Design, synthesis and biological evaluation of bakuchiol derivatives as multi-target agents for the treatment of Alzheimer's disease.

The concept of multi-target-directed ligands offers fresh perspectives for the creation of brand-new Alzheimer's disease medications. To explore their potential as multi-targeted anti-Alzheimer's drugs, eighteen new bakuchiol derivatives were designed, synthesized, and evaluated. The structures of the new compounds were elucidated by IR, NMR, and HRMS. Eighteen compounds were assayed for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in vitro using Ellman's method. It was shown that most of the compounds inhibited AChE and BuChE to varying degrees, but the inhibitory effect on AChE was relatively strong, with fourteen compounds showing inhibition of >50% at the concentration of 200 µM. Among them, compound 3g (IC50 = 32.07 ± 2.00 µM) and compound 3n (IC50 = 34.78 ± 0.34 µM) showed potent AChE inhibitory activities. Molecular docking studies and molecular dynamics simulation showed that compound 3g interacts with key amino acids at the catalytically active site (CAS) and peripheral anionic site (PAS) of acetylcholinesterase and binds stably to acetylcholinesterase. On the other hand, compounds 3n and 3q significantly reduced the pro-inflammatory cytokines TNF-α and IL-6 released from LPS-induced RAW 264.7 macrophages. Compound 3n possessed both anti-acetylcholinesterase activity and anti-inflammatory properties. Therefore, an in-depth study of compound 3n is expected to be a multi-targeted anti-AD drug.

Unraveling spatial metabolome of the aerial and underground parts of Scutellaria baicalensis by matrix-assisted laser desorption/ionization mass spectrometry imaging.

BACKGROUND: Scutellaria baicalensis Georgi, a traditional Chinese medicine, is clinically applied mainly as the dried root of Scutellaria baicalensis, and the aerial parts of Scutellaria baicalensis, its stems and leaves, are often consumed as "Scutellaria baicalensis tea" to clear heat, dry dampness, reduce fire and detoxify, while few comparative analyses of the spatial metabolome of the aerial and underground parts of Scutellaria baicalensis have been carried out in current research. METHODS: In this work, Matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) was used to visualize the spatial imaging of the root, stem, and leaf of Scutellaria baicalensis at a high resolution of 10 µm, respectively, investigating the spatial distribution of the different secondary metabolites in the aerial and underground parts of Scutellaria baicalensis. RESULTS: In the present results, various metabolites, such as flavonoid glycosides, flavonoid metabolites, and phenolic acids, were systematically characterized in Scutellaria baicalensis root, stem, and leaf. Nine glycosides, 18 flavonoids, one organic acid, and four other metabolites in Scutellaria baicalensis root; nine glycosides, nine flavonoids, one organic acid in Scutellaria baicalensis stem; and seven flavonoids and seven glycosides in Scutellaria baicalensis leaf were visualized by MALDI-MSI. In the underground part of Scutellaria baicalensis, baicalein, wogonin, baicalin, wogonoside, and chrysin were widely distributed, while there was less spatial location in the aerial parts. Moreover, scutellarein, carthamidin/isocarthamidin, scutellarin, carthamidin/isocarthamidin-7-O-glucuronide had a high distribution in the aerial parts of Scutellaria baicalensis. In addition, the biosynthetic pathways involved in the biosynthesis of significant flavonoid metabolites in aerial and underground parts of Scutellaria baicalensis were successfully localized and visualized. CONCLUSIONS: MALDI-MSI offers a favorable approach for investigating the spatial distribution and effective utilization of metabolites of Scutellaria baicalensis. The detailed spatial chemical information can not only improve our understanding of the biosynthesis pathways of flavonoid metabolites, but more importantly, suggest that we need to fully exert the overall medicinal value of Scutellaria baicalensis, strengthening the reuse and development of the resources of Scutellaria baicalensis aboveground parts.

Effect of electroacupuncture at "Jiaji" (EX-B2) on senescence of nucleus pulposus cells of degenerated lumbar intervertebral disc in rabbits. / 电针"夹脊"å¯¹è °æ¤Žé—´ç›˜é€€å˜å ”é€€å˜æ¤Žé—´ç›˜é«“æ ¸ç»†èƒžè¡°è€çš„å½±å“.

