Effect of resveratrol on SH-SY5Y cells studied by atomic force microscopy.

In this paper, the effects of resveratrol on the viability, morphology, biomechanics and bioelectricity of SH-SY5Y cells were studied by atomic force microscopy. MTT assay showed that resveratrol had a dose effect on SH-SY5Y cells, and its activity was related to drug concentration and drug action time. With the increase of resveratrol concentration or the extension of action time, the activity of SH-SY5Y cells decreased obviously. Atomic force microscope (AFM) was employed to quantitatively analyze the physical changes of cells. AFM study shows that resveratrol can transform SH-SY5Y cells from spindle to sphere, and increase the cell height and decrease the cell adhesion. Also, the elastic modulus increases under the action of low concentration of resveratrol decreases under the action of high concentration of resveratrol, and the electric signal decreases. This study reveals the impact of resveratrol on SH-SY5Y cells from the biological and biophysical perspectives, which is helpful for a more comprehensive understanding of the interaction mechanism between resveratrol and SH-SY5Y cells. These techniques have potential applications in evaluating the effects of chemical substances on cells and screening targeted drugs.

Comparison of Clinical Outcomes and Complications Between Endoscopic and Minimally Invasive Transforaminal Lumbar Interbody Fusion for Lumbar Degenerative Diseases: A Systematic Review and Meta-analysis.

STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVE: Minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) is a classic surgical procedure for the treatment of lumbar degenerative diseases (LDD). With the development of endoscopic technology, endoscopic transforaminal lumbar interbody fusion (Endo-TLIF) can also achieve adequate decompression and interbody fusion. However, whether Endo-TLIF is superior to MIS-TLIF has not been adequately studied. In this systematic review and meta-analysis, we aimed to evaluate the treatment difference between Endo-TLIF vs MIS-TLIF. METHODS: We conducted a systematic review and meta-analysis of the studies to compare the clinical outcomes and complications associated with Endo-TLIF vs. MIS-TLIF for the treatment of LDD. A literature search was conducted using the PubMed, Embase, Cochrane Library and Scopus databases for studies published up to April 1, 2022. Both retrospective and prospective studies that compared between Endo-TLIF and MIS-TLIF were included. RESULTS: A total of 8 studies involving 581 patients were finally included in this meta-analysis. Endo-TLIF significantly prolonged the operation time, but reduced the blood loss amount and length of hospital stay. Moreover, Endo-TLIF was superior to MIS-TLIF on relief of back pain and functional recovery in the early postoperative period. However, there were no significantly differences in long-term clinical outcomes, fusion rate and incidence of complications between Endo-TLIF and MIS-TLIF. CONCLUSIONS: Endo-TLIF was similar to MIS-TLIF in the long-term clinical outcomes, fusion and complication rates. Endo-TLIF prolongs the operation time, but shortens the length of hospital stay, and has the advantages of less surgical trauma, less blood loss, faster recovery, and early postoperative back pain relief.

Zhuanggu Zhitong Capsule alleviates postmenopausal osteoporosis in ovariectomized rats by regulating autophagy through AMPK/mTOR signaling pathway.

Background: Postmenopausal osteoporosis (PMOP) is the most common primary osteoporosis, which is prone to fractures and affect the health and quality of life of the elderly and even shorten their lifetime. Traditional Chinese medicine can not only effectively improve osteoporosis and reduce fracture rate, but also have tonifying and analgesic effects. The purpose of this study was to investigate the effects of Zhuanggu Zhitong (ZGZT) Capsule on autophagy related genes and proteins in PMOP rats, so as to elucidate the molecular mechanism of tonifying deficiency and regulating stasis in the treatment of osteoporosis and analgesia. Methods: The PMOP rat model was established by bilateral oophorectomy, and then the rats were randomly divided into control group, PMOP group, PMOP + ZGZT group and PMOP + E2 group. The changes of mechanical pain threshold of rats were detected by von Frey filaments, and the changes of mechanical pain threshold of rats in each group were compared. Computed tomography (CT) and dual-energy X-ray were used to measure the bone mineral density of lumbar bone tissue. Enzyme-linked immunosorbent assay (ELISA) and tartrate-resistant acid phosphatase (TRAP) staining were used to detect inflammatory factors and bone metabolism related indicators. Hematoxylin-eosin (HE) staining was used to observe the tissue morphology of lumbar vertebra tissue. Western blot (WB) and quantitative polymerase chain reaction (qPCR) were used to detect AMPK/mTOR pathway- and autophagy-related factor expression. Results: ZGZT can effectively restore the bone mineral density (BMD) of PMOP rats, improve the microstructure of lumbar vertebra of PMOP rats, restore the balance of bone metabolism, promote the expression of AMPK and autophagy related factors, inhibit the expression of mTOR and the release of inflammatory factors, and increase the mechanical pain threshold of PMOP rats, so as to effectively improve osteoporosis and relieving osteoporosis pain in PMOP rats. Conclusions: ZGZT affects autophagy by regulating AMPK/mTOR pathway, restores the homeostasis of bone metabolism and inhibits the release of inflammatory factors. Moreover, the regulation of feedback pathways between bone metabolism and inflammatory factors finally plays the role of "bone strengthening" and "pain relieving". ZGZT may be a new treatment for PMOP and relieving osteoporotic pain.

