Advancements in gradient bone scaffolds: enhancing bone regeneration in the treatment of various bone disorders.

Bone scaffolds are widely employed for treating various bone disorders, including defects, fractures, and accidents. Gradient bone scaffolds present a promising approach by incorporating gradients in shape, porosity, density, and other properties, mimicking the natural human body structure. This design offers several advantages over traditional scaffolds. A key advantage is the enhanced matching of human tissue properties, facilitating cell adhesion and migration. Furthermore, the gradient structure fosters a smooth transition between scaffold and surrounding tissue, minimizing the risk of inflammation or rejection. Mechanical stability is also improved, providing better support for bone regeneration. Additionally, gradient bone scaffolds can integrate drug delivery systems, enabling controlled release of drugs or growth factors to promote specific cellular activities during the healing process. This comprehensive review examines the design aspects of gradient bone scaffolds, encompassing structure and drug delivery capabilities. By optimizing the scaffold's inherent advantages through gradient design, bone regeneration outcomes can be improved. The insights presented in this article contribute to the academic understanding of gradient bone scaffolds and their applications in bone tissue engineering.

Spatial distribution of volatile organic compounds in contaminated soil and distinct microbial effect driven by aerobic and anaerobic conditions.

The vertical distribution of 35 volatile organic compounds (VOCs) was investigated in soil columns from two obsolete industrial sites in Eastern China. The total concentrations of ΣVOCs in surface soils (0-20 cm) were 134-1664 ng g-1. Contamination of VOCs in surface soil exhibited remarkable variability, closely related to previous production activities at the sampling sites. Additionally, the concentrations of ΣVOCs varied with increasing soil depth from 0 to 10 m. Soils at depth of 2 m showed ΣVOCs concentrations of 127-47,389 ng g-1. Among the studied VOCs, xylene was the predominant contaminant in subsoils (2 m), with concentrations ranging from n.d. to 45,400 ng g-1. Chlorinated alkanes and olefins demonstrated a greater downward migration ability compared to monoaromatic hydrocarbons, likely due to their lower hydrophobicity. As a result, this vertical distribution of VOCs led to a high ecological risk in both the surface and deep soil. Notably, the risk quotient (RQ) of xylene in subsoil (2 m, RQ up to 319) was much higher than that in surface soil. Furthermore, distinct effects of VOCs on soil microbes were observed under aerobic and anaerobic conditions. Specifically, after the 30-d incubation of xylene-contaminated soil, Ilumatobacter was enriched under aerobic condition, whereas Anaerolineaceae was enriched under anaerobic condition. Moreover, xylene contamination significantly affected methylotrophy and methanol oxidation functions for aerobic soil (t-test, p < 0.05). However, aromatic compound degradation and ammonification were significantly enhanced by xylene in anaerobic soil (t-test, p < 0.05). These findings suggest that specific VOC compound has distinct microbial ecological effects under different oxygen content conditions in soil. Therefore, when conducting soil risk assessments of VOCs, it is crucial to consider their ecological effects at different soil depths.

An octopamine-specific GRAB sensor reveals a monoamine relay circuitry that boosts aversive learning.

Octopamine (OA), analogous to norepinephrine in vertebrates, is an essential monoamine neurotransmitter in invertebrates that plays a significant role in various biological functions, including olfactory associative learning. However, the spatial and temporal dynamics of OA in vivo remain poorly understood due to limitations associated with the currently available methods used to detect it. To overcome these limitations, we developed a genetically encoded GPCR activation-based (GRAB) OA sensor called GRABOA1.0. This sensor is highly selective for OA and exhibits a robust and rapid increase in fluorescence in response to extracellular OA. Using GRABOA1.0, we monitored OA release in the Drosophila mushroom body (MB), the fly's learning center, and found that OA is released in response to both odor and shock stimuli in an aversive learning model. This OA release requires acetylcholine (ACh) released from Kenyon cells, signaling via nicotinic ACh receptors. Finally, we discovered that OA amplifies aversive learning behavior by augmenting dopamine-mediated punishment signals via Octß1R in dopaminergic neurons, leading to alterations in synaptic plasticity within the MB. Thus, our new GRABOA1.0 sensor can be used to monitor OA release in real-time under physiological conditions, providing valuable insights into the cellular and circuit mechanisms that underlie OA signaling.