OBJECTIVES: To observe the effect of electroacupuncture (EA) at "Jiaji"(EX-B2) on body mass, motor function, expression of caveolin-1 (Cav-1) in nucleus pulposus cells and annulus fibrosus tissue, telomerase activi-ty, relative telomere length and different cell cycle ratio of nucleus pulposus cells in rabbits with intervertebral disc degeneration(IVDD), so as to investigate its mechanism underlying delaying senescence of the degenerated lumbar intervertebral disc nucleus pulposus cells. METHODS: Twenty-five male New Zealand rabbits with mature bones were divided into control, sham operation, model, EA, and acupuncture groups, with 5 rabbits in each group. The IVDD model was established by inserting kirschner wires to the vertebral bone surface between the lumbar (L)4 and L5 vertebrae, followed by applying continuous axial pressure for 28 d. EA (2 Hz/15 Hz, 1-2 mA) or acupuncture (only insertion of acupuncture needles into bilateral EX-B2, but without electrical stimulation) was applied to bilateral EX-B2 for 20 min, once daily, 6 times a week for 4 weeks. The hindlimb locomotor function (locomotor score) was assessed by using Faden's and colleagues' methods. The general conditions of rabbits in each group were observed, and their body weight changes were measured every week. Nucleus pulposus cells were isolated using enzyme digestion method. After the treatment, the Cav-1 positive cell counts in nucleus pulposus cells and annulus fibrosus tissues were detected by immunohistochemistry, and the telomerase activity of nucleus pulposus cells was detected by PCR-ELISA. The relative telomere length of nucleus pulposus cells was measured by real-time quantitative polymerase chain reaction (real-time qPCR), and the cell cycle of nucleus pulposus was detected by flow cytometry. RESULTS: Compared with the sham operation group, the body mass from 4 to 11 week, locomotor score at 4, 7 and 11 week, telomerase activity, relative telomere length and the proportion of cells in G2/M phase of nucleus pulposus cells were significantly decreased (P<0.01), while Cav-1 positive cell counts of nucleus pulposus and annulus fibrosus tissue, and the proportion of nucleus pulposus cells in the G0/G1 phase considerably increased (P<0.01) in the model group. Relevant to the model group, the EA group rather than the acupuncture group had an increase in the body mass from 8 to 11 week, locomotor score at 11 week, telomerase activity, relative telomere length of nucleus pulposus cells, and the proportion of nucleus pulposus cells in G2/M phase (P<0.01), and a decrease in the Cav-1 positive cell counts of nucleus pulposus and annulus fibrosus tissue and the proportion of cells in G0/G1 phase (P<0.01). No significant differences were found between the model and acupuncture groups in all the indexes mentioned above. CONCLUSIONS: EA at EX-B2 has a bene-ficial effect in improving motor function in rabbits with IVDD, which may be related to its functions in reducing the expression of Cav-1 in nucleus pulposus cells and annulus fibrosus, improving cycle arrest, enhancing the telomerase activity and the relative telomere length of nucleus pulposus cells, delaying the senescence of nucleus pulposus cells of the degenerated lumbar intervertebral discs.

Comparison of dental anesthetic efficacy between the periodontal intraligamentary anesthesia and other infiltration anesthesia: a systematic review and meta-analysis.

Background: Uncertainty exists regarding the pain scores and the success rate of intraligamentary anesthesia compared to other infiltration anesthesia. Based on the conditions of clinical anesthesia techniques, we conducted a systematic review and meta-analysis to compare the efficacy of intraligamentary anesthesia with other infiltration anesthesia. Methods: The search was carried out in PubMed Central, Cochrane Central Register of Controlled Trials, MEDLINE (via OVID), Embase (via OVID), and Scopus from the inception to March 26, 2023. Results: Seven eligible randomized controlled trials were included in the meta-analysis. The results indicated no significant difference in the success rate (RR = 0.96; 95% CI [0.81-1.14]; p = 0.65; I2= 73%) and visual analog scale (VAS) during dental procedures (MD = 3.81; 95% CI [-0.54-8.16]; p = 0.09; I2= 97%) between intraligamentary anesthesia and other infiltration anesthesia. However, intraligamentary anesthesia exhibited a higher VAS score during injection than other infiltration anesthesia (MD = 8.83; 95% CI [4.86-12.79]; p < 0.0001; I2= 90%). A subgroup analysis according to infiltration techniques showed that supraperiosteal anesthesia had a lower VAS score during dental procedures than intraligamentary anesthesia. Conclusions: Intraligamentary anesthesia and other infiltration anesthesias have the same success rate and pain during dental procedures. However, the pain during injection of intraligamentary anesthesia is heavier than that of other infiltration anesthesia.

