Study of the electronic effect and quantitative spectra predictions of o-methoxyaniline-terminated monoazonaphthols: a combined experimental and DFT study.

A combined experimental and density functional theory (DFT) study on the UV-Vis spectra of o-methoxyaniline-terminated mono azo dyes was conducted. By applying time-dependent-DFT calculations, details of excitation processes were determined and visualization by hole-electron analysis was undertaken. Fragment-divided analysis revealed the contributions of different parts of the structures for the UV-Vis spectra, that richer/poorer electron density on aromatic rings lead to greater/less maximum absorption wavelengths (λmax) and larger/smaller half peak width (W1/2). Combining theoretical prediction with experimental verification, we answered the question of how the electronegativities of substituents affected the electron densities and how it affected the spectra. In addition, a linear model connecting the λmax and W1/2 to the chemical shifts obtained by NMR spectroscopy was constructed, which laid the foundation for construction of a spectral library.

Engineered high-strength biohydrogel as a multifunctional platform to deliver nucleic acid for ameliorating intervertebral disc degeneration.

Intervertebral disc degeneration (IVDD) is a leading cause of low back pain. The strategy of using functional materials to deliver nucleic acids provides a powerful tool for ameliorating IVDD. However, the immunogenicity of nucleic acid vectors and the poor mechanical properties of functional materials greatly limit their effects. Herein, antagomir-204-3p (AM) shows low immunogenicity and effectively inhibits the apoptosis of nucleus pulposus cells. Moreover, a high-strength biohydrogel based on zinc-oxidized sodium alginate-gelatin (ZOG) is designed as a multifunctional nucleic acid delivery platform. ZOG loaded with AM (ZOGA) exhibits great hygroscopicity, antibacterial activity, biocompatibility, and biodegradability. Moreover, ZOGA can be cross-linked with nucleus pulposus tissue to form a high-strength collagen network that improves the mechanical properties of the intervertebral disc (IVD). In addition, ZOGA provides an advantageous microenvironment for genetic expression in which AM can play an efficient role in maintaining the metabolic balance of the extracellular matrix. The results of the radiological and histological analyses demonstrate that ZOGA restores the height of the IVD, retains moisture in the IVD, and maintains the tissue structure. The ZOGA platform shows the sustained release of nucleic acids and has the potential for application to ameliorate IVDD, opening a path for future studies related to IVD.

Characteristics and Outcomes of Athletes With Slow Recovery From Sports-Related Concussion: A CARE Consortium Study.

BACKGROUND AND OBJECTIVES: Some athletes experience a slow recovery after sport-related concussion (SRC). There is little agreement on what constitutes slow recovery, however, and minimal data on the prevalence, predictors, or prognosis for this group. The objectives of this study were to apply an operationalized definition of slow recovery and characterize predictors and long-term prognosis of these individuals. METHODS: This is a prospective multisite observational study of collegiate athletes. Participants underwent multimodal assessments preseason and 5 additional time points after SRC. Time from injury to initiation of return to play progression (asymptomatic timepoint) and from injury to return to play (RTP) were the primary markers of recovery. RESULTS: One thousand seven hundred fifty-one concussed male and female collegiate athletes were studied. Eighty percent of participants reached the asymptomatic and/or RTP time points by days 14 and 24, respectively. Slow recovery was thus defined as exceeding 1 or both of those intervals (n = 399). This group was statistically more likely to be female (41.1% vs 35.6%, p = 0.05), have higher initial postinjury SCAT symptom severity scores (mean [SD]: 36.6 [23.4] vs 25.4 [19.9], p < 0.001), lower postinjury Standardized Assessment of Concussion scores (mean [SD]:25.74 [2.98] vs 26.26 [2.85], p = 0.004), perform worse on the postinjury Balance Error Scoring System (mean [SD]: 17.8 [8.9] vs 15.9 [8.5], p < 0.01), have fewer assessments in the first 14 days after injury (mean [SD]: 48.8 [29.7] vs 67.9 [24.6], p < 0.01), and be injured in practice (70.7% vs 65.1%, p = 0.04). 77.6% of the slow recovery group returned to play within 60 days of injury, and 83.4% (n = 349) returned to play within 90 days of injury. Only 10.6% had not returned to play 6 months postinjury. DISCUSSION: This study suggests an overall favorable prognosis for slowly recovering athletes and provides data for athletes and medical teams to consider in calibrating RTP expectations and making decisions about medical disqualification vs ongoing engagement in their sport.