Shared and distinct prefrontal cortex alterations of implicit emotion regulation in depression and anxiety: An fNIRS investigation.

BACKGROUND: Emotion regulation deficits, particularly in cognitive reappraisal, are crucial in depression and anxiety. However, research on the neural mechanisms of implicit emotion regulation is lacking, and it remains unclear whether these mechanisms are shared or distinct between the two disorders. METHODS: We investigated the neural mechanisms of implicit cognitive reappraisal in 28 individuals with major depressive disorder (MDD), 25 with generalized anxiety disorder (GAD), and 30 healthy controls (HC) using functional near-infrared spectroscopy (fNIRS). Participants completed an implicit cognitive reappraisal task and underwent neuropsychological and clinical assessments. RESULTS: We found that MDD patients reported higher levels of rumination and lower utilization of cognitive reappraisal, while GAD patients reported reduced use of perspective-taking. Notably, both MDD and GAD patients exhibited decreased activation in the dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC) compared to HC participants during implicit cognitive reappraisal. Specifically, inadequate OFC activation was observed in MDD patients, while GAD patients demonstrated OFC deactivation during the task. Furthermore, DLPFC activation showed a negative correlation with depression severity in MDD patients, while OFC activation was positively correlated with perspective-taking in GAD patients. LIMITATIONS: fNIRS has limited depth and spatial resolution. CONCLUSION: Our fNIRS study is the first to reveal shared and distinct neurobiological profiles of depression and anxiety in implicit emotion regulation. These findings underscore the significance of reduced DLPFC/OFC activation in emotion regulation impairment and highlight unique OFC activation patterns in these disorders. These insights have potential implications for developing cognitive-behavioral therapy and transcranial magnetic stimulation as treatment approaches.

Improved green and red GRAB sensors for monitoring spatiotemporal serotonin release in vivo.

The serotonergic system plays important roles in both physiological and pathological processes, and is a therapeutic target for many psychiatric disorders. Although several genetically encoded GFP-based serotonin (5-HT) sensors were recently developed, their sensitivities and spectral profiles are relatively limited. To overcome these limitations, we optimized green fluorescent G-protein-coupled receptor (GPCR)-activation-based 5-HT (GRAB5-HT) sensors and developed a red fluorescent GRAB5-HT sensor. These sensors exhibit excellent cell surface trafficking and high specificity, sensitivity and spatiotemporal resolution, making them suitable for monitoring 5-HT dynamics in vivo. Besides recording subcortical 5-HT release in freely moving mice, we observed both uniform and gradient 5-HT release in the mouse dorsal cortex with mesoscopic imaging. Finally, we performed dual-color imaging and observed seizure-induced waves of 5-HT release throughout the cortex following calcium and endocannabinoid waves. In summary, these 5-HT sensors can offer valuable insights regarding the serotonergic system in both health and disease.

Integrating chemical similarity and bioequivalence: an overall evaluation of the quality consistency of traditional decoction and dispensing granule decoction of Amomum villosum.

OBJECTIVE: This study aims to investigate the quality consistency between traditional decoction (TD) of Amomum villosum and its dispensing granule decoction (DGD). Fifteen batches of TD and nine batches of dispensing granules (manufactured by A, B, and C) were prepared and evaluated for their consistency. METHODS: Firstly, The chemical similarity of TD and DGD was examined using GC and HPLC, coupled with hierarchical cluster analysis (HCA), criteria importance though intercrieria correlation(CRITIC) weighting method, and principal component analysis (PCA). Secondly, the gastrointestinal motility experiments in mice, along with the CRITIC weighting method, were employed to assess the bioequivalence of TD and DGD of Amomum villosum. Finally, the entropy weight technique-gray relative analysis(GRA) method was used to compare the quality of Amomum villosum decoctions. RESULTS: ①The CRITIC weighting method indicated significantly higher scores for TD than DGD (p < 0.01). HCA and PCA results demonstrated a clear distinction between TD and DGD. ②Gastrointestinal motility test results revealed no significant difference between TD and DGD in other indicators (p > 0.05).③Gray relative analysis results showed that the relative correlation of TD was more significant than that of DGD. CONCLUSION: The chemical composition of DGD and TD differed. The biological activity of DGD-A/B was consistent with that of TD, while the difference between DGD-C and TD was significant. A comprehensive evaluation showed that TD exhibited better quality than DGD. DGD manufacturers should optimize the preparation process to enhance product quality.