Effects of green tea extract epigallocatechin-3-gallate (EGCG) on orthodontic tooth movement and root resorption in rats.

OBJECTIVE: To study the effect of EGCG on tooth movement and root resorption during orthodontic treatment in rats. METHODS: A total of thirty six male Wistar rats were randomly and equally divided into three groups: control, 50 mg/kg EGCG, and 100 mg/kg EGCG. During the experiment, the subjects were submitted to an orthodontic tooth movement (OTM) model, rats in the experimental groups were given the corresponding dose of EGCG, while rats in the control group were administrated with an equal volume of normal saline solution by gavage. After 14 days of OTM, the rats were sacrificed by transcardial perfusion. Micro-CT of rat maxillaes was taken to analyze OTM distance and root resorption. The maxillary samples were prepared as histological sections for H&E staining, tartrate-resistant acid phosphatase (TRAP) staining and immunohistochemical (IHC) staining to be observed and analyzed. RESULTS: The OTM distance and root resorption of rats in the dosed group decreased, and the number of TRAP positive cells in their periodontium decreased significantly. The expression level of RANKL was decreased in the EGCG group compared to the control group, while that of OPG, OCN and Runx2 was increased. Effects were more pronounced in 100 mg/kg group than in 50 mg/kg group. CONCLUSION: EGCG reduces OTM and orthodontic induced root resorption (OIRR) in rats, and is able to attenuate osteoclastogenesis on the pressure side and promote osteogenesis on the tension side.

Integrated pharmacokinetics and pharmacometabolomics to reveal the synergistic mechanism of a multicomponent Chinese patent medicine, Mailuo Shutong pills against thromboangiitis obliterans.

BACKGROUND: Mailuo Shutong Pills (MLST) have displayed pharmacological activity against thromboangiitis obliterans (TAO). However, the active ingredients and therapeutic mechanism of MLST against TAO remained to be further clarified. PURPOSE: The aim of this study was to explore the active components of MLST and their synergistic mechanism against TAO by integrating pharmacokinetics (PK) and pharmacometabolomics (PM). METHODS: TAO model rats were established by sodium laurate solution. Firstly, the efficacy of MLST was evaluated by gangrene score, blood flow velocity, and hematoxylin-eosin (H&E) staining. Secondly, PK research was conducted on bioavailable components to characterize their dynamic behaviors under TAO. Thirdly, multiple plasma and urine metabolic biomarkers for sodium laurate-induced TAO rats were found by untargeted metabolomics, and then variations in TAO-altered metabolites following MLST treatment were analyzed utilizing multivariate and bioinformatic analysis. Additionally, metabolic pathway analysis was performed using MetaboAnalyst. Finally, the dynamic link between absorbed MLST-compounds and TAO-associated endogenous metabolites was established by correlation analysis. RESULTS: MLST significantly alleviated gangrene symptoms by improving the infiltration of inflammatory cells and blood supply in TAO rats. Significant differences in metabolic profiles were found in 17 differential metabolites in plasma and 24 in urine between Sham and TAO rats. The 10 bioavailable MLST-compounds, such as chlorogenic acid and paeoniflorin, showed positive or negative correlations with various TAO-altered metabolites related to glutamate metabolism, histidine metabolism, arachidonic acid metabolism and so on. CONCLUSION: This study originally investigated the dynamic interaction between MLST and the biosystem, providing unique insight for disclosing the active components of MLST and their synergistic mechanisms against TAO, which also shed light on new therapeutic targets for TAO and treatment.

Postoperative Adjuvant Hepatic Arterial Infusion Chemotherapy With FOLFOX in Hepatocellular Carcinoma With Microvascular Invasion: A Multicenter, Phase III, Randomized Study.