CASMART, a one-step CRISPR Cas12a-mediated isothermal amplification for rapid and high-resolution digital detection of rare mutant alleles.

Convenient, ultrasensitive, and accurate detection of rare variants is essential for early cancer diagnosis and precision medicine, however, despite years of efforts, tools that have all these qualities remain elusive. Here, we developed a one-step CRISPR/Cas12a-based digital diagnostic platform for accurately quantifying mutant alleles, referred to as the CRISPR ASsoaciated Mutation Allele Rapid Test (CASMART). The platform accurately quantifies the variant allele frequency of EGFR L858R within 1 h at 42 °C and can detect mutant targets as low as 0.3 copies/µL (0.498 aM) in mock multiplex cfDNA samples. We further investigated the applicability of CASMART using human genomic samples with confirmed EGFR L858R mutations previously measured variant allele frequency by next-generation sequencing. Comparison across platforms revealed equivalent detection performance (Pearson's correlation coefficient, R2 = 0.9208) and high quantification accuracy for mutation allele frequency (intraclass correlation coefficient = 0.959). Our one-step approach enables easy and accurate variant allele frequency measurement of rare mutant alleles without PCR instrumentation, while the assay time was reduced by approximately half compared to the digital PCR with the shortest turnaround. The CASMART is an alternative to conventional single nucleotide polymorphism detection methods with great potential as a next-generation biosensor for rapidly quantifying the variant allele fraction, especially in resource-limited settings.

Semiparametric marginal regression for clustered competing risks data with missing cause of failure.

Clustered competing risks data are commonly encountered in multicenter studies. The analysis of such data is often complicated due to informative cluster size (ICS), a situation where the outcomes under study are associated with the size of the cluster. In addition, the cause of failure is frequently incompletely observed in real-world settings. To the best of our knowledge, there is no methodology for population-averaged analysis with clustered competing risks data with an ICS and missing causes of failure. To address this problem, we consider the semiparametric marginal proportional cause-specific hazards model and propose a maximum partial pseudolikelihood estimator under a missing at random assumption. To make the latter assumption more plausible in practice, we allow for auxiliary variables that may be related to the probability of missingness. The proposed method does not impose assumptions regarding the within-cluster dependence and allows for ICS. The asymptotic properties of the proposed estimators for both regression coefficients and infinite-dimensional parameters, such as the marginal cumulative incidence functions, are rigorously established. Simulation studies show that the proposed method performs well and that methods that ignore the within-cluster dependence and the ICS lead to invalid inferences. The proposed method is applied to competing risks data from a large multicenter HIV study in sub-Saharan Africa where a significant portion of causes of failure is missing.

Exercise-induced FNDC5/irisin protects nucleus pulposus cells against senescence and apoptosis by activating autophagy.

Intervertebral disc degeneration (IVDD) is a major cause of low back pain (LBP), and excessive senescence and apoptosis of nucleus pulposus (NP) cells are major pathological changes in IVDD. Physical exercise could effectively delay the process of intervertebral disc degeneration; however, its mechanism is still largely unknown. Irisin is an exercise-induced myokine released upon cleavage of the membrane-bound precursor protein fibronectin type III domain-containing protein 5 (FNDC5), and its levels increase after physical exercise. Here, we show that after physical exercise, FNDC5/irisin levels increase in the circulation and NP, senescence and apoptosis are reduced, autophagy is activated in NP tissue, and the progression of IVDD is delayed. Conversely, after knocking out FNDC5, the benefits of physical exercise are compromised. Moreover, the overexpression of FNDC5 in NP tissue effectively alleviated the degeneration of the intervertebral disc (IVD) in rats. By showing that FNDC5/irisin is an important mediator of the beneficial effects of physical exercise in the IVDD model, the study proposes FNDC5/irisin as a novel agent capable of activating autophagy and protecting NP from senescence and apoptosis.

