ABSTRACT
The first example of rhodium-catalyzed nondirected C-H activation/annulation reactions for the construction of fused heterocyclic cations is reported herein with excellent regioselectivity. Deuterium-labeling experiments indicated that the C(sp3)-H bond cleavage of the N-methyl group might be the rate-limiting step during the reaction process. This protocol provides an opportunity to rapidly access highly π-conjugated fused heterocyclic cations, which opens up a new avenue for efficient screening of single-molecular white-light-emitting materials, pure red-light-emitting materials, and π-conjugated radical materials. Importantly, novel white-light-emitting materials exhibited distinct anti-Kasha dual-emission and could rapidly be fabricated into robust organic and low-cost white light-emitting diodes.
ABSTRACT
The human gut microbiota is a complex ecosystem that plays a crucial role in promoting the interaction between the body and its environment. It has been increasingly recognized that the gut microbiota has diverse physiological functions. Recent studies have shown a close association between the gut microbiota and the development of certain tumors, including leukemia. Leukemia is a malignant clonal disease characterized by the uncontrolled growth of one or more types of blood cells, which is the most common cancer in children. The imbalance of gut microbiota is linked to the pathological mechanisms of leukemia. Probiotics, which are beneficial microorganisms that help maintain the balance of the host microbiome, play a role in regulating gut microbiota. Probiotics have the potential to assist in the treatment of leukemia and improve the clinical prognosis of leukemia patients. This study reviews the relationship between gut microbiota, probiotics, and the progression of leukemia based on current research. In addition, utilizing zebrafish leukemia models in future studies might reveal the specific mechanisms of their interactions, thereby providing new insights into the clinical treatment of leukemia. In conclusion, further investigation is still needed to fully understand the accurate role of microbes in leukemia.
ABSTRACT
Selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are reported to cause stress cardiomyopathy (SC). This study evaluated the association between SSRI/SNRI use and the occurrence of cardiomyopathy in the publicly available U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database. Disproportionate analysis and likelihood ratio tests were used to identify risk associated with SSRIs or SNRIs and the incidence of SC, using data from between from 2012 to 2022 acquired from the FAERS database. The study identified 132 individual case safety reports (ICSRs) of SC associated with SSRIs or SNRIs. Venlafaxine (48%) and fluoxetine (27%) were the most common antidepressants of the ICSRs. Approximately 80% of SC cases were reported in females, with individuals aged 45-65 years identified as a high-risk population. Both venlafaxine (ratio-scale information component [RSIC] 2.54, 95% CI 2.06-3.04) and fluoxetine (RSIC 3.20, 95% CI 2.31-4.47) were associated with SC, with likelihood ratio estimates of 3.55 (p = 0.02) for venlafaxine and 4.82 (p = 0.008) for fluoxetine. The median time to cardiomyopathy onset was 20 days, with hospitalization reported in 48.33% of patients. Venlafaxine and fluoxetine were associated with SC risk, particularly in middle-aged women. Caution should be exercised when using SSRIs or SNRIs combined with other serotonergic medications.
Subject(s)
Pharmacovigilance , Selective Serotonin Reuptake Inhibitors , Serotonin and Noradrenaline Reuptake Inhibitors , Takotsubo Cardiomyopathy , Humans , Female , Selective Serotonin Reuptake Inhibitors/adverse effects , Male , Middle Aged , Aged , Serotonin and Noradrenaline Reuptake Inhibitors/adverse effects , Takotsubo Cardiomyopathy/chemically induced , Takotsubo Cardiomyopathy/epidemiology , Adverse Drug Reaction Reporting Systems , Adult , United States/epidemiology , Venlafaxine Hydrochloride/adverse effects , Fluoxetine/adverse effects , Databases, Factual , Risk FactorsABSTRACT
OBJECTIVES: To investigate multi-dose and timings of COVID-19 vaccines in preventing antenatal infection. DESIGN: Prospective observational study investigating primary vaccinations, boosters, antenatal COVID-19 infections, neutralizing antibody (Nab) durability, and cross-reactivity to Delta and Omicron variants of concern (VOCs). RESULTS: Ninety-eight patients completed primary vaccination prepregnancy (29.6%) and antenatally (63.3%), 24.2% of whom had antenatal COVID-19, while 7.1% were unvaccinated (28.6% had antenatal COVID-19). None had severe COVID-19. Prepregnancy vaccination resulted in vaccination-to-infection delay of 23.3 weeks, which extended to 45.2 weeks with a booster, compared to 16.9 weeks following antenatal vaccination (P < 0.001). Infections occurred at 26.2 weeks gestation in women vaccinated prepregnancy compared to 36.2 weeks gestation in those vaccinated during pregnancy (P < 0.007). The risk of COVID-19 infection was higher without antenatal vaccination (hazard ratio [HR] 14.6, P = 0.05) and after prepregnancy vaccination without a booster (HR 10.4, P = 0.002). Antenatal vaccinations initially led to high Nab levels, with mild waning but subsequent rebound. Significant Nab enhancement occurred with a third-trimester booster. Maternal-neonatal Nab transfer was efficient (transfer ratio >1), and cross-reactivity to VOCs was observed. CONCLUSION: Completing vaccination during any trimester delays COVID-19 infection and maintains effective neutralizing activity throughout pregnancy, with robust cross-reactivity to VOCs and efficient maternal-neonatal transfer.
Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , COVID-19 Vaccines , COVID-19 , Immunization, Secondary , Pregnancy Complications, Infectious , SARS-CoV-2 , Vaccination , Humans , Pregnancy , Female , COVID-19/prevention & control , COVID-19/immunology , COVID-19 Vaccines/immunology , COVID-19 Vaccines/administration & dosage , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , SARS-CoV-2/immunology , Adult , Prospective Studies , Pregnancy Complications, Infectious/prevention & control , Pregnancy Complications, Infectious/immunology , Pregnancy Complications, Infectious/virology , Antibodies, Viral/blood , Antibodies, Viral/immunology , Cross Reactions/immunology , Young AdultABSTRACT
For decades, implant-associated infections (IAIs) caused by pathogenic bacteria have been associated with high failure and mortality rates in implantation surgeries, posing a serious threat to global public health. Therefore, developing a functionalized biomaterial coating with anti-fouling and anti-bacterial functions is crucial for alleviating implant infections. Herein, a near-infrared-responsive anti-bacterial and anti-adhesive coating (Ti-PEG-Cu2-xS) constructed on the surface of titanium (Ti) implants is reported. This coating is composed of nano-Cu2-xS with anti-bacterial activity and super-hydrophilic polyethylene glycol (PEG). Under near-infrared irradiation, the nano-catalyst Cu2-xS on the surface of Ti-PEG-Cu2-xS induces bacterial death by catalyzing the production of singlet oxygen (1O2). The Ti-PEG-Cu2-xS coating can effectively prevent bacterial adhesion and biofilm formation. This coating combines the antibacterial mechanisms of "active attack" and "passive defense", which can kill bacteria and inhibit biofilm formation. The results of in vitro and in vivo experiments have shown that Ti-PEG-Cu2-xS exhibits excellent anti-bacterial properties under near-infrared irradiation and can effectively prevent implant-related infections caused by Escherichia coli (E. coli) ATCC 8739 and Staphylococcus aureus (S. aureus). The antibacterial efficiency of Ti-PEG-Cu2-xS coatings against E. coli was 99.96% ± 0.058% and that of S. aureus was 99.66% ± 0.26%, respectively. In addition, the Ti-PEG-Cu2-xS coating has good blood compatibility and excellent bactericidal ability. Therefore, this multifunctional coating combines a non-adhesive surface strategy and a near-infrared phototherapy sterilization method, effectively blocking the initial attachment and proliferation of bacteria on implants via photothermal/photodynamic effects and providing a promising method for preventing bacterium-induced IAIs.