PURPOSE: To report the efficacy and safety of postoperative adjuvant hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil and oxaliplatin (FOLFOX) in hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI). PATIENTS AND METHODS: In this randomized, open-label, multicenter trial, histologically confirmed HCC patients with MVI were randomly assigned (1:1) to receive adjuvant FOLFOX-HAIC (treatment group) or routine follow-up (control group). The primary end point was disease-free survival (DFS) by intention-to-treat (ITT) analysis while secondary end points were overall survival, recurrence rate, and safety. RESULTS: Between June 2016 and August 2021, a total of 315 patients (ITT population) at five centers were randomly assigned to the treatment group (n = 157) or the control group (n = 158). In the ITT population, the median DFS was 20.3 months (95% CI, 10.4 to 30.3) in the treatment group versus 10.0 months (95% CI, 6.8 to 13.2) in the control group (hazard ratio, 0.59; 95% CI, 0.43 to 0.81; P = .001). The overall survival rates at 1 year, 2 years, and 3 years were 93.8% (95% CI, 89.8 to 98.1), 86.4% (95% CI, 80.0 to 93.2), and 80.4% (95% CI, 71.9 to 89.9) for the treatment group and 92.0% (95% CI, 87.6 to 96.7), 86.0% (95% CI, 79.9 to 92.6), and 74.9% (95% CI, 65.5 to 85.7) for the control group (hazard ratio, 0.64; 95% CI, 0.36 to 1.14; P = .130), respectively. The recurrence rates were 40.1% (63/157) in the treatment group and 55.7% (88/158) in the control group. Majority of the adverse events were grade 0-1 (83.8%), with no treatment-related death in both groups. CONCLUSION: Postoperative adjuvant HAIC with FOLFOX significantly improved the DFS benefits with acceptable toxicities in HCC patients with MVI.

A modified porous silicon microparticle potentiates protective systemic and mucosal immunity for SARS-CoV-2 subunit vaccine.

Development of optimal SARS-CoV-2 vaccines to induce potent, long-lasting immunity and provide cross-reactive protection against emerging variants remains a high priority. Here, we report that a modified porous silicon microparticle (mPSM) adjuvant to SARS-CoV-2 receptor-binding domain (RBD) vaccine activated dendritic cells and generated more potent and durable systemic humoral and type 1 helper T (Th) cell- mediated immune responses than alum-formulated RBD following parenteral vaccination, and protected mice from SARS-CoV-2 and Beta variant challenge. Notably, mPSM facilitated the uptake of SARS-CoV-2 RBD antigens by nasal and airway epithelial cells. Parenteral and intranasal prime and boost vaccinations with mPSM-RBD elicited stronger lung resident T and B cells and IgA responses compared to parenteral vaccination alone, which led to markedly diminished viral loads and inflammation in the lung following SARS-CoV-2 Delta variant challenge. Overall, our results suggest that mPSM is effective adjuvant for SARS-CoV-2 subunit vaccine in both systemic and mucosal vaccinations.

Roller microneedles transdermal delivery of compound lidocaine cream for enhancing the analgesic effect: A randomized self-controlled trial.

OBJECTIVE: The purpose of this article is to investigate whether the percutaneous delivery of compound lidocaine cream by roller microneedles can shorten the minimal effective onset time of anesthesia, enhance the intensity of anesthesia and prolong the analgesic time, so as to provide a theoretical basis for exploring a comfortable, safe and effective anesthesia method for photoelectric cosmetic surgery. METHODS: A total of 90 healthy volunteers, including 18 male and 72 female, met the criteria and were enrolled in the study from December 2020 to September 2021 in Department of Plastic and Burn Surgery of the First Affiliated Hospital of Chongqing Medical University. This study adopted a two-factor randomized block design of 3 (anesthesia time on the test side: 30, 45, 60 min) × 2 (the test side: the left and right side), and the subjects were divided into group A (n = 30), group B (n = 30), and group C (n = 30). On the test side, the compound lidocaine cream was used for topic anesthesia for 10 min, then the roller microneedle was used to roll on the treatment area, compound lidocaine cream was appropriately supplemented, and the topic anesthesia was kept continued for 20 min (group A), 35 min (group B), and 50 min (group C), respectively. The mirrorsymmetrical area of the test side of the three groups was the control side, and the compound lidocaine cream was used for topic anesthesia for 60 min. Photoelectric therapy was performed after anesthesia was completed. The analgesic effect of the subjects on both sides was comprehensively compared; the scores were obtained using the Kuttner Facial Expression Scale, the Frankl Treatment Compliance Scale, the Houpt Behavior Scale, and the Visual Analog Scale (VAS); the satisfaction with anesthesia was investigated. Before and after treatment the skin temperature, color and adverse reactions of the subjects were recorded. RESULTS: Comparing both sides of the same group, there was no significant difference in terms of the comprehensive evaluation, intraoperative comfort, tolerance, cooperation, pain or satisfaction between the 30-min test side and the routine anesthesia side in group A; the comprehensive evaluation, intraoperative tolerance, cooperation degree, pain degree and satisfaction evaluation of the subjects on the 45-min test side in group B were significantly better than those on the control side; the comprehensive evaluation, intraoperative comfort, tolerance, cooperation, pain and satisfaction of the subjects on the 60-min test side in group C were significantly better than those on the control side. Comparing groups on the control side, there was no significant difference in the comprehensive evaluation, intraoperative comfort, tolerance, cooperation, pain or satisfaction between the three groups of subjects on the control side. Comparing the three groups on the test side, with the prolongation of compound lidocaine cream indwelling time, the subjects' comprehensive evaluation, comfort and pain degree were significantly improved. There was no significant difference in postoperative bruising, swelling, pain, discoloration, redness, or tenderness between the test side and the control side. CONCLUSION: The percutaneous delivery of compound lidocaine cream by roller microneedles can not only shorten the effective time of anesthesia, but also has a good analgesic effect without obvious adverse reactions.