Real-world study for identifying the predictive factors of surgical intervention and the value of magnetic resonance imaging in patients with low back pain.

Background: Low back pain (LBP) is a prevalent disease and can be disabling. Currently, many patients with LBP with or without radiculopathy commonly undergo magnetic resonance imaging (MRI) for diagnosis and therapeutic assessment, yet the final intervention is mainly centered around nonoperative treatment. This study's aim was to identify the predictive factors of surgical treatment and the value of MRI in patients with LBP with or without radiculopathy. Methods: The study included a training cohort that consisted of 461 patients with MRI from January 2014 to December 2018. Demographic characteristics and MRI findings were collected from our medical records. We developed and validated 2 nomograms to predict the possibility of receiving surgical treatment in LBP patients, based on multivariable logistic regression analysis. The performance of the 2 nomograms was assessed in terms of their calibration, discrimination, and clinical usefulness. An independent validation cohort containing 163 patients was comparatively analyzed. Results: The baseline model incorporated 6 clinicopathological variables, while the MRI model consisted of 9 variables including several MRI findings. Internal validation revealed the good performance of the 2 nomograms in discrimination and calibration, with a concordance index (C-index) of 0.799 (95% CI: 0.743-0.855) for the baseline model and 0.834 (95% CI: 0.783-0.884) for the MRI model, which showed that the addition of MRI findings to the nomogram failed to achieve better prognostic value (Z statistic =-1.509; P=0.131). Application of the 2 models in the validation cohort also showed good discrimination (baseline model: C-index 0.75, 95% CI: 0.671-0.829; MRI model: C-index 0.777, 95% CI: 0.696-0.857) and calibration. No significant predictive benefit was found in the MRI model in the validation cohort (Z statistic =-0.588; P=0.557). Conclusions: This study showed that clinical demographic characteristics provide good prognostic value to determine whether LBP patients with or without radiculopathy require surgical treatment. The addition of MRI findings yielded no significantly incremental prognostic value.

The Natural History of Sport-Related Concussion in Collegiate Athletes: Findings from the NCAA-DoD CARE Consortium.

BACKGROUND: Sport-related concussion is recognized as a significant injury with variable recovery rates. OBJECTIVE: This study defined the acute natural history of sport concussion in male and female collegiate athletes participating in a broad array of sports. METHODS: We conducted a prospective, longitudinal investigation among collegiate student athletes (n = 34,709) from 30 academic institutions. Primary outcomes included the time (days) from injury until initiation of a return to participation (RTP) protocol and time from injury until medical clearance for unrestricted RTP. RESULTS: Concussed athletes (n = 1751, 19.2 years, 63.2% male) participating in 22 different sports began the RTP protocol in a median 6.4 (IQR 3.7-11.8) days. Time to initiate the RTP protocol was lengthened by less frequent post-injury assessments, greater initial post-injury symptom severity, limited contact sports participation, practice/training injuries, and three or more prior concussions. The median total RTP duration was 12.8 (IQR 8.7-20.1) days. Total RTP duration was shorter with ADHD medication usage, males, and greater assessment frequency; while greater initial post-injury symptom severity, practice-/training-related injuries, and three or more prior concussions had longer recoveries. CONCLUSION: Although median recovery times are consistent with previous guidelines, it was not until 1 month post-injury that a preponderance of collegiate athletes were cleared to begin the RTP protocol (92%) or cleared for unrestricted sport participation (85%). Intrinsic and extrinsic factors had a small effect, altering recovery trajectories by up to 2 days, suggesting a largely unified approach to post-injury monitoring and management across all athletes. These data represent a shift from previous classification parameters of normal clinical recovery.