Assessing the short-term effects of PM2.5 and O3 on cardiovascular mortality using high-resolution exposure: a time-stratified case cross-over study in Southwestern China.

Air pollution is a major risk factor of cardiovascular disease (CVD). To date, limited studies have estimated the effects of ambient air pollution on CVD mortality using high-resolution exposure assessment, which might fail to capture the spatial variation in exposure and introduce bias in results. Besides, the three-year action plan (TYAP, 2018-2020) was released; thus, the constitution and health effect of air pollutants may have changed. In this study, we estimated the short-term effect exposed to particulate matters with parameter less than 2.5 µm (PM2.5) and ozone (O3) with 0.05° × 0.05° resolution on CVD mortality and measured the influence of TYAP in the associations. We used random forest models with spatial weight matrices to attain high-resolution pollutant concentrations and conditional Poisson regression to assess the relationship between air pollution and cardiovascular mortality. With an increase of 10 µg/m3 in PM2.5 and O3 during 2018-2021 in the Sichuan Basin (SCB), CVD mortality increased 1.0134 (95% CI 1.0102, 1.0166) and 1.0083 (95% CI 1.0060, 1.0107), respectively, using high-resolution air pollutant concentration, comparing to 1.0070 (95% CI 1.0052, 1.0087) and 1.0057 (95% CI 1.0037, 1.0078) using data from air quality monitoring stations (AQMs). After TYAP, the relative risk (RR) due to PM2.5 rose up to 1.0149 (95% CI 1.0054, 1.0243), and the RR due to O3 rose up to 1.0089 (95% CI 1.0030, 1.0148) in Sichuan Province. We found significantly positive association of cardiovascular mortality and air pollution in Sichuan Province. And using high-resolution exposure would be more accurate to estimate the effect of air pollution on CVD. After TYAP, the cardiovascular mortality risk estimation due to PM2.5 decreased in elderly in SCB, and the risk due to O3 increased in Sichuan Province.

A novel holin from an Enterococcus faecalis phage and application in vitro and in vivo.

Enterococcus faecalis, a conditional pathogenic bacterium, is prevalent in the intestinal, oral, and reproductive tracts of humans and animals, causing a variety of infectious diseases. E. faecalis is the main species detected in secondary persistent infection from root canal therapy failure. Due to the abuse of antibacterial agents, E. faecalis has evolved its resistant ability. Therefore, it is difficult to treat clinical diseases infected by E. faecalis. Exploring new alternative drugs for treating E. faecalis infection is urgent. We cloned and expressed the gene of phage holin, purified the recombinant protein, and analyzed the antibacterial activity, lysis profile, and ability to remove bacterial biofilm. It showed that the crude enzyme of phage holin pEF191 exhibited superior bacterial inhibiting activity and a broader lysis host range compared to the parent phage PEf771. In addition, pEF191 demonstrated high efficacy in eliminating E. faecalis biofilm. The therapeutic results of the Sprague-Dawley (SD) rats model infected showed that pEf191 did not affect SD rats, indicating that pEF191 provided greater protection against E. faecalis infection in SD rats. Based on the 16 S rDNA data of SD rats intestinal microorganism population, holin pEF191 exhibited no impact on the diversity of intestinal microorganisms at the phylum and genus levels and improved the relative abundance of favorable bacteria. Thus, pEF191 may serve as a promising alternative to antibiotics in the management of E. faecalis infection.

Research on rapid quality identification method of Panax notoginseng powder based on artificial intelligence sensory technology and multi-source information fusion technology.

Panax notoginseng powder (PNP) has high medicinal value and is widely used in the medical and health food industries. However, the adulteration of PNP in the market has dramatically reduced its efficacy. Therefore, this study intends to use artificial intelligence sensory (AIS) and multi-source information fusion (MIF) technology to try to establish a quality evaluation system for different grades of PNP and adulterated Panax notoginseng powder (AD-PNP). The highest accuracy rate reached 100% in identifying PNP grade and adulteration. In the prediction of adulteration ratio and total saponin content, the optimal determination coefficients of the test set were 0.9965 and 0.9948, respectively, and the root mean square errors were 0.0109 and 0.0123, respectively. Therefore, the grade identification method of PNP and the evaluation system of AD-PNP based on AIS and MIF technology can rapidly and accurately evaluate the quality of PNP.