Potential Mechanisms of Biejiajian Pill in the Treatment of Diabetic Atherosclerosis Based on Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulation.

Background: Biejiajian pill (BJJP), a classical traditional Chinese formula, has been reported that it has an effective treatment for diabetic atherosclerosis in recent years, but its underlying mechanisms remain elusive. The study aimed to explore the potential mechanisms of BJJP on diabetic atherosclerosis by integrating network pharmacology, molecular docking, and molecular dynamics simulation. Methods: The active components of BJJP were collected by TCMSP and TCMID, and then the potential targets were obtained from the SwissTargetPrediction database. The targets related to diabetic atherosclerosis were identified from the GeneCards and OMIM databases. The intersection of the potential targets regulated by active components of BJJP and the targets of diabetic atherosclerosis were common targets, which were visualized by the Venn diagram. The common targets were imported into the STRING database to construct a protein-protein interaction (PPI) network. The network of "Medicine-Compound-Target" was constructed with Cytoscape 3.7.1 software. GO functional enrichment analysis and KEGG pathway enrichment analysis were performed using the DAVID database and visualized through bioinformatics. The intersecting targets were input into Cytoscape 3.7.1 software, and the Network Analyzer tool was employed to screen out the key targets. Then molecular docking was used to verify the binding affinity between the active compounds and the key targets, and molecular dynamics simulation was used to investigate the stability of the binding models. Results: A total of 81 active components, 186 targets of BJJP, and 4041 targets of diabetic atherosclerosis were obtained. Furthermore, 121 overlapping targets were identified. GO functional enrichment analysis revealed that these targets were correlated with the oxidation-reduction process, negative regulation of apoptotic process, inflammatory response, and other biological processes. The results of the KEGG pathway enrichment analysis showed that the common targets mainly participated in proteoglycans in cancer, PPAR signaling pathway, adherens junction, insulin resistance, HIF-1 signaling pathway, PI3K-Akt signaling pathway, etc. The results of molecular docking confirmed that the core active components in BJJP could bind well to the key targets. Results from molecular dynamics simulation showed that the binding energies of AKT1-Luteolin, MMP9-quercetin, and MMP9-luteolin complexes were -28.93 kJ·mol-1, -37.12 kJ·mol-1, and -62.91 kJ·mol-1, respectively. Conclusion: The study revealed that BJJP is characterized as multicomponent, multitarget, and multipathway to treat diabetic atherosclerosis, which is helpful to provide ideas and a basis for pharmacological research and clinical application in the future.

Biejiajian Pill Ameliorates Diabetes-Associated Atherosclerosis through Inhibition of the NLRP3 Inflammasome.

Objective: To research the efficacy of Biejiajian pill (BJJ) on diabetes-associated atherosclerosis and explore its subsequent mechanisms. Methods: Diabetes-associated atherosclerosis (AS) was established in apolipoprotein E knockout (ApoE -/- ) mice using high-fat diet and streptozotocin. Atorvastatin (ATV, 10 mg/kg/day) or BJJ-L (BJJ low-dose, 0.9 g/kg/day), BJJ-M (BJJ medium-dose, 1.8 g/kg/day), and BJJ-H (BJJ high-dose, 3.6 g/kg/day) were administered to diabetic ApoE -/- mice for 12 continuous weeks. The normal control group consisted of 10 male C57BL/6J mice. Atherosclerosis plaques, vascular endothelial function, fasting blood glucose, lipid metabolism, inflammatory factors, NLRP3 inflammasome expression, and mitochondria and autophagy changes were evaluated. Results: The atherosclerotic lesions areas in the aortas were analyzed through Oil Red O and H&E staining, and they were reduced in the BJJ-H and BJJ-M groups. In the BJJ group, endothelin-1 (ET-1) levels were decreased, whereas endothelial nitric oxide synthase (eNOS) was increased. Fasting blood glucose levels in the BJJ and ATV groups were gradually decreased. Lipid metabolism parameters such as TG, TC, and LDL-C were reduced, while HDL-C was elevated in BJJ groups. The serum IL-1ß and IL-18 were decreased under BJJ therapy. The aortic mRNA and protein expressions of NF-κB, TXNIP, NLRP3, ASC, caspase-1, and IL-1ß were inhibited in BJJ-H and BJJ-M groups, especially in the BJJ-H group. Electron microscopy revealed an increase in autophagy in each treatment group. Conclusions: The findings reveal that BJJ could alleviate diabetic atherosclerosis in diabetic ApoE -/- mice by inhibiting NLRP3 inflammasome.

