Therapeutic potential of gene therapy for gastrointestinal diseases: Advancements and future perspectives.

Advancements in understanding the pathogenesis mechanisms underlying gastrointestinal diseases, encompassing inflammatory bowel disease, gastrointestinal cancer, and gastroesophageal reflux disease, have led to the identification of numerous novel therapeutic targets. These discoveries have opened up exciting possibilities for developing gene therapy strategies to treat gastrointestinal diseases. These strategies include gene replacement, gene enhancement, gene overexpression, gene function blocking, and transgenic somatic cell transplantation. In this review, we introduce the important gene therapy targets and targeted delivery systems within the field of gastroenterology. Furthermore, we provide a comprehensive overview of recent progress in gene therapy related to gastrointestinal disorders and shed light on the application of innovative gene-editing technologies in treating these conditions. These developments are fueling a revolution in the management of gastrointestinal diseases. Ultimately, we discuss the current challenges (particularly regarding safety, oral efficacy, and cost) and explore potential future directions for implementing gene therapy in the clinical settings for gastrointestinal diseases.

α-ketoglutaric acid ameliorates intervertebral disc degeneration by blocking the IL-6/JAK2/STAT3 pathway.

Intervertebral disc degeneration (IVDD) is the major cause of low back pain. Alpha-ketoglutaric acid (α-KG), an important intermediate in energy metabolism, has various functions, including epigenetic regulation, maintenance of redox homeostasis, and anti-aging, but whether it can ameliorate IVDD has not been reported. Here, we examined the impacts of long-term administration of a-KG on aging-associated IVDD in adult rats. In vivo and in vitro experiments showed that α-KG supplementation effectively ameliorated IVDD in rats and the senescence of nucleus pulposus cells (NPCs). α-KG supplementation significantly attenuated senescence, apoptosis and MMP-13 protein expression, and it increased the synthesis of aggrecan and collagen II in IL-1ß-treated NPCs. In addition, α-KG supplementation reduced the levels of IL-6, phosphorylated JAK2 and STAT3, and the nuclear translocation of p-STAT3 in IL-1ß-induced degenerating NPCs. The effects of α-KG were enhanced by AG490 in NPCs. The underlying mechanism may involve the inhibition of JAK2/STAT3 phosphorylation and the reduction of IL-6 expression. Our findings may help in the development of new therapeutic strategies for IVDD.

MXene-Induced Flexible, Water-Retention, Semi-Interpenetrating Network Hydrogel for Ultra-Stable Strain Sensors with Real-Time Gesture Recognition.

As water-saturated polymer networks, hydrogels are a growing family of soft materials that have recently become promising candidates for flexible electronics application. However, it remains still difficult for hydrogel-based strain sensors to achieve the organic unity of mechanical properties, electrical conductivity, and water retention. To address this challenge, based on the template, the excellent properties of MXene nanoflakes (rich surface functional groups, high specific surface area, hydrophilicity, and conductivity) are fully utilized in this study to prepare the P(AA-co-AM)/MXene@PDADMAC semi-interpenetrating network (semi-IPN) hydrogel. The proposed hydrogel continues to exhibit excellent strain response and flexibility after 30 days of storage at room temperature, and its performance do not decrease after 1100 cycles. Considering these characteristics, a hydrogel-based device for converting sign language into Chinese characters is successfully developed and optimized using machine learning. Therefore, this study provides novel insight and application directions for hydrogel families.

Human iPSC-derived endothelial cells promote CNS remyelination via BDNF and mTORC1 pathway.