In Situ Tumor Vaccination with Calcium-Linked Degradable Coacervate Nanocomplex Co-Delivering Photosensitizer and TLR7/8 Agonist to Trigger Effective Anti-Tumor Immune Responses.

In situ anti-tumor vaccination is an attractive type of cancer immunotherapy which relies on the effectiveness of dendritic cells (DCs) to engulf tumor antigens, become activated, and present antigens to T cells in lymphoid tissue. Here, a multifunctional nanocomplex based on calcium crosslinked polyaspartic acid conjugated to either a toll-like receptor (TLR)7/8 agonist or a photosensitizer is reported. Intratumoral administration of the nanocomplex followed by laser irradiation induces cell killing and hence generation of a pool of tumor-associated antigens, with concomitant promotion of DCs maturation and expansion of T cells in tumor-draining lymph nodes. Suppression of tumor growth is observed both at the primary site and at the distal site, thereby hinting at successful induction of an adaptive anti-tumor response. This strategy holds promise for therapeutic application in a pre-operative and post-operative setting to leverage to mutanome of the patient's own tumor to mount immunological memory to clear residual tumor cells and metastasis.

An Intelligent Nanovehicle Armed with Multifunctional Navigation for Precise Delivery of Toll-Like Receptor 7/8 Agonist and Immunogenic Cell Death Amplifiers to Eliminate Solid Tumors and Trigger Durable Antitumor Immunity.

Cancer immunotherapy is revolutionary in oncology and hematology. However, a low response rate restricts the clinical benefits of this therapy owing to inadequate T lymphocyte infiltration and low delivery efficiency of immunotherapeutic drugs. Herein, an intelligent nanovehicle (folic acid (FA)/1-(4-(aminomethyl) benzyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (IMDQ)-oxaliplatin (F/IMO)@CuS) armed with multifunctional navigation is designed for the accurate delivery of cargoes to tumor cells and dendritic cells (DCs), respectively. The nanovehicle is based on a near infrared-responsive inorganic CuS nanoparticles, acting as a photosensitizer and carrier of the chemotherapeutic agent oxaliplatin, and enters tumor cells owing to the presence of folic acid on the surface of CuS upon intratumoral injection. Furthermore, a toll-like receptor (TLR) 7/8 agonist-conjugated polymer, anchored on the surface of CuS, is modified with mannose to bind with DCs in the tumor microenvironment. Upon exposure to laser irradiation, nanovehicles disassemble, releasing oxaliplatin, to ablate tumor cells and amplify immunogenic cell death in combination with photothermal therapy. Mannose-modified polymer-TLR7/8 agonist conjugates are subsequently exposed, leading to the activation of DCs and proliferation of T cells. Collectively, these intelligent nanovehicles reduce tumor burden, exert a robust antitumor immune response, and generate long-term immune protection to prevent tumor recurrence.

Decision-Making System for the Diagnosis of Syndrome Based on Traditional Chinese Medicine Knowledge Graph.

The clinical informatization of traditional Chinese medicine (TCM) focuses on serving users and assisting in diagnosis. The rules of clinical knowledge play an important role in improving the TCM informatization service. However, many rules are difficult to find because of the complexity of the data in the current TCM syndrome prediction. Therefore, we proposed an end-to-end model, called Decision-making System for the Diagnosis of Syndrome (DSDS), which is based on the knowledge graph (KG) of TCM. This paper introduces the link prediction for the diagnosis of syndrome by dismantling medical records into multiple symptoms. In addition, based on the symptoms and predicted syndromes, the most relevant syndrome could be determined by the scoring and voting method in this paper. The results show that the accuracy of DSDS is 80.6%.