Potential Mechanisms and Effects of Chinese Medicines in Treatment of Diabetic Atherosclerosis by Modulating NLRP3 Inflammasome: A Narrative Review.

Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) is an intracellular sensor that detects endogenous danger signals and environmental irritants to assemble into the NLRP3 inflammasome. Activation of the NLRP3 inflammasome leads to the secretion of the proinflammatory cytokines interleutkin (IL)-1ß and IL-18 and induces pyroptosis. Recent studies have shown that the NLRP3 inflammasome participates in the initiation and progression of diabetic atherosclerosis through pathological mechanisms such as ß-cell dysfunction, insulin resistance, endothelial cell dysfunction, monocyte adhesion and infiltration, and smooth muscle cell proliferation and migration. In diabetic atherosclerosis, Chinese medicine has been proven effective for the inflammatory response mediated by the NLRP3 inflammasome. This review summarizes the latest progress on the NLRP3 inflammasome in the pathogenesis and potential Chinese medicine treatment of diabetic atherosclerosis.

Modeling the Steady-State Effects of Mean Arterial Pressure on the Kidneys.

Goal: We describe the relationship between mean arterial pressure (MAP) and glomerular filtration rate (GFR) since therapies affecting MAP can have large effects on kidney function. Methods: We developed a closed-loop, steady-state mechanistic model of the human kidney with a reduced parameter set estimated from measurements. Results: The model was first validated against literature models. Further, GFR was validated against intensive care patient data (root mean squared error (RMSE) 13.5 mL/min) and against hypertensive patients receiving sodium nitroprusside (SNP) (RMSE less than 5 mL/min). A sensitivity analysis of the model reinforced the fact that vascular resistance is inversely related to GFR and showed that changes to either vascular resistance or renal autoregulation cause a significant change in sodium concentration in the descending limb of Henle. Conclusions: This model can be used to determine the impact of MAP on GFR and overall kidney health. The modeling framework lends itself to personalization of the model to a specific human.

Alveolar Tissue Fiber and Surfactant Effects on Lung Mechanics-Model Development and Validation on ARDS and IPF Patients.

Goal: Alveolar compliance is a main determinant of lung airflow. The compliance of the alveoli is a function of their tissue fiber elasticity, fiber volume, and surface tension. The compliance varies during respiration because of the nonlinear nature of fiber elasticity and the time-varying surface tension coating the alveoli. Respiratory conditions, like acute respiratory distress syndrome (ARDS) and idiopathic pulmonary fibrosis (IPF) affect fiber elasticity, fiber volume and surface tension. In this paper, we study the alveolar tissue fibers and surface tension effects on lung mechanics. Methods: To better understand the lungs, we developed a physiology-based mathematical model to 1) describe the effect of tissue fiber elasticity, fiber volume and surface tension on alveolar compliance, and 2) the effect of time-varying alveolar compliance on lung mechanics for healthy, ARDS and IPF conditions. Results: We first present the model sensitivity analysis to show the effects of model parameters on the lung mechanics variables. Then, we perform model simulation and validate on healthy non-ventilated subjects and ventilated ARDS or IPF patients. Finally, we assess the robustness and stability of this dynamic system. Conclusions: We developed a mathematical model of the lung mechanics comprising alveolar tissue and surfactant properties that generates reasonable lung pressures and volumes compared to healthy, ARDS, and IPF patient data.

Modeling of Transport Mechanisms in the Respiratory System: Validation via Congestive Heart Failure Patients.

The heart and lungs are intricately related. For congestive heart failure patients, fluid (plasma) backs up into the pulmonary system. As a result, pulmonary capillary pressure increases, causing fluid to seep into the lungs (pulmonary edema) within minutes. This excess fluid induces extra stress during breathing that affects respiratory health. In this paper, we focus on the effect that high pulmonary capillary pressure has on the development of this extravascular lung water (EVLW). A mathematical model of pulmonary fluid and mass transport mechanisms is developed in order to quantitatively analyze the transport phenomena in the pulmonary system. The model is then validated on 15 male heart failure patients from published literature [1]. The model shows reasonable estimation of EVLW in heart failure patients, which is useful in assessing the severity of pulmonary edema.

