Developing hydrogels for gene therapy and tissue engineering.

Hydrogels are a class of highly absorbent and easily modified polymer materials suitable for use as slow-release carriers for drugs. Gene therapy is highly specific and can overcome the limitations of traditional tissue engineering techniques and has significant advantages in tissue repair. However, therapeutic genes are often affected by cellular barriers and enzyme sensitivity, and carrier loading of therapeutic genes is essential. Therapeutic gene hydrogels can well overcome these difficulties. Moreover, gene-therapeutic hydrogels have made considerable progress. This review summarizes the recent research on carrier gene hydrogels for the treatment of tissue damage through a summary of the most current research frontiers. We initially introduce the classification of hydrogels and their cross-linking methods, followed by a detailed overview of the types and modifications of therapeutic genes, a detailed discussion on the loading of therapeutic genes in hydrogels and their characterization features, a summary of the design of hydrogels for therapeutic gene release, and an overview of their applications in tissue engineering. Finally, we provide comments and look forward to the shortcomings and future directions of hydrogels for gene therapy. We hope that this article will provide researchers in related fields with more comprehensive and systematic strategies for tissue engineering repair and further promote the development of the field of hydrogels for gene therapy.

A novel role for microtubule affinity-regulating kinases in neuropathic pain.

BACKGROUND AND PURPOSE: Neuropathic pain affects millions of patients, but there are currently few viable therapeutic options available. Microtubule affinity-regulating kinases (MARKs) regulate the dynamics of microtubules and participate in synaptic remodelling. It is unclear whether these changes are involved in the central sensitization of neuropathic pain. This study examined the role of MARK1 or MARK2 in regulating neurosynaptic plasticity induced by neuropathic pain. EXPERIMENTAL APPROACH: A rat spinal nerve ligation (SNL) model was established to induce neuropathic pain. The role of MARKs in nociceptive regulation was assessed by genetically knocking down MARK1 or MARK2 in amygdala and systemic administration of PCC0105003, a novel small molecule MARK inhibitor. Cognitive function, anxiety-like behaviours and motor coordination capability were also examined in SNL rats. Synaptic remodelling-associated signalling changes were detected with electrophysiological recording, Golgi-Cox staining, western blotting and qRT-PCR. KEY RESULTS: MARK1 and MARK2 expression levels in amygdala and spinal dorsal horn were elevated in SNL rats. MARK1 or MARK2 knockdown in amygdala and PCC0105003 treatment partially attenuated pain-like behaviours along with improving cognitive deficit, anxiogenic-like behaviours and motor coordination in SNL rats. Inhibition of MARKs signalling reversed synaptic plasticity at the functional and structural levels by suppressing NR2B/GluR1 and EB3/Drebrin signalling pathways both in amygdala and spinal dorsal horn. CONCLUSION AND IMPLICATIONS: These results suggest that MARKs-mediated synaptic remodelling plays a key role in the pathogenesis of neuropathic pain and that pharmacological inhibitors of MARKs such as PCC0105003 could represent a novel therapeutic strategy for the management of neuropathic pain.

Natural Materials for 3D Printing and Their Applications.

In recent years, 3D printing has gradually become a well-known new topic and a research hotspot. At the same time, the advent of 3D printing is inseparable from the preparation of bio-ink. Natural materials have the advantages of low toxicity or even non-toxicity, there being abundant raw materials, easy processing and modification, excellent mechanical properties, good biocompatibility, and high cell activity, making them very suitable for the preparation of bio-ink. With the help of 3D printing technology, the prepared materials and scaffolds can be widely used in tissue engineering and other fields. Firstly, we introduce the natural materials and their properties for 3D printing and summarize the physical and chemical properties of these natural materials and their applications in tissue engineering after modification. Secondly, we discuss the modification methods used for 3D printing materials, including physical, chemical, and protein self-assembly methods. We also discuss the method of 3D printing. Then, we summarize the application of natural materials for 3D printing in tissue engineering, skin tissue, cartilage tissue, bone tissue, and vascular tissue. Finally, we also express some views on the research and application of these natural materials.

Research Progress on Emerging Polysaccharide Materials Applied in Tissue Engineering.

The development and application of polysaccharide materials are popular areas of research. Emerging polysaccharide materials have been widely used in tissue engineering fields such as in skin trauma, bone defects, cartilage repair and arthritis due to their stability, good biocompatibility and reproducibility. This paper reviewed the recent progress of the application of polysaccharide materials in tissue engineering. Firstly, we introduced polysaccharide materials and their derivatives and summarized the physicochemical properties of polysaccharide materials and their application in tissue engineering after modification. Secondly, we introduced the processing methods of polysaccharide materials, including the processing of polysaccharides into amorphous hydrogels, microspheres and membranes. Then, we summarized the application of polysaccharide materials in tissue engineering. Finally, some views on the research and application of polysaccharide materials are presented. The purpose of this review was to summarize the current research progress on polysaccharide materials with special attention paid to the application of polysaccharide materials in tissue engineering.