Damage of myelin is a component of many diseases in the central nervous system (CNS). The activation and maturation of the quiescent oligodendrocyte progenitor cells (OPCs) are the crucial cellular processes for CNS remyelination, which is influenced by neuroinflammation in the lesion microenvironment. Endothelial cells derived from human induced pluripotent stem cells (hiPSC-ECs) have shown promise in restoring function in various preclinical animal models. Here we ask whether and whether transplantation of hiPSC-ECs could benefit remyelination in a mouse model of CNS demyelination. Our results show that in vitro, hiPSC-ECs increase OPC proliferation, migration and differentiation via secreted soluble factors including brain-derived neurotrophic factor (BDNF). hiPSC-ECs also promote the survival of oligodendrocyte lineage cells in vitro and in vivo. Transplantation of hiPSC-ECs into a toxin-induced demyelination lesion in mouse corpus callosum (CC) leads to increased density of oligodendrocyte lineage cells and level of myelin in demyelinated area, correlated with a decreased neuroinflammation and an increased proportion of pro-regenerative M2 phenotype in microglia/macrophages. The hiPSC-EC-exposed oligodendrocyte lineage cells showed significant increase in the level of phosphorylated S6 ribosomal protein (pS6) both in vitro and in vivo, indicating an involvement of mTORC1 pathway. These results suggest that hiPSC-ECs may benefit myelin protection and regeneration which providing a potential source of cell therapy for a wide range of diseases and injuries associated with myelin damage.

Region-specific sympatho-adrenergic regulation of specialized vasculature in bone homeostasis and regeneration.

Type H vessels couple angiogenesis with osteogenesis, while sympathetic cues regulate vascular and skeletal function. The crosstalk between sympathetic nerves and type H vessels in bone remains unclear. Here, we first identify close spatial connections between sympathetic nerves and type H vessels in bone, particularly in metaphysis. Sympathoexcitation, mimicked by isoproterenol (ISO) injection, reduces type H vessels and bone mass. Conversely, beta-2-adrenergic receptor (ADRB2) deficiency maintains type H vessels and bone mass in the physiological condition. In vitro experiments reveal indirect sympathetic modulation of angiogenesis via paracrine effects of mesenchymal stem cells (MSCs), which alter the transcription of multiple angiogenic genes in endothelial cells (ECs). Furthermore, Notch signaling in ECs underlies sympathoexcitation-regulated type H vessel formation, impacting osteogenesis and bone mass. Finally, propranolol (PRO) inhibits beta-adrenergic activity and protects type H vessels and bone mass against estrogen deficiency. These findings unravel the specialized neurovascular coupling in bone homeostasis and regeneration.

The cerebellopontine angle cistern volumetric differences in trigeminal neuralgia patients with and without vertebrobasilar compression: a case-matched study.

Previous studies have indicated that the small cerebellopontine angle (CPA) cistern plays a role in the pathogenesis of trigeminal neuralgia (TN), but they are likely not involved in TN associated with vertebrobasilar artery (VBA) compression because of its rarity. Forty-four patients with VBA-associated TN and 44 age-, sex-, and hypertension-matched TN patients without VBA compression (non-VBA-associated) were included. All patients underwent high-resolution MRI. The CPA cistern volumes were measured bilaterally. The presence of vertebrobasilar dolichoectasia (VBD) and laterality of the vertebrobasilar junction (VBJ) were observed. The CPA cistern volume on the affected side was smaller than the unaffected side (714.4 ± 372.8 vs 890.2 ± 462.2 mm3, p < 0.001) in non-VBA-associated TN patients, while VBA-associated TN patients show a larger CPA cistern on the affected side than the unffected side (1107.0 ± 500.5 vs 845.3 ± 314.8 mm3, p < 0.001). The prevalence of VBD was higher in patients with VBA-associated TN than in matched non-VBA-associated TN patients (90.9% vs 4.5%, p < 0.001). A positive correlation between the laterality of VBJ and the affected side was found in the VBA-associated TN group (p < 0.0001). Large CPA cistern may be a neuroradiological feature of VBA-associated TN, and most of the VBA-associated TN is accompanied by VBD. The presence of VBD and the lateral shift of VBJ may expand the CPA cistern by squeezing the surrounding tissue on the affected side and also increase the chance of VBA compression on the trigeminal nerve, resulting in the genesis of VBA-associated TN.

[Application characteristics and modern research progress of "bone-approaching" acupuncture].