Sinensetin Reduces Osteoarthritis Pathology in the Tert-Butyl Hydroperoxide-Treated Chondrocytes and the Destabilization of the Medial Meniscus Model Mice via the AMPK/mTOR Signaling Pathway.

As a common degenerative disease, osteoarthritis (OA) usually causes disability in the elderly and socioeconomic burden. Previous studies have shown that proper autophagy has a protective effect on OA. Sinensetin (Sin) is a methylated flavonoid derived from citrus fruits. Studies have shown that Sin is a good autophagy inducer and has shown excellent therapeutic effects in a variety of diseases; however, its role in the treatment of OA is not fully understood. This study proved the protective effect of Sin on OA through a series of in vivo and in vitro experiments. In vitro experiments have shown that Sin may inhibit chondrocyte apoptosis induced by tert-butyl hydroperoxide (TBHP); at the same time, it might also inhibit the production of MMP13 and promote the production of aggrecan and collagen II. Mechanism studies have shown that Sin promotes chondrocyte autophagy by activating AMPK/mTOR signaling pathway. On the contrary, inhibition of autophagy can partially abolish the protective effect of Sin on TBHP-treated chondrocytes. In vivo experiments show that Sin may protect against DMM-induced OA pathogenesis. These results provide evidence that Sin serves as a potential candidate for the treatment of OA.

Gum polysaccharide/nanometal hybrid biocomposites in cancer diagnosis and therapy.

Biopolymers are of prime importance among which gum polysaccharides hold an eminent standing owing to their high availability and non-toxic nature. Gum biopolymers offer a greener alternative to synthetic polymers and toxic chemicals in the synthesis of metal nanostructures. Metal nanostructures accessible via eco-friendly means endow astounding characteristics to gum-based biocomposites in the field of diagnosis and therapy towards cancer diseases. In this review, assorted approaches for the assembly of nanomaterials mediated by gum biopolymers are presented and their utility in cancer diagnosis and therapy, e.g., bioimaging, radiotherapy, and phototherapy, are deliberated to provide a groundwork for future stimulative research.

Efficacy and safety of continuous infusion of Rh-endostatin combined with platinum-based chemotherapy for advanced triple-negative breast cancer.

BACKGROUND: This study aimed to prospectively evaluate and investigate the efficacy and safety of recombinant human endostatin (Rh-endostatin) combined with platinum-based regimens for advanced triple-negative breast cancer (TNBC) patients. METHODS: This study was a prospective, single-arm, single-center, open-label trial. From January 2017 to August 2019, 21 women aged 18-70 years with histologically confirmed advanced TNBC were enrolled. Rh-endostatin at 30 mg/d was continuously pumped for 7 days and used synchronously with the chemotherapy cycle. The primary endpoint of this study was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), overall survival (OS), and toxicity. RESULTS: The median PFS (mPFS) was 8.8 months (95% CI: 7.2-10.4 months), and the median OS was 13.3 months (95% CI: 11.6-15.0 months). The ORR and CBR for the whole population were 47.6% and 52.4%, respectively. Patients sensitive to anthracycline and taxane drugs showed a significantly longer mPFS compared to those who were resistant to anthracycline and taxane drugs (mPFS: 8.8 vs. 5.3 months, P=0.038). For patients who received first- and second-line therapy or beyond, the mPFS was 8.8 and 5.3 months, respectively, with a significant difference (P=0.025). No statistically significant differences in the mPFS between pemetrexed combined with platinum and gemcitabine/taxanes combined with platinum were observed. The most common grade 3-4 hematologic toxicities were neutropenia (14.3%) and anemia (14.3%). One patient (4.8%) experienced febrile neutropenia. No grade 3-4 non-hematologic toxicities were observed, and no treatment-related deaths were reported in this study. CONCLUSIONS: This study revealed that Rh-endostatin might enhance the antitumor effects of platinum-based chemotherapy for advanced TNBC patients with well-tolerated toxicities, which may provide a new basis and novel idea for the treatment of TNBC. However, further investigations and validation of its long-term efficacy and toxicity are warranted in the future.

