fritillaria steroidal alkaloids and their multi-target therapeutic mechanisms: insights from network pharmacology.

Medicinal Fritillaria herbs, known for their rich content of steroidal alkaloids, have emerged as promising candidates in the treatment of chronic diseases due to their diverse pharmacological properties. Leveraging advancements in network pharmacology and molecular docking, this study explores the multi-target mechanisms through which these alkaloids exert therapeutic effects. The integration of bioinformatics, systems biology, and pharmacology in drug discovery has provided insights into the molecular interactions and pathways influenced by Fritillaria steroidal alkaloids. This review synthesizes comprehensive literature from 1985 to 2024, revealing the potential of these compounds in addressing respiratory diseases, inflammation, and cancer. The integration of traditional Chinese medicine (TCM) with modern pharmacological techniques underscores the relevance of these compounds in next-generation drug discovery. While initial findings are promising, further empirical validation is necessary to fully harness the therapeutic potential of Fritillaria steroidal alkaloids.

Review of simultaneous treatment with intradetrusor onabotulinumtoxinA injections during transurethral prostate surgery for men with bladder outlet obstruction and overactive bladder

ABSTRACT Bladder outlet obstruction (BOO) is common in males with benign prostate enlargement (BPE) and often presents with different lower urinary tract symptoms. Overactive bladder (OAB) has been reported to be related to BOO, although it can also be idiopathic. The storage symptoms of BOO are often similar to those of OAB. The etiology and pathophysiology of both BPE and OAB are multifactorial with metabolic syndrome known as one of the factors. As of today, transurethral prostate surgery remains the gold standard for treating BOO associated with BPE. Intradetrusor onabotulinumtoxinA (BoNT-A) injections have been shown to be effective in treating OAB. However, they are usually administered after transurethral prostate surgery. In view of the strong therapeutic effects of both surgery and injections, the feasibility of combining them in one setting to increase patient comfort, convenience, and possibly results while decreasing costs is appealing to physicians. However, patient safety and possible complications have to be considered. In this article, we review available studies of concurrent intradetrusor BoNT-A injections during transurethral prostate surgery. Although there is no definitive evidence supporting the concurrent use of intradetrusor BoNT-A during transurethral prostate surgery, there are no reports of increased complications too. Further large-scale randomized controlled trials would be necessary to validate the feasibility of combining the treatments in one setting and observe for possible complications.

Sustainable Polymeric Biomaterials from Alternative Feedstocks.

As materials engineered to interact with biological systems for medical purposes, polymeric biomedical materials have revolutionized and are indispensable in modern healthcare. However, aging populations and improving healthcare standards worldwide have resulted in ever-increasing demands for such biomaterials. Currently, many clinically used polymers are derived from nonrenewable petroleum resources, thus spurring the need for exploring alternatives for the next generation of sustainable biomaterials. Other than biomass, this Perspective also spotlights carbon dioxide and postuse plastics as viable resources potentially suitable for biomaterial production. For each alternative feedstock, key recent developments and practical considerations are discussed, including emerging biomaterial applications, possible feedstock sources, and hindrances toward translation and practical adoption. Other than replacements for petroleum-derived polymers, we explore how utilization of these alternatives capitalizes on their intrinsic physiochemical and material properties to achieve their desired therapeutic effects. We hope that this Perspective can stimulate further development in sustainable biomaterials to achieve practical therapeutic benefits as part of a circular materials economy with minimal environmental impact.

Taiwan Chingguan Yihau may improve post-COVID-19 respiratory complications through PI3K/AKT, HIF-1, and TNF signaling pathways revealed by network pharmacology analysis.

The emergence of new SARS-CoV-2 variants with a higher contagious capability and faster transmissible speed has imposed an incessant menace on global health and the economy. The SARS-CoV-2 infection might reoccur and last much longer than expected. Thence, there is a high possibility that COVID-19 can cause long-term health problems. This condition needs to be investigated thoroughly, especially the post-COVID-19 complications. Respiratory tract disorders are common and typical complications after recovery. Until now, there has been a lack of data on specialized therapeutic medicine for post-COVID-19 complications. The clinical efficacy of NRICM101 has been demonstrated in hospitalized COVID-19 patients. This herbal medicine may also be a promising therapy for post-COVID-19 complications, thanks to its phytochemical constituents. The potential pharmacological mechanisms of NRICM101 in treating post-COVID-19 respiratory complications were investigated using network pharmacology combined with molecular docking, and the results revealed that NRICM101 may exert a beneficial effect through the three primary pathways: PI3K/AKT, HIF-1, and TNF signaling pathways. Flavonoids (especially quercetin) have a predominant role and synergize with other active compounds to produce therapeutic effectiveness. Most of the main active compounds exist in three chief herbal ingredients, including Liquorice root (Glycyrrhiza glabra), Scutellaria root (Scutellaria baicalensis), and Mulberry leaf (Morus alba). To our knowledge, this is the first study of the NRICM101 effect on post-COVID-19 respiratory complications. Our findings may provide a better understanding of the potential mechanisms of NRICM101 in treating SARS-CoV-2 infection and regulating the immunoinflammatory response to improve post-COVID-19 respiratory complications.