The paper explores the evolution of "bone-approaching" acupuncture, its effect target and mechanism. The concrete operation procedure of "bone-approaching" method is recorded originally in Huangdi Neijing (Inner Canon of Yellow Emperor) as short needling and Shu needling (referring to the category of the five needling technique). The periosteum is the most effective stimulation target of "bone-approaching" acupuncture for analgesia, regaining consciousness and regulating spirit. The "bone-approaching" acupuncture is not only prominently effective on bone bi syndrome, but also has the unique effect on painful, encephalogenic and emotional diseases. The paper summarizes and improves "bone-approaching" acupuncture, i.e. "touching bone surface" with needle tip by slow insertion, "touching bone surface" without pain by swift insertion and "touching bone" with needle body by oblique insertion. It contributes to the inheritance, development and supplementation to the bone needling techniques in Huangdi Neijing and is significant for broadening the clinical application range of acupuncture.

Genomes of cultivated and wild Capsicum species provide insights into pepper domestication and population differentiation.

Pepper (Capsicum spp.) is one of the earliest cultivated crops and includes five domesticated species, C. annuum var. annuum, C. chinense, C. frutescens, C. baccatum var. pendulum and C. pubescens. Here, we report a pepper graph pan-genome and a genome variation map of 500 accessions from the five domesticated Capsicum species and close wild relatives. We identify highly differentiated genomic regions among the domesticated peppers that underlie their natural variations in flowering time, characteristic flavors, and unique resistances to biotic and abiotic stresses. Domestication sweeps detected in C. annuum var. annuum and C. baccatum var. pendulum are mostly different, and the common domestication traits, including fruit size, shape and pungency, are achieved mainly through the selection of distinct genomic regions between these two cultivated species. Introgressions from C. baccatum into C. chinense and C. frutescens are detected, including those providing genetic sources for various biotic and abiotic stress tolerances.

Tauopathy promotes spinal cord-dependent production of toxic amyloid-beta in transgenic monkeys.

Tauopathy, characterized by the hyperphosphorylation and accumulation of the microtubule-associated protein tau, and the accumulation of Aß oligomers, constitute the major pathological hallmarks of Alzheimer's disease. However, the relationship and causal roles of these two pathological changes in neurodegeneration remain to be defined, even though they occur together or independently in several neurodegenerative diseases associated with cognitive and movement impairment. While it is widely accepted that Aß accumulation leads to tauopathy in the late stages of the disease, it is still unknown whether tauopathy influences the formation of toxic Aß oligomers. To address this, we generated transgenic cynomolgus monkey models expressing Tau (P301L) through lentiviral infection of monkey embryos. These monkeys developed age-dependent neurodegeneration and motor dysfunction. Additionally, we performed a stereotaxic injection of adult monkey and mouse brains to express Tau (P301L) via AAV9 infection. Importantly, we found that tauopathy resulting from embryonic transgenic Tau expression or stereotaxic brain injection of AAV-Tau selectively promoted the generation of Aß oligomers in the monkey spinal cord. These Aß oligomers were recognized by several antibodies to Aß1-42 and contributed to neurodegeneration. However, the generation of Aß oligomers was not observed in other brain regions of Tau transgenic monkeys or in the brains of mice injected with AAV9-Tau (P301L), suggesting that the generation of Aß oligomers is species- and brain region-dependent. Our findings demonstrate for the first time that tauopathy can trigger Aß pathology in the primate spinal cord and provide new insight into the pathogenesis and treatment of tauopathy.

Role of ferroptosis and immune infiltration in intervertebral disc degeneration: novel insights from bioinformatics analyses.