Electroacupuncture promotes microglial M2 polarization in ischemic stroke via annexin A1.

BACKGROUND: Neuroinflammation is the leading cause of neurological sequelae in ischemic stroke. Recently, we reported that the anti-inflammatory mediator annexin A1 (ANXA1) favored microglial M2 polarization in brain injury. The purpose of this study was to investigate electroacupuncture (EA) treatment and its potentially ANXA1-mediated anti-inflammatory effects in the middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model of stroke. METHODS: Treatment with EA consisted of dense-sparse frequencies (alternating 4 Hz sparse waves for 1.5 s and 16 Hz dense waves for 1.5 s) at CV24 and GV26. Intracerebroventricular (ICV) injection of Boc-2 (5 µM) or short hairpin RNA (sh)ANXA1 (2 µL) 3 days before EA was performed to block the effects of ANXA1. RESULTS: EA pretreatment enhanced expression of ANXA1 and its receptor, formyl peptide receptor (FPR), when compared to MCAO/R alone. EA treatment also rescued MCAO/R-induced deficits in neurological performance, and learning and memory, and reduced infarct volume. Double immunofluorescent labeling showed that EA prevented MCAO/R-induced changes in microglial activation and morphology. EA also reduced the release of pro-inflammatory cytokines, such as interleukin (IL)-1ß, inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF)-α, while increasing the release of anti-inflammatory cytokines, such as arginase-1 (Arg-1) and brain-derived neurotrophic factor (BDNF). All EA-induced effects were either partially or completely prevented by prior administration of FPR antagonist Boc-2 or shANXA1. CONCLUSION: The current study provides strong evidence that EA treatment has protective effects against ischemic stroke in the MCAO/R mouse model and that the mechanism likely involves the promotion of M2 polarization in microglia via ANXA1.

A modified porous silicon microparticle promotes mucosal delivery of SARS-CoV-2 antigen and induction of potent and durable systemic and mucosal T helper 1 skewed protective immunity.

Development of optimal SARS-CoV-2 vaccines to induce potent, long-lasting immunity and provide cross-reactive protection against emerging variants remains a high priority. Here, we report that a modified porous silicon microparticle (mPSM)-adjuvanted SARS-CoV-2 receptor-binding domain (RBD) vaccine activated dendritic cells and generated more potent and durable SARS-CoV-2-specific systemic humoral and type 1 helper T (Th) cell-mediated immune responses than alum-formulated RBD following parenteral vaccination, and protected mice from SARS-CoV-2 and Beta variant infection. mPSM facilitated the uptake of SARS-CoV-2 RBD antigens by nasal and airway epithelial cells. Parenteral and intranasal prime and boost vaccinations with mPSM-RBD elicited potent systemic and lung resident memory T and B cells and SARS-CoV-2 specific IgA responses, and markedly diminished viral loads and inflammation in the lung following SARS-CoV-2 Delta variant infection. Our results suggest that mPSM can serve as potent adjuvant for SARS-CoV-2 subunit vaccine which is effective for systemic and mucosal vaccination.

The Adc regulon mediates zinc homeostasis in Streptococcus mutans.

Zinc (Zn2+ ) is an essential divalent trace metal for living cells. Intracellular zinc homeostasis is critical to the survival and virulence of bacteria. Thus, the frequent fluctuations of salivary zinc, caused by the low physiological level and the frequent exogenous zinc introduction, present a serious challenge for bacteria colonizing the oral cavity. However, the regulation strategies to keep intracellular Zn2+ homeostasis in Streptococcus mutans, an important causative pathogen of dental caries, are unknown. Because zinc uptake is primarily mediated by an ATP-binding ABC transporter AdcABC in Streptococcus strains, we examined the function of AdcABC and transcription factor AdcR in S. mutans in this study. The results demonstrated that deletion of either adcA or adcCB gene impaired the growth but enhanced the extracellular polymeric matrix production in S. mutans, both of which could be relieved after excessive Zn2+ supplementation. Using RNA sequencing analysis, quantitative reverse transcription polymerase chain reaction examination, LacZ-reporter studies, and electrophoretic mobility shift assay, we showed that a MarR (multiple antibiotic resistance regulator) family transcription factor, AdcR, negatively regulates the expression of the genes adcR, adcC, adcB, and adcA by acting on the adcRCB and adcA promoters in response to Zn2+ concentration in their environmental niches. The deletion of adcR increases the sensitivity of S. mutans to excessive Zn2+ supply. Taken together, our findings suggest that Adc regulon, which consists of a Zn2+ uptake transporter AdcCBA and a Zn2+ -responsive repressor AdcR, plays a prominent role in the maintenance of intracellular zinc homeostasis of S. mutans.