The Therapeutic Effect of Monopolar Radiofrequency Therapy on Urinary Symptoms and Sexual Function

Objectives: Stress urinary incontinence (SUI) negatively affects the quality of life and sexual function in women. This study aimed to evaluate the efficacy of radiofrequency (RF) therapy in reducing SUI symptoms and its impact on sexual function. Methods: Thirty-four women with SUI were enrolled and underwent a single RF treatment session using the Viveve® System (Viveve Medical Inc., USA) with parameters of 90 J/cm2 and 220 pulses per hour. Assessments at baseline and 6 months post treatment included perineal ultrasound and personal interviews to evaluate lower urinary tract symptoms and sexual function. Urodynamic studies, voiding diaries, and questionnaires such as the Female Sexual Function Index (FSFI), Overactive Bladder Symptom Score (OABSS), Urogenital Distress Inventory-6 (UDI-6), Incontinence Impact Questionnaire-7 (IIQ-7), and International Consultation on Incontinence Questionnaire—Short Form (ICIQ-SF) measured outcomes. Results: RF therapy significantly improved sexual function, with higher FSFI scores in all domains except pain at 6 months. SUI symptoms were significantly reduced, as indicated by improved scores on OABSS, UDI-6, IIQ-7, and ICIQ-SF, alongside better voiding diary results. Anatomical changes included reduced bladder neck mobility, decreased vaginal width, and a reduced rotation angle of the proximal urethra. Conclusions: RF therapy is effective and safe for treating mild to moderate SUI and enhances sexual function, potentially due to changes in vaginal topography. These results suggest RF therapy as a viable non-surgical option for managing SUI and improving sexual health.

Effect of Electrical Stimulation of Lingual Nerve on Xerostomia: A Randomized Controlled Trial.

Xerostomia is a subjective sensation of dry mouth affecting millions of people worldwide. Current management has limitations, often causing side effects. This study aims to investigate whether electrical stimulation of the lingual nerve could offer effective relief for xerostomia sufferers. Eligible participants were randomly assigned (1:1) to either the experimental or sham group, receiving electrical stimulation of the lingual nerve (n = 24) or sham stimulation (n = 23) for 12 wk. The primary outcome is the changes in xerostomia score using a 100-mm visual analog scale throughout the therapy. Participants assessed their dryness and assigned corresponding scores, with lower scores indicating more severe dry mouth. Secondary outcomes included remission rate in dry mouth frequency, changes in stimulated/unstimulated salivary flow rate (SSFR/USFR), and changes in Oral Health Impact Profile-14 (OHIP-14) questionnaire scores, where higher scores indicate greater impact on oral quality of life. At week 12, the electrical stimulation group showed greater improvement in xerostomia score compared to the sham group, with a mean between-group difference of 13.8 (95% confidence interval [CI], 10.0-17.6). The therapeutic effect of electrical stimulation was also confirmed by secondary outcomes. The remission rate of dry mouth was higher at 12 wk in the electrical stimulation group (61.9% [95% CI, 40.9%-79.3%] vs. 28.6% [95% CI, 13.8%-50.0%]). Participants in the electrical stimulation group also experienced a greater increase in USFR, with a mean difference of 14.5 (6.1-23.0) μL/min. Moreover, they exhibited significant improvement in OHIP-14 score after 12 wk of therapy, with a mean between-group difference of -10.0 (-13.9 to -6.2). No significant difference was observed between the 2 groups for SSFR (P = 0.702). Electric stimulation offers promise as a noninvasive, nonpharmacological strategy for the management of xerostomia. Further research is needed to understand its long-term effectiveness, optimal parameters, and underlying mechanisms. The study confirmed that electrical stimulation of the lingual nerve is a promising noninvasive and nonpharmacological modality for relief of xerostomia.