Can Acupuncture Improve Chronic Spinal Pain? A Systematic Review and Meta-Analysis.

STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVE: To investigate the effect and safety of acupuncture for the treatment of chronic spinal pain. METHODS: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, the WHO Clinical Trial Registry, and the US National Library of Medicine clinical trial registry were searched from January 1, 2000, to November 1, 2019. Randomized controlled trials (RCTs) involving patients with chronic spinal pain treated by acupuncture versus sham acupuncture, no treatment, or another treatment were included. RESULTS: Data was extracted from 22 RCTs including 2588 patients. Pooled analysis revealed that acupuncture can reduce chronic spinal pain compared to sham acupuncture (weighted mean difference [WMD] -12.05, 95% confidence interval [CI] -15.86 to -8.24), mediation control (WMD -18.27, 95% CI -28.18 to -8.37), usual care control (WMD -9.57, 95% CI -13.48 to -9.44), and no treatment control (WMD -17.10, 95% CI -24.83 to -9.37). In terms of functional disability, acupuncture can improve physical function at immediate-term follow-up (standardized mean difference [SMD] -1.74, 95% CI -2.04 to -1.44), short-term follow-up (SMD -0.89, 95% CI -1.15 to -0.62), and long-term follow-up (SMD -1.25, 95% CI -1.48 to -1.03). CONCLUSION: In summary, compared to no treatment, sham acupuncture, or conventional therapy such as medication, massage, and physical exercise, acupuncture has a significantly superior effect on the reduction in chronic spinal pain and function improvement. Acupuncture might be an effective treatment for patients with chronic spinal pain and it is a safe therapy.

Differences in sport-related concussion for female and male athletes in comparable collegiate sports: a study from the NCAA-DoD Concussion Assessment, Research and Education (CARE) Consortium.

OBJECTIVES: To examine sex differences in sport-related concussion (SRC) across comparable sports. METHODS: Prospective cohort of collegiate athletes enrolled between 2014 and 2017 in the Concussion Assessment, Research and Education Consortium study. RESULTS: Among 1071 concussions (females=615; 57.4%), there was no difference in recovery (median days to full return to play) (females=13.5 (IQR 9.0, 23.1) vs males=11.8 (IQR 8.1, 19.0), p=0.96). In subgroup analyses, female recovery was longer in contact (females=12.7 days (IQR 8.8, 21.4) vs males=11.0 days (IQR 7.9, 16.2), p=0.0021), while male recovery was longer in limited contact sports (males=16.9 days (IQR 9.7, 101.7) vs females=13.8 days (IQR 9.1, 22.0), p<0.0001). There was no overall difference in recovery among Division I schools (females=13.7 (IQR 9.0, 23.1) vs males=12.2 (IQR 8.2 19.7), p=0.5), but females had longer recovery at the Division II/III levels (females=13.0 (IQR 9.2, 22.7) vs males=10.6 (IQR 8.1, 13.9), p=0.0048). CONCLUSION: Overall, no difference in recovery between sexes across comparable women's and men's sports in this collegiate cohort was found. However, females in contact and males in limited contact sports experienced longer recovery times, while females had longer recovery times at the Division II/III level. These disparate outcomes indicate that, while intrinsic biological sex differences in concussion recovery may exist, important, modifiable extrinsic factors may play a role in concussion outcomes.

The endocrine role of bone: Novel functions of bone-derived cytokines.

Bone-derived cytokines refer to various proteins and peptides that are released from the skeleton and can distribute in organisms to regulate homeostasis by targeting many organs, such as the pancreas, brain, testicles, and kidneys. In addition to providing support and movement, many studies have disclosed the novel endocrine function of bone, and bone can modulate glucose and energy metabolism as well as phosphate metabolism by versatile bone-derived cytokines. However, this specific exoskeletonfunction of bone-derived cytokines in the regulation of homeostasis and the pathological response caused by skeletal dysfunction are still not very clear, and elucidation of the above mechanisms is of great significance for understanding the pathological processes of metabolic disorders and in the search for novel therapeutic measures for maintaining organ stability and physical fitness.