Background: Intervertebral disc degeneration (IVDD), which contributes to stenosis of the spinal segment, commonly causes lower back pain. The process of IVDD degradation entails gradual structural adjustments accompanied by extreme transformations in metabolic homeostasis. However, the molecular and cellular mechanisms associated with IVDD are poorly understood. Methods: The RNA-sequencing datasets GSE34095 and GSE56081 were obtained from the Gene Expression Omnibus (GEO) database. Ferroptosis-related differentially expressed genes (DEGs) were identified from these gene sets. The protein-protein interaction (PPI) network was established and visualized using the STRING database and Cytoscape software, and the key functional modules of ferroptosis-related genes were identified. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on the DEGs. Weighted gene co-expression network analysis (WGCNA), immune infiltration analysis in the GEO database, and other GSE series were used as validation datasets. The xCELL algorithm was performed to investigate the immune cell infiltration differences between the degenerated IVDD and control groups. Results: The major genes involved in nucleus pulposus tissue immune infiltration and ferroptosis-related genes were mined by bioinformatics analysis. A total of 3,056 DEGs were obtained between the IVDD tissue and control groups. The DEGs were enriched in the cell cycle; apoptosis; necroptosis; and the PI3K-Akt, Hippo, and HIF-1 signaling pathways. PCR and Western blot techniques were utilized to confirm the differential ferroptosis-related genes. The results indicated that the protein expression levels of NCOA4 and PCBP1 were elevated, while the protein expression level of GPX4 was reduced in NPCs following IL-1ß treatment. Our study has found that severe disc tissue degeneration leads to a noteworthy increase in the expression of CD8A in naive T cells, CCR7 in memory CD4+ cells, GZMB in natural killer (NK) cells, and CD163 and CD45 in macrophages. Conclusion: Our data demonstrate that ferroptosis occurs in IVDD, suggesting that ferroptosis may also increase IVDD improvement by triggering immune infiltration. This work was conducted to further understand IVDD pathogenesis and identify new treatment strategies.

Levels and health risk assessment of potential toxic elements in three dominant fish species from the Beibu Gulf, South China Sea.

In this study, eight potential toxic elements (PTEs) and stable isotope ratios (δ13C and δ15N) were analyzed in three dominant fish species of the Beibu Gulf, namely Saurida tumbil, Pennahia macrocephalus and Upeneus sulphureus. The mean contents (mg/kg, dry weight) of As, Cd, Cr, Cu, Mn, Ni, Pb and Zn in the three species of fish were 10.94, 0.11, 0.55, 2.00, 5.80, 0.47, 0.39, 41.70, respectively. Cr, Mn and Pb showed potential biomagnification effects in fish bodies while Cu and Zn were biodiluted through the food chain. The results of the health risk assessment showed that the total hazard quotient (THQ) ranged from 0.11 to 0.32 and 1.34 to 1.70 and the total carcinogenic risk (TCR) ranged from 5.44 × 10-4 to 1.35 × 10-3 and 6.35 × 10-3 to 1.57 × 10-2 for adults and children, respectively. These results suggest that consumption of the three fish species by adults lead to carcinogenic health risks and consumption of the three fish species by children would result in significant adverse health effects.

Triglyceride-glucose index and the risk of stroke in American adults: findings from the atherosclerosis risk in communities study.

OBJECTIVES: The associations between the triglyceride-glucose (TyG) index with subsequent stroke in American adults are unknown. The aim of this study was to determine the associations between baseline and trajectories of TyG index with subsequent stroke in American adults. METHODS: A total of 10,132 participants free of a history of stroke at baseline were included. We quantified the association of baseline and trajectories of TyG index with incident total stroke, ischemic stroke and intracerebral hemorrhage using Cox regression, restricted cubic splines and logistic regression analysis. RESULTS: There were 909 incident stroke cases over a median follow-up of 26.6 years. After adjustment for potential confounders, each unit increase in the TyG index was associated with a 32.1% higher risk of incident stroke. Compared with participants in the lowest quartile of the baseline TyG index, those in the highest quartile had a greater risk of incident stroke [HR (95% CI) 1.254 (1.014-1.552)]. Restricted cubic splines showed that the risk of stroke increased in participants with a higher TyG index, especially when the TyG index was > 8.6. Results were similar for incident ischemic stroke. Compared with participants in the lowest quartile of the baseline TyG index, those in the second quartile had a lower risk of intracerebral hemorrhage [HR (95% CI) 0.494 (0.262-0.931)]. Five discrete trajectories with stable TyG indexes at various levels at follow-up visits were identified, and parallel results were observed for the associations of trajectories of TyG index with outcomes. CONCLUSIONS: The TyG index independently predict stroke progression.

Neural Invasion is an Independent Prognostic Factor in Young and Lymph Node Negative Gastric Cancer Patients Underwent Curative Gastrectomy.