Isoliquiritigenin as a modulator of the Nrf2 signaling pathway: potential therapeutic implications

Nuclear factor erythroid-2-related factor 2 (Nrf2), a transcription factor responsible for cytoprotection, plays a crucial role in regulating the expression of numerous antioxidant genes, thereby reducing reactive oxygen species (ROS) levels and safeguarding cells against oxidative stress. Extensive research has demonstrated the involvement of Nrf2 in various diseases, prompting the exploration of Nrf2 activation as a potential therapeutic approach for a variety of diseases. Consequently, there has been a surge of interest in investigating the Nrf2 signaling pathway and developing compounds that can modulate its activity. Isoliquiritigenin (ISL) (PubChem CID:638278) exhibits a diverse range of pharmacological activities, including antioxidant, anticancer, and anti-tumor properties. Notably, its robust antioxidant activity has garnered significant attention. Furthermore, ISL has been found to possess therapeutic effects on various diseases, such as diabetes, cardiovascular diseases, kidney diseases, and cancer, through the activation of the Nrf2 pathway. This review aims to evaluate the potential of ISL in modulating the Nrf2 signaling pathway and summarize the role of ISL in diverse diseases prevention and treatment through modulating the Nrf2 signaling pathway.

Unveiling the role of CXCL8/CXCR2 in intervertebral disc degeneration: A path to promising therapeutic strategies

BackgroundIntervertebral disc degeneration(IVDD) is the primary etiology of low back pain and radicular pain. Recent studies have found that chemokines play a role in IVDD, but the underlying mechanism is largely unclear. MethodsBioinformatics analysis was employed to screen CXCL8 as the target gene. The expression levels of CXCL8 and CXCR2 were quantified using RT-qPCR, western blot(WB), immunohistochemistry(IHC), and enzyme-linked immuno-sorbent assay(ELISA). In the IVDD mouse model, X-ray images, Safranin O-fast green staining(SO-FG), IHC, and WB were conducted to assess the therapeutic effects of CXCL8 on IVDD. Reactive oxygen species (ROS) production, apoptosis of nucleus pulposus cells (NPCs), and the involvement of the NF-κB pathway were evaluated through WB, flow cytometry, immunofluorescence(IF), and Tunnel assay. ResultsIn our study, we observed that CXCL8 emerged as one of the chemokines that were up-regulated in IVDD. The mitigation of extracellular matrix degradation (ECM) and the severity of IVDD were significantly achieved by neutralizing CXCL8 or its receptor CXCR2(SB225002, CXCR2 antagonist). The release of CXCL8 from infiltrated macrophages within intervertebral discs (IVDs) was predominantly observed upon stimulation. CXCL8 exerted its effects on NPCs by inducing apoptosis and ECM degradation through the activation of CXCR2. Specifically, the formation of the CXCL8/CXCR2 complex triggered the NF-κB signaling pathway, resulting in an abnormal increase in intracellular ROS levels and ultimately contributing to the development of IVDD. ConclusionOur findings suggest that macrophage-derived CXCL8 and subsequent CXCR2 signaling play crucial roles in mediating inflammation, oxidative stress, and apoptosis in IVDD. Targeting the CXCL8/CXCR2 axis may offer promising therapeutic strategies to ameliorate IVDD. The translational potential of this articleThis study indicates that CXCL8 can effectively exacerbate the excessive apoptosis and oxidative stress of NPCs through activating the NF-κB pathway. This study may provide new potential targets for preventing and reversing IVDD.

Memory, trauma, and self: Remembering and recovering from sexual abuse in psychedelic-assisted therapy

AbstractBackground and AimsThis article examines the therapeutic potential of psilocybin in addressing Post-Traumatic Stress Disorder as the result of sexual abuse. PTSD is a prevalent form of mental distress resistant to most conventional treatment methods.MethodsThrough an in-depth analysis of the narratives of two individuals with longstanding, treatment-resistant mental health conditions, who participated in a weeklong group-based psychedelic retreat involving psilocybin, the study unveils the intricate interplay between psychedelic-assisted therapy, memory, and narrative in the healing process.ResultsThe research findings suggest that beyond the commonly acknowledged therapeutic effects of psychedelic drugs, psilocybin can facilitate the retrieval of repressed or forgotten traumatic memories, allowing for conscious awareness, recognition, and reconciliation. A noteworthy aspect of the healing progression observed is the re-narration of one's identity and biographical circumstances following the recovery of unresolved traumatic memories.ConclusionsThis study underscores the importance of memory and self-narrative in the therapeutic landscape of psychedelic-assisted therapy for trauma. The article concludes by advocating for continued exploration in future research regarding the complex dynamics of memory and self-narrative in the healing journey within psychedelic science and trauma studies.