Current Understanding of the Applications of Photocrosslinked Hydrogels in Biomedical Engineering.

Hydrogel materials have great application value in biomedical engineering. Among them, photocrosslinked hydrogels have attracted much attention due to their variety and simple convenient preparation methods. Here, we provide a systematic review of the biomedical-engineering applications of photocrosslinked hydrogels. First, we introduce the types of photocrosslinked hydrogel monomers, and the methods for preparation of photocrosslinked hydrogels with different morphologies are summarized. Subsequently, various biomedical applications of photocrosslinked hydrogels are reviewed. Finally, some shortcomings and development directions for photocrosslinked hydrogels are considered and proposed. This paper is designed to give researchers in related fields a systematic understanding of photocrosslinked hydrogels and provide inspiration to seek new development directions for studies of photocrosslinked hydrogels or related materials.

Quantitative Analysis for the Delineation of the Subthalamic Nuclei on Three-Dimensional Stereotactic MRI Before Deep Brain Stimulation Surgery for Medication-Refractory Parkinson's Disease.

Delineation of the subthalamic nuclei (STN) on MRI is critical for deep brain stimulation (DBS) surgery in patients with Parkinson's disease (PD). We propose this retrospective cohort study for quantitative analysis of MR signal-to-noise ratio (SNR), contrast, and signal difference-to-noise ratio (SDNR) of the STN on pre-operative three-dimensional (3D) stereotactic MRI in patients with medication-refractory PD. Forty-five consecutive patients with medication-refractory PD who underwent STN-DBS surgery in our hospital from January 2018 to June 2021 were included in this study. All patients had whole-brain 3D MRI, including T2-weighted imaging (T2WI), T2-weighted fluid-attenuated inversion recovery (FLAIR), and susceptibility-weighted imaging (SWI), at 3.0 T scanner for stereotactic navigation. The signal intensities of the STN, corona radiata, and background noise were obtained after placing regions of interest (ROIs) on corresponding structures. Quantitative comparisons of SNR, contrast, and SDNR of the STN between MR pulse sequences, including the T2WI, FLAIR, and SWI. Subgroup analysis regarding patients' sex, age, and duration of treatment. We used one-way repeated measures analysis of variance for quantitative comparisons of SNR, contrast, and SDNR of the STN between different MR pulse sequences, and we also used the dependent t-test for the post hoc tests. In addition, we used Mann-Whitney U test for subgroup analyses. Both the contrast (0.33 ± 0.07) and SDNR (98.65 ± 51.37) were highest on FLAIR (all p < 0.001). The SNR was highest on SWI (276.16 ± 115.5), and both the SNR (94.23 ± 31.63) and SDNR (32.14 ± 17.23) were lowest on T2WI. Subgroup analyses demonstrated significantly lower SDNR on SWI for patients receiving medication treatment for ≥13 years (p = 0.003). In conclusion, on 3D stereotactic MRI of medication-refractory PD patients, the contrast and SDNR for the STN are highest on FLAIR, suggesting the optimal delineation of STN on FLAIR.

PCC-0105002, a novel small molecule inhibitor of PSD95-nNOS protein-protein interactions, attenuates neuropathic pain and corrects motor disorder associated with neuropathic pain model.

In view of postsynaptic density 95kDA (PSD95) tethers neuronal NO synthase (nNOS) to N-methyl-d-aspartate receptor (NMDAR), the PSD95-nNOS complex represents a therapeutic target of neuropathic pain. This study therefore sought to explore the ability of PCC-0105002, a novel PSD95-nNOS small molecule inhibitor, to alter pain sensitivity in rodent neuropathic pain models. Firstly, the IC50 of PCC-0105002 for PSD95 and NOS1 binding activity was determined using an Alpha Screen assay kit. Then, we examined the effects of PCC-0105002 in the mouse formalin test and in the rat spinal nerve ligation (SNL) model, and explored the ability of PCC-0105002 to mediate analgesia and to effect motor coordination in a rota-rod test. Moreover, the mechanisms whereby PCC-0105002 mediates analgesia was explored via western blotting, Golgi staining, and co-immunoprecipitation experiments in dorsal horn. The outcomes indicated that PCC-0105002 exhibited dose-dependent attenuation of phase II pain-associated behaviors in the formalin test. The result indicated that PCC-0105002 disrupted the PSD95-nNOS interaction with IC50 of 1.408 µM. In the SNL model, PCC-0105002 suppressed mechanical allodynia, thermal hyperalgesia, and abnormal dorsal horn wide dynamic range neuron discharge. PCC-0105002 mediated an analgesic effect comparable to that of MK-801, while it was better able to enhance motor coordination as compared with MK-801. Moreover, PCC-0105002 altered signaling downstream of NMDAR and thus functionally and structurally attenuating synaptic plasticity through respective regulation of the NR2B/GluR1/CaMKIIα and Rac1/RhoA pathways. These findings suggest that the novel PSD95-nNOS inhibitor PCC-0105002 is an effective agent for alleviating neuropathic pain, and that it produces fewer motor coordination-associated side effects than do NMDAR antagonists.