BACKGROUND: The prognostic significance of neural invasion (NI) in gastric cancer (GC) has not been established. This study is to investigate the characteristic and prognostic value of NI in GC. METHODS: 592 patients who had undergone gastrectomy for GC were retrospectively analyzed. NI was defined when cancer cells infiltrated into the perineurium or neural fascicles by hematoxylin and eosin staining of surgical specimens. NI and the other clinical factors were analyzed. RESULTS: NI was detected in 270 of the 592 patients. NI was associated with tumor size, site, depth of invasion, lymph node metastasis, TNM stage, D dissection, tumor differentiation, Lauren classification, and blood vessel invasion. NI was associated with the overall survival. Multivariate analysis indicated that NI was not an independent prognostic factor for total patients, while NI independently predicted prognosis for age < 60 and lymph node metastasis negative patients by subgroup analysis. Concomitant existence of NI with tumor size ≥3cm, TNM stage III, or diffused Lauren classification independently predicted prognosis. CONCLUSIONS: The frequency of NI is high in GC patients and increases with disease progression. NI is related to poor survival in GC patients who underwent curative gastrectomy and provides independent prognostic value for young and lymph node metastasis negative patients.

How APTMS Acts as a Bridge to Enhance the Compatibility of the Interface between the Hydrophilic Poly(vinyl alcohol) Film and the Hydrophobic Stearic Acid Coating.

The hydrophobic modification of poly(vinyl alcohol) (PVA) film as a biodegradable packaging material has received significant attention in recent research. Despite the use of stearic acid (SA) as a coating for the PVA film, a challenge persists due to the poor compatibility between SA and PVA. This study addressed the aforementioned issue by utilizing (3-aminopropyl)trimethoxysilane (APTMS) as a bridging agent to establish a connection between the hydrophilic PVA film and the hydrophobic SA coating through hydrogen bonding and chemical reactions. First, SEM and EDS analyses confirmed the enhanced interfacial compatibility between the SA coating and the PVA film. Subsequently, the results from 1H NMR, FTIR, and XPS experiments presented evidence of hydrogen bonding and chemical reactions among APTMS, SA, and the PVA film. Interestingly, the PVA-APTMS-SA film demonstrated a contact angle of 120.77°, a water absorption of 7.81%, and a water vapor transmission rate of 8.69 g/m2/h. Furthermore, such a composite film displayed exceptional adhesion performance, requiring detachment stresses of 9.86 ± 0.91 and 6.17 ± 0.75 MPa when tested on glass and marble surfaces, respectively. In conclusion, the PVA-APTMS-SA film exhibited significant potential in extending the freshness of fresh-cut apples, making it a promising eco-friendly packaging material for food preservation.

Accuracy of the Yakebot dental implant robotic system versus fully guided static computer-assisted implant surgery template in edentulous jaw implantation: A preliminary clinical study.

AIMS: To compare the accuracy of the Yakebot dental implant robotic system with that of fully guided static computer-assisted implant surgery (CAIS) template in edentulous implantation. MATERIALS AND METHODS: Thirteen patients with edentulous were recruited and divided into two groups: the Yake robotic system group (experimental) (n = 5) and the CAIS group (control) (n = 8). Postoperative cone-beam computed tomography (CBCT) was performed immediately, and the 3-dimensional positions of implants were obtained and compared with that in the preoperative design. The comparison showed platform, apical, depth, and angular deviations. A value of p < 0.05 was considered statistically significant. RESULTS: A total of 84 implants (36 in the robotic group and 48 in the CAIS group) were placed. The mean deviation at the implant platform, apex, depth, and angle in the CAIS group was 1.37 ± 0.72 mm, 1.28 ± 0.68 mm, 0.88 ± 0.47 mm, and 3.47 ± 2.02°, respectively. However, the mean deviation at the implant platform, apex, depth, and angle in the robotic group was 0.65 ± 0.25 mm, 0.65 ± 0.22 mm, 0.49 ± 0.24 mm, and 1.43 ± 1.18°, respectively. Significant differences in the four types of deviation (p < 0.05) between the two groups were observed. CONCLUSION: The accuracy of robotic system in edentulous implant placement was superior to that of the CAIS template, suggesting that robotic system is more accurate, safe, and flexible, can be considered a promising treatment in clinical practice.

