Bioengineered Zinc Oxide Nanoparticle-Loaded Hydrogel for Combinative Treatment of Spinal Cord Transection

Spinal cord injury (SCI) is one of the most destructive diseases. The neuroinflammation microenvironment needs comprehensive mitigation of damages. Thus, regulation of local, microenvironment drugs could be a potential effective treatment. However, clinical studies on SCI with common treatment have reported it to cause systemic toxicity and side effects. Zinc oxide nanoparticles (ZnONPs) have been widely reported to have satisfying anti-inflammation function. Furthermore, green synthesis procedures can improve the capability and possible utilization of ZnONPs. However, the efficient administration and underlying mechanism of ZnONPs in SCI treatment remain unclear. Herein, an innovative approach was built by utilizing ZnONPs loaded in a skeletal muscle-derived adhesive hydrogel (ZnONPs-Gel). Different from the systemic application of ZnONPs, the local administration of ZnONPs-Gel offered the ZnONPs-loaded extracellular matrix with beneficial biocompatibility to the injured spinal cord, thereby promoting effective function recovery. Mechanistically, the ZnONPs-Gel treatment not only markedly reduced ROS production but also decreased apoptosis in the injured spinal cord. Therefore, the strategy based on local administration of the ZnONPs-Gel in the early stage of SCI may be an effective therapeutic treatment.

Systemic L-ornithine supplementation specifically increases ovarian putrescine levels during ovulation in mice

In all mammalian species examined thus far, the ovaries produce a burst of ornithine decarboxylase (ODC) and putrescine during ovulation or after application of human chorionic gonadotropin (hCG). Aged mice have significantly reduced levels of this periovulatory ODC and putrescine rise. Putrescine supplementation, in vitro during oocyte maturation or in mouse drinking water during the periovulatory period, reduces egg aneuploidies and embryo resorption, improving fertility of aged mice. These studies suggest that periovulatory putrescine supplementation may be a simple and effective therapy for reproductive aging for women. However, putrescine supplementation is expected to increase widespread tissue putrescine levels, raising concerns of nonspecific and unwanted side effects. Given that ODC is highly expressed in the ovaries during ovulation but otherwise exhibits low activity in most tissues, we hypothesized that periovulatory supplementation of L-ornithine, the substrate of ODC, might be suitable for delivering putrescine specifically to the ovaries. In this study, we have demonstrated that systemic application of L-ornithine via oral gavage or subcutaneous injection increased ovarian putrescine levels; the increase was restricted to animals that had been injected with hCG. Furthermore, L-ornithine specifically increased ovarian putrescine levels without affecting putrescine levels in any other tissues. However, our attempts to improve fertility of aged mice through L-ornithine supplementation in mouse drinking water produced either no effects (1% L-ornithine) or negative impact on fertility (4% ornithine). Our results suggest that it might not be feasible to achieve fertility-enhancing ovarian putrescine levels via L-ornithine supplementation in drinking water without encountering undesired consequences of high dose of exogenous L-ornithine.

Fascial-sheath regional anesthesia for operations on the anterior abdominal wall and abdominal organs

The use of central segmental blockades (spinal and epidural) is associated with a large number of contraindications and complications including life-threatening. The combination of general anesthesia with opioids is associated with a slow recovery of the gastrointestinal tract and other side effects of their systemic application. Therefore the search for alternative methods of pain relief in the context of Enhanced Recovery After Surgery protocols is becoming an increasingly relevant research topicn. Relative to central blocks, the fascial sheath block of peripheral nerves under ultrasound guidance is a technically simple and safe technique. This article provides a brief overview of the main blocks used for anesthesia of the anterior abdominal wall.