Mesenchymal Stem Cell-Secreted Exosome Promotes Chemoresistance in Breast Cancer via Enhancing miR-21-5p-Mediated S100A6 Expression.

Emerging evidence has shown the role of mesenchymal stem cell-derived exosome (MSC-exo) in inducing resistance of cancer cells to chemotherapy. However, it remains unclear whether the change of MSC-exo in response to chemotherapy also contributes to chemoresistance. In this study, we investigated the effect of a standard-of-care chemotherapeutic agent, doxorubicin (Dox), on MSC-exo and its contribution to the development of Dox resistance in breast cancer cells (BCs). We found that the exosome secreted by Dox-treated MSCs (Dt-MSC-exo) induced a higher degree of Dox resistance in BCs when compared with non-treated MSC-exo. By analysis of the MSC-exo-induced transcriptome change in BCs, we identified S100A6, a chemoresistant gene, as a top-ranked gene induced by MSC-exo in BCs, which was further enhanced by Dt-MSC-exo. Furthermore, we found that Dox induced the expression of miR-21-5p in MSCs and MSC-exo, which was required for the expression of S100A6 in BCs. Importantly, silencing of miR-21-5p expression in MSCs and MSC-exo abolished the resistance of BCs to Dox, indicating an exosomal miR-21-5p-regulated S100A6 in chemoresistance. Our study thus uncovered a novel mechanistic insight into the role of MSC-secreted exosome in the development of chemoresistance in the tumor microenvironment.

A three-gene signature based on tumour microenvironment predicts overall survival of osteosarcoma in adolescents and young adults.

Evidences shows that immune and stroma related genes in the tumour microenvironment (TME) play a key regulator in the prognosis of Osteosarcomas (OSs). The purpose of this study was to develop a TME-related risk model for assessing the prognosis of OSs. 82 OSs cases aged ≤25 years from TARGET were divided into two groups according to the immune/stromal scores that were analyzed by the Estimate algorithm. The differentially expressed genes (DEGs) between the two groups were analyzed and 122 DEGs were revealed. Finally, three genes (COCH, MYOM2 and PDE1B) with the minimum AIC value were derived from 122 DEGs by multivariate cox analysis. The three-gene risk model (3-GRM) could distinguish patients with high risk from the training (TARGET) and validation (GSE21257) cohort. Furthermore, a nomogram model included 3-GRM score and clinical features were developed, with the AUC values in predicting 1, 3 and 5-year survival were 0.971, 0.853 and 0.818, respectively. In addition, in the high 3-GRM score group, the enrichment degrees of infiltrating immune cells were significantly lower and immune-related pathways were markedly suppressed. In summary, this model may be used as a marker to predict survival for OSs patients in adolescent and young adults.

Sinapic Acid Inhibits IL-1ß-Induced Apoptosis and Catabolism in Nucleus Pulposus Cells and Ameliorates Intervertebral Disk Degeneration.

BACKGROUND: Low back pain (LBP) is a very common condition and leads to serious pain, disability, and price tag all over the world. Intervertebral disk degeneration (IDD) is one of the major reasons that contributed to LBP. The levels of interleukin 1 beta (IL-1ß) increase significantly in degenerative disks. IL-1ß also accelerates IDD. Sinapic acid (SA) has the effect of anti-inflammatory, antioxidant and antimicrobial. However, the effect of SA on IDD has never been studied. Therefore, the aim of this study was to figure out whether SA has protective effect on nucleus pulposus (NP) cells and further explore the possible underlying mechanism. METHODS: The nucleus pulposus (NP) tissues of rats were collected and cultured into NP cells. The NP cells were stimulated by IL-1ß and treated with SA. In vitro treatment effects were evaluated by ELISA, Western blot assay, immunofluorescence, TUNEL method and real-time PCR. We conducted percutaneous needle puncture in the rat tail to build intervertebral disk degeneration model and treated rats with SA. In vivo treatment effects were evaluated by hematoxylin and eosin (HE) and safranin O (SO) staining and magnetic resonance imaging (MRI) method. RESULTS: Our results showed that SA not only inhibited apoptosis but also suppressed inflammatory mediators including nitric oxide (NO), prostaglandin E2 (PGE2), cyclooxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS) interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) in IL-1ß-stimulated NP cells. As to extracellular matrix (ECM), SA could increase collagen II and aggrecan levels and reduce the expression of MMP13 and ADAMTS5 during the stimulation of IL-1ß. Furthermore, SA could activate nuclear factor-erythroid 2-related factor-2 (Nrf2) to inhibit nuclear factor κB (NF-κB) induced by IL-1ß. Nrf2 knockdown partly reduced the protective effect of SA on NP cells. Correspondingly, SA ameliorated IDD by promoting Nrf2 expression. In vivo results also showed that SA could delay the progression of IDD. CONCLUSION: In conclusion, we demonstrated that SA could protect the degeneration of NP cells and revealed the underlying mechanism of SA on Nrf2 activation in NP cells.