A 26-week toxicological study of Xuezhikang (XZK), red yeast rice extract, in Beagle dogs with a 4-week recovery period.

Xuezhikang (XZK) is an extract derived from red yeast rice that is commonly used to treat cardiovascular conditions as a traditional Chinese medicine, both within China and globally. Genotoxicity, acute toxicity, and a 26-week toxicity study in rat have been reported in our previous publication. The present study was designed to assess the long-term safety of XZK when administered orally to dogs. Dogs were treated with encapsulated XZK at a maximum dose of 2000 mg/kg followed by 1000 mg/kg and 500 mg/kg (n = 6/sex/group) for this 26-week oral toxicity study. Control animals were given an empty capsule. Treated animals were then monitored through measurements of body weight, body temperature, food intake, ophthalmic and electrocardiogram examinations, general clinical observations, mortality rates, and clinical and anatomic pathological findings. Additionally, blood samples were collected and used to conduct hematological and biochemical analysis. Several abnormalities were found in all groups including: fecal abnormalities (including mucoid, poorly formed, or liquid feces). Moreover, reduced CHOL and TRIG values were seen in all XZK groups (p < 0.05), increased WBC and NEUT levels in 500 mg/kg group (males only, p < 0.05), and elevated AST, ALT, and ALP activities in 2000 mg/kg group (p < 0.05). These changes were resolved in the recovery period. The results indicated that XZK may temporarily impact the liver enzyme levels, but were not considered adverse effects. These findings yielded a NOAEL for XZK in dogs of 2000 mg/kg.

WITHDRAWN: PCC-0105002, a novel small molecule inhibitor of PSD95-nNOS protein-protein interactions, attenuates neuropathic pain and corrects motor coordination-associated side effects in neuropathic pain model.

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Effects of dexmedetomidine on oxidative stress and inflammatory response in lungs during mechanical ventilation in COPD rats.

Effects of dexmedetomidine (Dex) on oxidative stress and inflammatory response in lungs during mechanical ventilation in chronic obstructive pulmonary disease (COPD) rats were investigated. Eleven out of 38 SD rats were randomly selected as the blank control group, and the other 27 rats were subjected to modeling. After the modeling, 11 rats in the blank control group and 11 rats randomly selected from the model group received non-invasive test for lung function. Three rats from the blank control group and 3 rats from the model group were selected for hematoxylin and eosin (HE) staining to confirm successful modeling, and the other 24 rats were randomly divided into 3 groups, 8 rats in each group, including model control, Dex low-dose and Dex high-dose group. A COPD rat model was established by passive cigarette smoking and intratracheal instillation of lipopolysaccharide. Each group underwent mechanical ventilation for 2 h. The Dex low-dose group and Dex high-dose group were intravenously administered at 1.0 µg/kg/h and 5.0 µg/kg/h of Dex, and the other two groups received intravenous drip of the same amount of normal saline. Blood gas analysis was performed to calculate carbon dioxide partial pressure (PaCO2), oxygen partial pressure (PaO2) and blood pH. HE staining was performed to analyze pulmonary pathological features of COPD rat model. Serum inflammatory factors interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-α) and malondialdehyde (MDA) were detected by ELISA, and the levels of antioxidant enzymes superoxide dismutase 2 (SOD2) and catalase were analyzed by western blot analysis. After 28 days of modeling, TV, PEF, FEV0.3 and FEV0.3/FVC decreased significantly in the COPD model group. HE staining showed that in the model group, the alveolar cells became larger, the alveolar wall became thinner, and some alveolar walls were even broken. The lung lobule showed obvious cell degeneration, necrosis and shedding, and the interstitial inflammatory cell infiltration, suggesting that the COPD rat model was successfully established. After 2 h of mechanical ventilation and Dex intravenous infusion, PaCO2 decreased, PaO2 increased, and blood pH value increased (p<0.05). Inflammatory factors IL-8 and TNF-α decreased (p<0.05). Oxidative stress index MDA also decreased (p<0.05), antioxidant enzymes SOD2 and catalase increased (p<0.05). Dexmedetomidine can improve the oxidative stress response during mechanical ventilation in rats with COPD, and can reduce the inflammation of lung tissue, thus protecting the lung tissue of COPD rats.