Effects of comprehensive care on complications, oxygenation indexes and guardian's psychological mood of children with neonatal respiratory distress syndrome.

OBJECTIVE: To observe the effects of comprehensive care on complications, oxygenation indexes of children with neonatal respiratory distress syndrome (NRDS), as well as their guardian's psychological mood. METHODS: Totally 205 cases of children with NRDS admitted to our hospital from February 2018 to December 2019 were recruited and divided into two groups according to different nursing interventions. Cases receiving comprehensive care were included in the research group (RG, n=108), and cases receiving routine care were included in the control group (CG, n=97). The curative effect, improvement of clinical symptoms, complications during nursing process, improvement of oxygenation indexes, degree of lung injury, improvement of physiological health were observed and compared, as well as the improvement of parents' psychological mood and their satisfaction with this nursing intervention. RESULTS: After care, RG had significantly better improvement of clinical indexes than that in CG, with notably lower PaCO2 and higher PaO2 and SaO2. Besides, children in RG showed remarkably lower Murray score and APACHE-II score, and the patients of children in RG also had lower SAS and SDS scores. The overall response rate (ORR) of children in RG was evidently higher than that in CG, the incidence of total complications in RG was evidently lower than that in CG, and the nursing satisfaction of parents in RG was evidently higher than that in CG. CONCLUSION: Comprehensive care is effective for children with NRDS, which can improve oxygenation indexes and lung injury, reduce the incidence of complications, and improve the psychological mood of parents.

Electroacupuncture Inhibits Autophagy of Neuron Cells in Postherpetic Neuralgia by Increasing the Expression of miR-223-3p.

Postherpetic neuralgia (PHN) is a complication of herpes zoster viral infection. Its main manifestations are continuous or intermittent burning-like and electroshock-like pain in the affected nerves. Electroacupuncture (EA) is widely used in clinical treatment and exerts effects in alleviating neuropathic pain. In this study, we investigated the effect and underlying mechanism of EA on PHN. Sprague-Dawley rats were treated with resiniferatoxin (RTX) to establish a PHN model and subjected to EA and/or miR-223-3p overexpression (OV) or interference. Mechanical withdrawal latency was measured as an indication of pain sensitivity. Hematoxylin-eosin staining and transmission electron microscopy were performed to observe neuron cell morphology and autophagic vacuoles, respectively. ELISA was performed to detect reactive oxygen species (ROS) production and the levels of tumor necrosis factor- (TNF-) α, inducible nitric oxide synthase (iNOS), interleukin- (IL-) 6, and IL-10. Changes in autophagy and apoptosis-related miRNAs were detected by immunofluorescence and qRT-PCR, respectively. In RTX-treated rats, OV and EA reduced pain sensitivity, decreased the number of eosinophils, and increased that of nerve cells. ROS generation and the levels of TNF-α and iNOS were significantly reduced, while those of IL-6 and IL-10 were increased. OV and EA induced fewer autophagic vacuoles than those in the model group. The expression of autophagy-related protein microtubule-associated protein 1 light chain 3-II, ATG9, and Rab1 was decreased by OV and EA, whereas that of P62 was increased. qRT-PCR revealed that miR-223-3p expression in the model group decreased but was increased by EA. EA inhibits neuron cell autophagy in PHN by increasing miR-223-3p expression.

Stimuli-responsive drug delivery systems for head and neck cancer therapy.