Spatial distribution and risk assessment of polycyclic aromatic hydrocarbons in soils from contaminated sites in Eastern China.

A total of 16 polycyclic aromatic hydrocarbons (PAHs) were measured in 28 soil column samples from two contaminated industrial sites in Eastern China. The total concentration of 16 PAHs (∑PAHs) in the surface soil (0-20 cm) was measured up to 52,600 ng/g (dry weight basis) with a remarkable spatial difference in the studied contaminated sites. The concentrations of the ∑PAHs in soils decreased with the increase in soil depth (0-10 m). The surface and subsurface soil presented a tenfold higher concentration than the soil with depth greater than 4 m. Additionally, the vertical migration tendency of the PAHs was found to be correlated significantly with their hydrophobicity (R2 = 0.79, P < 0.01). Naphthalene (with lowest octanol-water partition coefficient among the studied PAHs) showed the greatest average soil depth at which its peak concentration occurred. Furthermore, risk quotient analysis by using benzo[a]pyrene as reference compound showed that 71.4% of the samples exhibited high ecological risk for soil. Moreover, the total carcinogenic risk of the PAHs in the surface soil samples was assessed at 5.61 × 10-5-1.28 × 10-4 and 4.41 × 10-6-9.43 × 10-5 for male and female workers, respectively, in which 67.9%-71.4% of the samples showed potential risk. Generally, these results suggest a further consideration of ecological and health risks associated with PAHs in contaminated sites in Eastern China.

Using a novel strategy to investigate the spatially autocorrelated and clustered associations between short-term exposure to PM2.5 and mortality and the attributable burden: A case study in the Sichuan Basin, China.

Due to the lack of statistical methods, few studies have investigated the spatial autocorrelated distribution in the association between short-term exposure to PM2.5 and mortality and used a statistical manner to explore the association-clustered regions, which play important roles in identifying high-sensitivity/susceptibility regions. The Sichuan Basin (SCB) is one of the most PM2.5-polluted areas, and the extreme economic imbalance may cause considerable spatial heterogeneity and clustering in PM2.5-mortality association. In this work, we used a recently proposed strategy by us to investigate the spatially autocorrelated and clustered association between daily PM2.5 and cardiorespiratory mortality from 2015 to 2019 in 130 counties of the SCB. First, generalized additive models were independently constructed to obtain the county-level association estimations. Then, an estimation-error-based spatial scan statistic was used to detect the association-clustered regions. Third, multivariate conditional meta autoregression was used to obtain the spatially autocorrelated association distribution, based on which the attributable deaths were mapped and their inequality was evaluated using the Gini coefficient and Lorenz curve. Results showed that two significantly association-clustered regions were detected. One is mainly located in the megacity Chengdu where PM2.5 presented a significantly stronger association with no threshold effect at low-level PM2.5 but a threshold at high-level PM2.5. In the other cluster, a threshold effect at low-level PM2.5 but no threshold at high-level PM2.5 were found. The mortality risk at low/middle-level PM2.5 decreased from Chengdu as the center to the surrounding areas. A total of 29,129 (2.0 %) deaths were attributable to the excess PM2.5 exposure. The attributable deaths also decreased from Chengdu as the center to the surrounding areas with Gini coefficients of 0.43 and 0.3 for absolute and relative attributable deaths, respectively. This novel strategy provided a new epidemiological perspective regarding the association and implicated that Chengdu is significantly deserving of more attention regarding PM2.5-related health loss.