Pitfalls of NMDA Receptor Modulation by Neuroactive Steroids. The Effect of Positive and Negative Modulation of NMDA Receptors in an Animal Model of Schizophrenia

Evidence from clinical and preclinical studies implicates dysfunction of N-methyl-D-aspartate receptors (NMDARs) in schizophrenia progression and symptoms. We investigated the antipsychotic effect of two neuroactive steroids in an animal model of schizophrenia induced by systemic application of MK-801. The neuroactive steroids differ in their mechanism of action at NMDARs. MS-249 is positive, while PA-Glu is a negative allosteric NMDAR modulator. We hypothesized that the positive NMDA receptor modulator would attenuate deficits caused by MK-801 co-application more effectively than PA-Glu. The rats were tested in a battery of tests assessing spontaneous locomotion, anxiety and cognition. Contrary to our expectations, PA-Glu exhibited a superior antipsychotic effect to MS-249. The performance of MS-249-treated rats in cognitive tests differed depending on the level of stress the rats were exposed to during test sessions. In particular, with the increasing severity of stress exposure, the performance of animals worsened. Our results demonstrate that enhancement of NMDAR function may result in unspecific behavioral responses. Positive NMDAR modulation can influence other neurobiological processes besides memory formation, such as anxiety and response to stress.

Systemic therapy of MSCs in bone regeneration: a systematic review and meta-analysis

Objectives Over the past decades, many studies focused on mesenchymal stem cells (MSCs) therapy for bone regeneration. Due to the efficiency of topical application has been widely dicussed and systemic application was also a feasible way for new bone formation, the aim of this study was to systematically review systemic therapy of MSCs for bone regeneration in pre-clinical studies. Methods The article search was conducted in PubMed and Embase databases. Original research articles that assessed potential effect of systemic application of MSCs for bone regeneration in vivo were selected and evaluated in this review, according to eligibility criteria. The efficacy of MSC systemic treatment was analyzed by random effects meta-analysis, and the outcomes were expressed in standard mean difference (SMD) and its 95% confidence interval. Subgroup analyses were conducted on animal species and gender, MSCs types, frequency and time of injection, and bone diseases. Results Twenty-three articles were selected in this review, of which 21 were included in meta-analysis. The results showed that systemic therapy increased bone mineral density (SMD 3.02 [1.84, 4.20]), bone volume to tissue volume ratio (2.10 [1.16, 3.03]), and the percentage of new bone area (7.03 [2.10, 11.96]). Bone loss caused by systemic disease tended to produce a better response to systemic treatment (p=0.05 in BMD, p=0.03 in BV/TV). Conclusion This study concluded that systemic therapy of MSCs promotes bone regeneration in preclinical experiments. These results provided important information for the systemic application of MSCs as a potential application of bone formation in further animal experiments.

Treatment of Rheumatoid Arthritis with Gene Therapy Applications: Biosafety and Bioethical Considerations

Rheumatoid Arthritis (RA) is an autoimmune and inflammatory disease that affects the synovium (lining that surrounds the joints), causing the immune system to attack its own healthy tissues. Treatment options, to the current day, have serious limitations and merely offer short-term alleviation to the pain. Using a theoretical exercise based on literature, a new potentially viable therapy has been proposed. The new therapy focusses on a long-term treatment of RA based on gene therapy, which is only active when inflammation of the joint occurs. This treatment will prevent side effects of systemic application of drugs. Furthermore, the benefits of this treatment for the patient from a socio-economic perspective has been discussed, focusing on the quality of life of the patent and lower costs for the society.