Integrated network pharmacology, metabolomics and molecular docking analysis to reveal the mechanisms of quercetin in the treatment of hyperlipidemia

Hyperlipidemia (HLP) is a significant contributor to cardiovascular diseases. Quercetin (QUE), a naturally occurring flavonoid with diverse bioactivities, has garnered attention due to its potential therapeutic effects. However, the precise mechanisms underlying the effects of QUE on HLP remain unclear. In this study, an ultra-high-performance liquid chromatography-quadrupole/electrostatic field Orbitrap high-resolution mass spectrometry (UPLC-Q-Exactive-MS) metabolomics strategy was employed to obtain metabolite profiles, and potential biomarkers were identified following data analysis. Network pharmacology and Drug Affinity Responsive Target Stability (DARTS) assays were utilized to explore the potential targets of QUE for HLP treatment. The results of metabolomics and network pharmacology were then integrated to identify the key targets and metabolic pathways involved in the therapeutic action of the QUE against HLP. Molecular docking and experimental validation were performed to confirm these key targets. A comprehensive database search identified 138 QUE-HLP-related targets. A protein-protein interaction (PPI) network was constructed using STRING, and the shared targets were filtered with Cytoscape. Among these, AKT1, TNF, VEGFA, mTOR, SREBP1, and SCD emerged as potential therapeutic targets. These findings were validated using in vitro cell experiments. Additionally, the mechanism of action of QUE against HLP was evaluated by integrating network pharmacology with metabolomics, identifying two metabolomic pathways crucial to HLP treatment. DARTS experiments confirmed the stable binding of QUE to FASN, p-mTOR, SREBP1, and p-AKT. In HepG2 cells treated with palmitic acid (PA), QUE significantly reduced the mRNA expression of ACLY, ACACA, FASN, and SCD (p < 0.05). Western blot analysis revealed that PA significantly increased protein expression of p-mTOR, SREBP1, FASN, and p-AKT (p < 0.05). In summary, our study provides novel insights into the protective mechanisms of QUE against HLP and offers valuable information regarding its potential benefits in clinical treatment.

Anti-fibrotic Potential of WJ-MSC Exosomes in Liver Fibrosis: Mechanistic Insights and Dose-Response Efficacy

Background: Hepatic fibrosis is a biological response characterized by the accumulation of extracellular matrix (ECM) during the wound healing process. Hepatic stellate cells (HSCs) play a pivotal role in fibrogenesis, transitioning from quiescent to myofibroblast cell types and leading to excessive ECM production. Platelet-derived growth factor (PDGF), a potent mitogen, is produced by activated HSCs, stimulating cell proliferation and migration. Objectives: This study aims to analyze the impact of Wharton's jelly mesenchymal stem cell (WJ-MSC)-derived exosomes on HSC activation induced by PDGF during liver fibrosis. Methods: Hepatic stellate cells-T6 cells were treated with PDGF-BB for 24 hours to induce activation, followed by treatment with varying concentrations of WJ-MSC-derived exosomes (0, 25, and 50 µg/mL) for another 24 hours. The effects of exosome treatment on HSC activation were evaluated through flow cytometry, differentiation assays, dynamic light scattering (DLS), transmission electron microscopy (TEM), RT-PCR, and western blot analysis. Results: Our study yields promising results, highlighting the potential therapeutic effects of WJ-MSC-derived exosomes on liver fibrosis. The dose-dependent decrease in fibrotic markers such as α-SMA, COLA1, and phosphorylated AKT protein in PDGF-BB-treated HSC-T6 cells suggests that WJ-MSC exosomes exert an anti-fibrotic effect by inhibiting HSC activation. Conclusions: These findings suggest that exosomes derived from WJ-MSCs hold therapeutic promise for liver fibrosis treatment by targeting key pathways involved in HSC activation and fibrogenesis. Further investigation into the underlying mechanisms of this anti-fibrotic effect and the potential clinical applications of WJ-MSC-derived exosomes in liver fibrosis management is warranted.