Overexpression of Central ACE2 (Angiotensin-Converting Enzyme 2) Attenuates the Pressor Response to Chronic Central Infusion of Ang II (Angiotensin II): A Potential Role for Nrf2 (Nuclear Factor [Erythroid-Derived 2]-Like 2).

We investigated the mechanism by which ACE2 (angiotensin-converting enzyme 2) overexpression alters neurohumoral outflow and central oxidative stress. Nrf2 (nuclear factor [erythroid-derived 2]-like 2) is a master antioxidant transcription factor that regulates cytoprotective and antioxidant genes. We hypothesized that upregulation of central ACE2 inhibits the pressor response to Ang II (angiotensin II) by reducing reactive oxygen species through a Nrf2/antioxidant enzyme-mediated mechanism in the rostral ventrolateral medulla. Synapsin human Angiotensin Converting Enzyme 2 positive (SynhACE2+/+) mice and their littermate controls synhACE2-/- were used to evaluate the consequence of intracerebroventricular infusion of Ang II. In control mice, Ang II infusion evoked a significant increase in blood pressure and norepinephrine excretion, along with polydipsia and polyuria. The pressor effect of central Ang II was completely blocked in synhACE2+/+ mice. Polydipsia, norepinephrine excretion, and markers of oxidative stress in response to central Ang II were also reduced in synhACE2+/+ mice. The MasR (Mas receptor) agonist Ang 1-7 and blocker A779 had no effects on blood pressure. synhACE2+/+ mice showed enhanced expression of Nrf2 in the rostral ventrolateral medulla which was blunted following Ang II infusion. Ang II evoked nuclear translocation of Nrf2 in cultured Neuro 2A (N2A) cells. In synhACE2-/- mice, the central Ang II pressor response was attenuated by simultaneous intracerebroventricular infusion of the Nrf2 activator sulforaphane; blood pressure was enhanced by knockdown of Nrf2 in the rostral ventrolateral medulla in Nrf2 floxed (Nrf2f/f) mice. These data suggest that the hypertensive effects of intracerebroventricular Ang II are attenuated by selective overexpression of brain synhACE2 and may be mediated by Nrf2-upregulated antioxidant enzymes in the rostral ventrolateral medulla.

4D-Printed Dynamic Materials in Biomedical Applications: Chemistry, Challenges, and Their Future Perspectives in the Clinical Sector.

Most of the biomedical materials printed using 3D bioprinting are static and are unable to alter/transform with dynamic changes in the internal environment of the body. The emergence of four-dimensional (4D) printing addresses this problem. By preprogramming dynamic polymer materials and their nanocomposites, 4D printing is able to produce the desired shapes or transform functions under specific conditions or stimuli to better adapt to the surrounding environment. In this review, the current and potential applications of 4D-printed materials are introduced in different aspects of the biomedical field, e.g., tissue engineering, drug delivery, and sensors. In addition, the existing limitations and possible solutions are discussed. Finally, the current limitations of 4D-printed materials along with their future perspective are presented to provide a basis for future research.