Exploring the Therapeutic Effects of Multifunctional N-Salicylic Acid Tryptamine Derivative against Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. Neuroinflammation and oxidative stress play an important role in the whole course of PD, which have been the focus of PD drug development. In our previous research, a series of N-salicylic acid tryptamine derivatives were synthesized, and the biological evaluation showed that the compound LZWL02003 has good anti-neuroinflammatory activity and displayed great therapeutic potency for neurodegenerative disease models. In this work, the neuroprotective efficiency of LZWL02003 against PD in vitro and in vivo has been explored. It was found that LZWL02003 could protect human neuron cells SH-SY5Y from MPP+-induced neuronal damage by inhibiting ROS generation, mitochondrial dysfunction, and cellular apoptosis. Moreover, LZWL02003 could improve cognition, memory, learning, and athletic ability in a rotenone-induced PD rat model. In general, our study has demonstrated that LZWL02003 has good activity against PD in in vitro and in vivo experiments, which can potentially be developed into a therapeutic candidate for PD.

Baricitinib improves pulmonary fibrosis in mice with rheumatoid arthritis-associated interstitial lung disease by inhibiting the Jak2/Stat3 signaling pathway.

OBJECTIVE: The study explored improvements in pulmonary inflammation and fibrosis in a bovine type II collagen-induced rheumatoid arthritis-associated interstitial lung disease mouse model after treatment with baricitinib and the possible mechanism of action. METHODS: A rheumatoid arthritis-associated interstitial lung disease mouse model was established, siRNA Jak2 and lentiviral vectors were transfected with human embryonic lung fibroblast cells. And the levels of relevant proteins in mouse lung tissue and human embryonic lung fibroblasts were detected by Western blotting. RESULTS: The levels of JAK2, p-JAK2, p-STAT3, p-SMAD3, SMA, TGFßR2, FN and COL4 were increased in the lung tissues of model mice (P < 0.5) and decreased after baricitinib intervention (P < 0.05). The expression levels of p-STAT3, p-SMAD3, SMA, TGFßR2, FN and COL4 were reduced after siRNA downregulation of the JAK2 gene (P < 0.01) and increased after lentiviral overexpression of the JAK2 gene (P < 0.01). CONCLUSION: Baricitinib alleviated fibrosis in the lung tissue of rheumatoid arthritis-associated interstitial lung disease mice, and the mechanism of action may involve the downregulation of Smad3 expression via inhibition of the Jak2/Stat3 signaling pathway, with consequent inhibition of the profibrotic effect of transforming growth factor-ß1.

Development of a variety and quality evaluation method for Amomi fructus using GC, electronic tongue, and electronic nose.

Amomi fructus is rich in volatile components and valuable as a medicine and edible spice. However, the quality of commercially available A. fructus varies, and issues with mixed sources and adulteration by similar products are common. In addition, due to incomplete identification methods, rapid detection of the purchased A. fructus quality is still an issue. In this study, we developed qualitative and quantitative evaluation models to assess the variety and quality of A. fructus using GC, electronic tongue, and electronic nose to provide a rapid and accurate variety and quality evaluation method of A. fructus. The models performed well; the qualitative authenticity model had an accuracy of 1.00 (n = 64), the accuracy of the qualitative origin model was 0.86 (n = 44), and the quantitative model was optimal on the sensory fusion data from the electronic tongue and electronic nose combined with borneol acetate content, with R 2 = 0.7944, RMSEF = 0.1050, and RMSEP = 0.1349. The electronic tongue and electronic nose combined with GC quickly and accurately evaluated the variety and quality of A. fructus, and the introduction of multi-source information fusion technology improved the model prediction accuracy. This study provides a useful tool for quality evaluation of medicine and food.

Prevalence of Diabetic Kidney Disease with Different Subtypes in Hospitalized Patients with Diabetes and Correlation Between eGFR and LncRNA XIST Expression in PBMCs.