Effect of tetracyclines on pulpal and periodontal healing after tooth replantation: a systematic review of human and animal studies

Background Pulpal and periodontal healing are two main concerns of delayed replantation of avulsed teeth. The objective of this review was to evaluate the effectiveness of topical and systemic application of tetracyclines on pulpal and periodontal healing after tooth replantation. Methods A comprehensive electronic search was conducted in six databases. This systematic review was carried out according to Cochrane Handbook and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Results After exclusion of 246 irrelevant papers, 14 animal studies and one human study were included in this review. The human study showed that avulsed permanent teeth treated with doxycycline did not show a better clinical outcome for pulp and periodontal healing compared with treatment with normal saline. As for animal studies, significant more pulpal healing was observed in immature teeth treated with topical doxycycline in two researches, while another one study showed that there is no difference between teeth treated with normal saline and teeth treated with doxycycline. Systemic doxycycline exerted no significant effect on pulpal revascularization illustrated by one research. Only one out of four articles illustrated the positive effect of systemic tetracyclines on periodontal healing. One paper reported that intracanal application of demeclocycline promoted favorable periodontal healing. Two articles showed topical doxycycline contributed to favorable periodontal healing, while five studies showed no significant effect of topical tetracyclines on periodontal healing. Conclusions As a result of data heterogeneity and limitations of the studies, the effect of topical or systemic application of tetracyclines on pulpal and periodontal healing is inconclusive. More studies are required to get more clinically significant conclusions.

Promoting sustainable proliferation of NK cells by up-regulating IL2 and IL12 through CRISPR-CAS9Promoting sustainable proliferation of NK cells by up-regulating IL2 and IL12 through CRISPR-CAS9

NK cells are an important part of human immunity and are often used in clinical antitumor adoptive cell immunotherapy.However, the small number and low activity of NK cells in the tumor microenvironment limit its clinical efficacy.Studies have found that cytokines IL2 and IL12 play key roles in the proliferation of NK cells and the improvement of the activity of killing tumor cells, the toxic and side effects, however, are relatively large when the systemic application reaches the effective concentration. To study the effect of autocrine secretion of IL2 and IL12 on proliferation and anti-tumor activity of NK92 cell lines by editing NK cells' genes, and to construct NK92 cells with sustainable proliferation. Lentivirus was transfected into NK92 cells through the synergistic effect of crispr/cas9 localization gene editing technology and VP64 transcriptional activation domain to construct NK92-IL2-IL12 cell lines. The expression levels of IL2 and IL12 in the cell lines were detected by qPCR and ELISA.NK92 cell lines were inoculated into mouse tumor and the proliferation and anti-tumor effect of NK cells in tumor were observed. The vector plasmids IL2 and IL12 were successfully transferred into NK92 cells, which activated the up-regulated expression of IL2/IL12 in NK92, significantly increased the activity and lethality of NK92 cells, and sustained the proliferation of NK92 cells in mouse tumor.IL2 and IL12 can significantly promote the proliferation and killing activity of NK92 cell lines through autocrine, which have stronger anti-tumor activity than the wild-type ones, with continuous proliferation in the tumor.

Pten is a key intrinsic factor regulating raphe 5-HT neuronal plasticity and depressive behaviors in mice

Serotonin (5-HT)-based antidepressants, selective serotonin reuptake inhibitors (SSRIs) aim to enhance serotonergic activity by blocking its reuptake. We propose PTEN as a target for an alternative approach for regulating 5-HT neuron activity in the brain and depressive behaviors. We show that PTEN is elevated in central 5-HT neurons in the raphe nucleus by chronic stress in mice, and selective deletion of Pten in the 5-HT neurons induces its structural plasticity shown by increases of dendritic branching and density of PSD95-positive puncta in the dendrites. 5-HT levels are elevated and electrical stimulation of raphe neurons evokes more 5-HT release in the brain of condition knockout (cKO) mice with Pten-deficient 5-HT neurons. In addition, the 5-HT neurons remain normal electrophysiological properties but have increased excitatory synaptic inputs. Single-cell RNA sequencing revealed gene transcript alterations that may underlay morphological and functional changes in Pten-deficient 5-HT neurons. Finally, Pten cKO mice and wild-type mice treated with systemic application of PTEN inhibitor display reduced depression-like behaviors. Thus, PTEN is an intrinsic regulator of 5-HT neuron activity, representing a novel therapeutic strategy for producing antidepressant action.