Head and neck cancer (HNC) is among the most common malignancy that has a profound impact on human health and life quality. The treatment for HNC, especially for the advanced cancer is stage-dependent and in need of combined therapies. Various forms of adjuvant treatments such as chemotherapy, phototherapy, hyperthermia, gene therapy have been included in the HNC therapy. However, there are still restrictions with traditional administration such as limited in situ therapeutic effect, systemic toxicity, drug resistance, etc. In recent years, stimuli-responsive drug delivery systems (DDSs) have attracted the great attention in HNC therapy. These intelligent DDSs could respond to unique tumor microenvironment, external triggers or dual/multi stimulus with more specific drug delivery and release, leading to enhanced treatment efficiency and less reduced side effects. In this article, recent studies on stimuli-responsive DDSs for HNC therapy were summarized, which could respond to endogenous and exogenous triggers including pH, matrix metalloproteinases (MMPs), reactive oxygen species (ROS), redox condition, light, magnetic field and multi stimuli. Their therapeutic remarks, current limits and future prospect for these intelligent DDSs were discussed. Furthermore, multifunctional stimuli-responsive DDSs have also been reviewed. With the modification of drug carriers or co-loading with therapeutic agents. Those intelligent DDSs showed more biofunctions such as combined therapeutic effects or integration of diagnosis and treatment for HNC. It is believed that stimuli-responsive drug delivery systems showed great potential for future clinic translation and application for the treatment of HNC.

Pharmacological basis of tanshinone and new insights into tanshinone as a multitarget natural product for multifaceted diseases.

Drug development has long included the systematic exploration of various resources. Among these, natural products are one of the most important resources from which novel agents are developed due to the multiple pharmacologic effects of these natural products on diseases. Tanshinone, a representative natural product, is the main compound extracted from the dried root and rhizome of Salvia miltiorrhiza Bge. Research on tanshinone began in the early 1930s. With the in-depth investigation of an increasing number of identified analogs, tanshinone has demonstrated a wide variety of bioactivities and contradicted the saying, 'You can't teach an old dog new tricks'. This review is focused on the pharmacological action of tanshinone and status of research on tanshinone in recent years. The mechanism of tanshinone has also drawn much attention, with the findings of representative targets and pathways of tanshinone. The most recent studies have comprehensively shown that tanshinone can be used to treat leukemia and solid carcinoma, protect against cardiovascular and cerebrovascular diseases, and alleviate liver- and kidney-related diseases, among its other effects. Multiple signaling pathways, including antiproliferative, antiapoptotic, anti-inflammatory, and antioxidative stress pathways, are involved in its actions.

Compound Dan Zhi tablet attenuates experimental ischemic stroke via inhibiting platelet activation and thrombus formation.

BACKGROUND: Compound Dan Zhi tablet (DZT) is a commonly used traditional Chinese medicine formula. It has been used for the treatment of ischemic stroke for many years in clinical. However, its pharmacological mechanism is unclear. PURPOSE: The aim of the current study was to understand the protective effects and underlying mechanisms of DZT on ischemic stroke. METHODS: Fifteen representative chemical markers in DZT were determined by ultra-performance liquid chromatography coupled with tandem quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). The protective effect of DZT against ischemic stroke was studied in a rat model of middle cerebral artery occlusion (MCAO), and the mechanism was further explored through a combination of network pharmacology and experimental verification. RESULTS: Quantitative analysis showed that the contents of phenolic acids, furan sulfonic acids, tanshinones, flavonoids, saponins and phthalides in DZT were calculated as 7.47, 0.788, 0.627, 0.531 and 0.256 mg/g, respectively. Phenolic acids were the most abundant constituents. Orally administered DZT (1.701 g kg-1) significantly alleviated the infarct size and neurological scores in MCAO rats. The network analysis predicted that 53 absorbed active compounds in DZT-treated plasma targeted 189 proteins and 47 pathways. Ten pathways were associated with anti-platelet activity. In further experiments, DZT (0.4 and 0.8 mg mL-1) markedly inhibited in vitro prostaglandin G/H synthase 1 (PTGS1) activity. DZT (0.4 and 0.8 mg mL-1) significantly inhibited in vitro platelet aggregation in response to ADP or AA. DZT (113 and 226 mg kg-1, p.o.) also produced a marked inhibition of ADP- or AA-induced ex vivo platelet aggregation with a short duration of action. DZT decreased the level of thromboxane A2 (TXA2) in MCAO rats. In the carrageenan-induced tail thrombosis model and ADP-induced acute pulmonary thromboembolism mice model, DZT (113 and 226 mg kg-1, p.o.) prevented thrombus formation. Importantly, DZT (113 and 226 mg kg-1, p.o.) exhibited a low bleeding liability. CONCLUSION: DZT protected against cerebral ischemic injury. The inhibition of TXA2 level, platelet aggregation and thrombosis formation might involve in the protective mechanism.