Ruthenium and Iron Co-doped Molybdenum Carbide as a Stable Hydrogen Evolution Electrocatalyst in Harsh Electrolyte.

Electrocatalytic water splitting is one of the most commercially valuable pathways of hydrogen production especially combined with renewable electricity; however, efficient and durable electrocatalysts are urgently needed to reduce electric energy consumption. Here, we reported a Ru and Fe co-doped Mo2C on nitrogen doped carbon via a controllable two-step method, which can be used for efficient and enduring hydrogen evolution reaction. At 10, 100 and 200 mA cm-2 in acidic electrolyte, the resultant Ru-Fe/Mo2C@NC delivered low overpotentials of 31, 78 and 103 mV, respectively, which are comparable to that of the commercial Pt/C (20 wt%). At an applied current density of 100 mA cm-2, stable hydrogen production was conducted for 120 h without obvious degradation. In alkaline media, Ru-Fe/Mo2C@NC can also deliver a current density of 100 mA cm-2 for more than 100 h. Furthermore, the Ru-Fe/Mo2C@NC electrocatalyst was used as cathode in an anion exchange membrane water electrolyzer under industrial environments for robust hydrogen production. The characterization and electrochemical results prove the synergism effects between Ru, Fe dopants and Mo2C for promoting hydrogen evolution activity. This work would pave a new avenue to fabricate low-cost, high-performance hydrogen evolution electrocatalysts for industrial water electrolyzers.

Research progress in the molecular mechanism of ferroptosis in Parkinson's disease and regulation by natural plant products.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder of the central nervous system after Alzheimer's disease. The current understanding of PD focuses mainly on the loss of dopamine neurons in the substantia nigra region of the midbrain, which is attributed to factors such as oxidative stress, alpha-synuclein aggregation, neuroinflammation, and mitochondrial dysfunction. These factors together contribute to the PD phenotype. Recent studies on PD pathology have introduced a new form of cell death known as ferroptosis. Pathological changes closely linked with ferroptosis have been seen in the brain tissues of PD patients, including alterations in iron metabolism, lipid peroxidation, and increased levels of reactive oxygen species. Preclinical research has demonstrated the neuroprotective qualities of certain iron chelators, antioxidants, Fer-1, and conditioners in Parkinson's disease. Natural plant products have shown significant potential in balancing ferroptosis-related factors and adjusting their expression levels. Therefore, it is vital to understand the mechanisms by which natural plant products inhibit ferroptosis and relieve PD symptoms. This review provides a comprehensive look at ferroptosis, its role in PD pathology, and the mechanisms underlying the therapeutic effects of natural plant products focused on ferroptosis. The insights from this review can serve as useful references for future research on novel ferroptosis inhibitors and lead compounds for PD treatment.

Intraarticular vancomycin decreased the risk of acute postoperative periprosthetic joint infection without increasing complication in primary total joint arthroplasty- a prospective study.

OBJECTIVES: To investigate the preventive effect of intraarticularly administered vancomycin on acute postoperative periprosthetic joint infection (PJI) in total joint arthroplasty (TJA). METHODS: Consecutive patients who underwent unilateral primary TJA were prospectively enrolled. The patients were divided into vancomycin group and control group according to whether 1g of vancomycin powder suspended in 30ml normal saline was intraarticularly administered after arthrotomy closure. Acute postoperative PJI and aseptic wound complication were evaluated within three months postoperatively. Vancomycin-associated toxicity including acute renal failure, ototoxicity and anaphylaxis was also evaluated. RESULTS: In terms of demographic parameters and comorbidities, no significant difference was found between the two groups. Intra-articular vancomycin significantly lowered the risk of acute postoperative PJI after primary TJA (p=0.015) and primary total knee arthroplasty (p=0.031). However, for patients who underwent total hip arthroplasty, the PJI rate was comparable between the two groups. Overall, the risk of aseptic wound complication between the two groups was also similar. Vancomycin-associated acute renal injury, ototoxicity, or anaphylaxis was not observed. CONCLUSIONS: Intra-articular injection of 1g of vancomycin suspension after arthrotomy closure during TJA lowered the risk of acute postoperative PJI without increasing the risk of aseptic wound complication and vancomycin-associated systemic toxicity.