Multi-resolution classification of exhaled aerosol images to detect obstructive lung diseases in small airways.

Exhaled aerosol patterns have been used to detect obstructive respiratory diseases in the upper airways. Signals from small airway diseases are weak and may not manifest themselves in the exhaled aerosol patterns. Therefore, it will be more challenging to detect abnormalities in small airways. The objective of this study is to develop a simulation-based classification model that can accurately classify small airway diseases. The model performance was evaluated in five obstructed models that are located in lung bifurcations G7-9. The exhaled aerosol images were quantified using local fractal dimensions at different sampling resolutions (n × n). The datasets were classified using both the random forest (RF) and support vector machine (SVM) algorithms. Results show that RF performs slightly and persistently better than SVM. The sampling resolution of 12 × 12 gave the optimal classification for both algorithms. Based on the lung models with predefined obstructive levels, the optimal classification accuracy is 87.0% for 5-class classification, and is 92.5% for 4-class classification by regrouping the mislabeled samples. The proposed model with multi-resolution fractal feature extraction and RF algorithm appears to be sensitive enough to accurately distinguish airway abnormalities in small airways beyond G7 with healthy bronchiole diameter <4 mm. This aerosol-based breath test is promising to develop into an alternative or supplemental tool to the low-dose CT scanning for lung cancer screening.

Simulation study of electric-guided delivery of 0.4µm monodisperse and polydisperse aerosols to the ostiomeatal complex.

Despite the high prevalence of rhinosinusitis, current inhalation therapy shows limited efficacy due to extremely low drug delivery efficiency to the paranasal sinuses. Novel intranasal delivery systems are needed to enhance targeted delivery to the sinus with therapeutic dosages. An optimization framework for intranasal drug delivery was developed to target polydisperse charged aerosols to the ostiomeatal complex (OMC) with electric guidance. The delivery efficiency of a group of charged aerosols recently reported in the literature was numerically assessed and optimized in an anatomically accurate nose-sinus model. Key design variables included particle charge number, particle size and distribution, electrode strength, and inhalation velocity. Both monodisperse and polydisperse aerosol profiles were considered. Results showed that the OMC delivery efficiency was highly sensitive to the applied electric field and electrostatic charges carried by the particles. Through the synthesis of electric-guidance and point drug release, focused deposition with significantly enhanced dosage in the OMC can be achieved. For 0.4 µm charged aerosols, an OMC delivery efficiency of 51.6% was predicted for monodisperse aerosols and 34.4% for polydisperse aerosols. This difference suggested that the aerosol profile exerted a notable effect on intranasal deliveries. Sensitivity analysis indicated that the OMC deposition fraction was highly sensitive to the charge and size of particles and was less sensitive to the inhalation velocity considered in this study. Experimental studies are needed to validate the numerically optimized designs. Further studies are warranted to investigate the targeted OMC delivery with both electric and acoustics controls, the latter of which has the potential to further deliver the drug particles into the sinus cavity.

Visualization and Quantification of Nasal and Olfactory Deposition in a Sectional Adult Nasal Airway Cast.

PURPOSE: To compare drug deposition in the nose and olfactory region with different nasal devices and administration techniques. A Sar-Gel based colorimetry method will be developed to quantify local deposition rates. METHODS: A sectional nasal airway cast was developed based on an MRI-based nasal airway model to visualize deposition patterns and measure regional dosages. Four nasal spray pumps and four nebulizers were tested with both standard and point-release administration techniques. Delivered dosages were measured using a high-precision scale. The colorimetry correlation for deposited mass was developed via image processing in Matlab and its performance was evaluated through comparison to experimental measurements. RESULTS: Results show that the majority of nasal spray droplets deposited in the anterior nose while only a small fraction (less than 4.6%) reached the olfactory region. For all nebulizers considered, more droplets went beyond the nasal valve, leading to distinct deposition patterns as a function of both the nebulizer type (droplet size and initial speed) and inhalation flow rate. With the point-release administration, up to 9.0% (±1.9%) of administered drugs were delivered to the olfactory region and 15.7 (±2.4%) to the upper nose using Pari Sinus. CONCLUSIONS: Standard nasal devices are inadequate to deliver clinically significant olfactory dosages without excess drug losses in other nasal epitheliums. The Sar-Gel based colorimetry method appears to provide a simple and practical approach to visualize and quantify regional deposition.