INTRODUCTION: Diabetic kidney disease (DKD) has become the leading cause of end-stage kidney disease (ESKD) in most countries. Recently, long noncoding RNA XIST has been found involved in the development of DKD. METHODS: A total of 1184 hospitalized patients with diabetes were included and divided into four groups based on their estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR): normal control group (nDKD), DKD with normoalbuminuric and reduced eGFR (NA-DKD), DKD with albuminuria but without reduced eGFR (A-DKD), and DKD with albuminuria and reduced eGFR (Mixed), and then their clinical characteristics were analyzed. Peripheral blood mononuclear cells (PBMCs) of patients with DKD were isolated, and lncRNA XIST expression was detected by real-time quantitative PCR. RESULTS: The prevalence of DKD in hospitalized patients with diabetes mellutus (DM) was 39.9%, and the prevalence of albuminuria and decreased eGFR was 36.6% and 16.2%, respectively. NA-DKD, A-DKD, and Mixed groups accounted for 23.7%, 3.3%, and 12.9%, respectively. Women with DKD had considerably lower levels of lncRNA XIST expression in their PBMCs compared to nDKD. There was a significant correlation between eGFR level and lncRNA XIST expression (R = 0.390, P = 0.036) as well as a negative correlation between HbA1c and lncRNA XIST expression (R = - 0.425, P = 0.027) in female patients with DKD. CONCLUSIONS: Our study revealed that 39.9% of DM inpatients who were admitted to the hospital had DKD. Importantly, lncRNA XIST expression in PBMCs of female patients with DKD was significantly correlated with eGFR and HbA1c.

Development of o-aminobenzamide salt derivatives for improving water solubility and anti-undifferentiated gastric cancer.

Background: Gastric cancer is one of the cancers with wide incidence, difficult treatment and high mortality in the world, especially in Asia and Africa. In our previous work, a novel o-aminobenzamide analogue F8 was identified as an early preclinical candidate for treatment of undifferentiated gastric cancer (IC50 of 0.26 µM for HGC-27). However, the poor water solubility of compound F8 prevents its further progress in preclinical studies. Aim: To improve the water solubility and drug-likeness of F8 via salt formation. Method: Different acids and F8 were reacted to obtain different salt forms. Physicochemical property screening, pharmacokinetic property research, and antitumor biological activity evaluation in vitro and in vivo were used to obtain the optimal salt form with the best druggability. Results: our continuous efforts have finally confirmed F8·2HCl as the optimal salt form with maintained in vitro antitumor activity, improved water solubility and pharmacokinetic properties. Importantly, the F8·2HCl displayed superior in vivo antitumor efficacy (TGI of 70.1% in 75 mg/kg) in HGC-27 xenograft model. The further immunohistochemical analysis revealed that F8·2HCl exerts an antitumor effect through the regulation of cell cycle-related protein (CDK2 and p21), apoptosis-related protein Cleaved Caspase-3, proliferation marker Ki67, and cell adhesion molecule E-cadherin. In addition, F8·2HCl showed acceptable safety in the in vivo acute toxicity assay. Conclusion: Salting is an effective means to improve the drug-like properties of compound F8, and F8·2HCl can serve as a promising therapeutic agent against undifferentiated gastric cancer.

Combined health effects of PM2.5 components on respiratory mortality in short-term exposure using BKMR: A case study in Sichuan, China.

One of the major causes of global mortality is respiratory diseases. Fine particulate matter (PM2.5) increased the risk of respiratory death in short-term exposure. PM2.5 is the chemical mixture of components with different health effects. The combined health effects of PM2.5 are determined by the role of each component and the potential interaction between components, but they have not been studied in short-term exposure. Sichuan Province (SC), with high respiratory mortality and heavy PM2.5 pollution, had distinctive regional differences in four regions in sources and proportions of PM2.5, so it was divided into four regions to explore the combined health effects of PM2.5 components on respiratory mortality in short-term exposure and to identify the main hazardous components. Due to the multicollinear, interactive, and nonlinear characteristics of the associations between PM2.5 components and respiratory mortality, Bayesian kernel machine regression (BKMR) was used to characterize the combined health effects, along with quantile-based g-computation (QGC) as a reference. Positive combined effects of PM2.5 were found in all four regions of Sichuan using BKMR with excess risks (ER) of 0.0101-0.0132 (95 % CI: 0.0093-0.0158) and in the central basin and northwest basin using QGC with relative risks (RR) of 1.0064 (95 % CI: 1.0039, 1.0089) and 1.0044 (95 % CI: 1.0022, 1.0066), respectively. In addition, the adverse health effect was larger in cold seasons than that in warm seasons, so vulnerable people should reduce outdoor activities in heavily polluted days, especially in the cold season. For the components of PM2.5, the BC and OM mainly from traffic, dominated the adverse health effects on respiratory mortality. Furthermore, NO3- might aggravate the adverse health effects of BC/OM. Therefore, BC/OM and NO3- should be focused together in air pollution control.