Design and Testing of Electric-Guided Delivery of Charged Particles to the Olfactory Region: Experimental and Numerical Studies.

Neurological drugs delivered to the olfactory region can enter the brain via olfactory pathways and bypass the blood-brain barrier. However, clinical applications of the direct nose-to-brain delivery are rare because of the extremely low olfactory doses using conventional nasal devices. This poor bioavailability is mainly caused by two factors: the complex nasal structure that traps particles in the anterior nose and the complete lack of control over particle motions after their release at the nostrils. In this study, the feasibility of electric-guided delivery to the olfactory region was tested in an anatomically accurate nasal airway model both experimentally and numerically. The nose replicas were prepared using 3-D printing and could be dissembled to reveal the local deposition patterns within the nasal cavity. A test platform was developed that included a dry powder charging system and a particle point-release nozzle. Numerical modeling was conducted using COMSOL and compared to corresponding experiments. Compared to conventional nasal devices, electric-guidance of charged particles noticeably reduced particle losses in the anterior nose and increased depositions in the olfactory region. The thickness and relative permittivity of the wall were observed to affect the electric field strength and olfactory dosages. Consistent deposition patterns were obtained between experiments and numerical simulations in both 2-D and 3-D nose models. Two conceptual designs were proposed to generate, charge, and control aerosols. Results of this study indicate that it is feasible to use an electric field to control charged particles in the human nose. Both electric-guidance and point-release of particles are essential to achieve targeted olfactory delivery. Future studies to refine the aerosol charging and release systems are needed for further enhancement of olfactory dosages.

Detecting Lung Diseases from Exhaled Aerosols: Non-Invasive Lung Diagnosis Using Fractal Analysis and SVM Classification.

BACKGROUND: Each lung structure exhales a unique pattern of aerosols, which can be used to detect and monitor lung diseases non-invasively. The challenges are accurately interpreting the exhaled aerosol fingerprints and quantitatively correlating them to the lung diseases. OBJECTIVE AND METHODS: In this study, we presented a paradigm of an exhaled aerosol test that addresses the above two challenges and is promising to detect the site and severity of lung diseases. This paradigm consists of two steps: image feature extraction using sub-regional fractal analysis and data classification using a support vector machine (SVM). Numerical experiments were conducted to evaluate the feasibility of the breath test in four asthmatic lung models. A high-fidelity image-CFD approach was employed to compute the exhaled aerosol patterns under different disease conditions. FINDINGS: By employing the 10-fold cross-validation method, we achieved 100% classification accuracy among four asthmatic models using an ideal 108-sample dataset and 99.1% accuracy using a more realistic 324-sample dataset. The fractal-SVM classifier has been shown to be robust, highly sensitive to structural variations, and inherently suitable for investigating aerosol-disease correlations. CONCLUSION: For the first time, this study quantitatively linked the exhaled aerosol patterns with their underlying diseases and set the stage for the development of a computer-aided diagnostic system for non-invasive detection of obstructive respiratory diseases.

Numerical optimization of targeted delivery of charged nanoparticles to the ostiomeatal complex for treatment of rhinosinusitis.

BACKGROUND: Despite the prevalence of rhinosinusitis that affects 10%-15% of the population, current inhalation therapy shows limited efficacy. Standard devices deliver <5% of the drugs to the sinuses due to the complexity of nose structure, secluded location of the sinus, poor ventilation, and lack of control of particle motions inside the nasal cavity. METHODS: An electric-guided delivery system was developed to guide charged particles to the ostiomeatal complex (OMC). Its performance was numerically assessed in an MRI-based nose-sinus model. Key design variables related to the delivery device, drug particles, and patient breathing were determined using sensitivity analysis. A two-stage optimization of design variables was conducted to obtain the best performance of the delivery system using the Nelder-Mead algorithm. RESULTS AND DISCUSSION: The OMC delivery system exhibited high sensitivity to the applied electric field and electrostatic charges carried by the particles. Through the synthesis of electric guidance and point drug release, the new delivery system eliminated particle deposition in the nasal valve and turbinate regions and significantly enhanced the OMC doses. An OMC delivery efficiency of 72.4% was obtained with the optimized design, which is one order of magnitude higher than the standard nasal devices. Moreover, optimization is imperative to achieve a sound delivery protocol because of the large number of design variables. The OMC dose increased from 45.0% in the baseline model to 72.4% in the optimized system. The optimization framework developed in this study can be easily adapted for the delivery of drugs to other sites in the nose such as the ethmoid sinus and olfactory region.