Subject(s)
Anti-Bacterial Agents , Coated Materials, Biocompatible , Copper , Escherichia coli , Infrared Rays , Staphylococcus aureus , Titanium , Titanium/chemistry , Titanium/pharmacology , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Copper/chemistry , Copper/pharmacology , Escherichia coli/drug effects , Coated Materials, Biocompatible/chemistry , Coated Materials, Biocompatible/pharmacology , Staphylococcus aureus/drug effects , Animals , Microbial Sensitivity Tests , Biofilms/drug effects , Surface Properties , Mice , Polyethylene Glycols/chemistry , Polyethylene Glycols/pharmacology , Prostheses and Implants , Bacterial Adhesion/drug effects , Biofouling/prevention & controlABSTRACT
Diabetic wounds are a significant clinical challenge. Developing effective antibacterial dressings is crucial for preventing wound ulcers caused by bacterial infections. In this study, a self-healing antibacterial hydrogel (polyvinyl alcohol (PVA)-polylysine-gum arabic, PLG hydrogels) with near-infrared photothermal response was prepared by linking PVA and a novel polysaccharide-amino acid compound (PG) through borate bonding combined with freeze-thaw cycling. Subsequently, the hydrogel was modified by incorporating inorganic nanoparticles (modified graphene oxide (GM)). The experimental results showed that the PLGM3 hydrogels (PLG@GM hydrogels, 3.0 wt%) could effectively kill bacteria and promote diabetic wound tissue healing under 808-nm near-infrared laser irradiation. Therefore, this hydrogel system provides a new idea for developing novel dressings for treating diabetic wounds.
Subject(s)
Gum Arabic , Hydrogels , Polylysine , Polyvinyl Alcohol , Wound Healing , Wound Healing/drug effects , Polyvinyl Alcohol/chemistry , Hydrogels/chemistry , Hydrogels/pharmacology , Animals , Polylysine/chemistry , Polylysine/pharmacology , Gum Arabic/chemistry , Gum Arabic/pharmacology , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Diabetes Mellitus, Experimental , Rats , Sterilization/methods , Male , Mice , Graphite/chemistry , Graphite/pharmacologyABSTRACT
An analytical method was developed for the screening of 172 veterinary drugs in traditional Chinese medicine Galli Gigerii Endothelium Corneum by high-performance liquid chromatography tandem mass spectrometry. The samples were pretreated by a modified QuEChERS method. A Zorbax Eclipse plus C18 column (1.8 µm, 3.0 × 150 mm2, Agilent) was used for the separation of analytes by gradient elution. All analytes were detected by electrospray ionization mass spectrometry with multiple reaction monitoring mode. Good linearity with R ≥ 0.99 was exhibited for all analytes within the respective range. The recoveries of all monitored analytes ranged from 55.4 to 127.6% at three spiked levels (limit of quantitation-LOQ, 2-fold LOQ, 10-fold LOQ), with relative standard deviations <17.8%. The estimated LOQ levels were 0.2-20 µg/kg. The application of this method provides a reference for the safety control of traditional Chinese medicines.
Subject(s)
Tandem Mass Spectrometry , Veterinary Drugs , Tandem Mass Spectrometry/methods , Chromatography, High Pressure Liquid/methods , Animals , Veterinary Drugs/analysis , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/analysis , Reproducibility of Results , Limit of Detection , Medicine, Chinese Traditional , Linear Models , Liquid Chromatography-Mass SpectrometryABSTRACT
BACKGROUND: Hypertension is one of the major public health problems in China. Limited evidence exists regarding sex differences in the association between hypertension and air pollutants, as well as the impact of dietary factors on the relationship between air pollutants and hypertension. The aim of this study was to investigate the sex-specific effects of dietary patterns on the association between fine particulate matter (PM2.5), ozone(O3) and hypertension in adults residing in Jiangsu Province of China. METHODS: A total of 3189 adults from the 2015 China Adult Chronic Disease and Nutrition Surveillance in Jiangsu Province were included in this study. PM2.5 and O3 concentrations were estimated using satellite space-time models and assigned to each participant. Dietary patterns were determined by reduced rank regression (RRR), and multivariate logistic regression was used to assess the associations of the obtained dietary patterns with air pollutants and hypertension risk. RESULTS: After adjusting for confounding variables, we found that males were more sensitive to long-term exposure to PM2.5 (Odds ratio (OR) = 1.42 95%CI:1.08,1.87), and females were more sensitive to long-term exposure to O3 (OR = 1.61 95%CI:1.15,2.23). Traditional southern pattern identified through RRR exhibited a protective effect against hypertension in males (OR = 0.73 95%CI: 0.56,1.00). The results of the interaction between dietary pattern score and PM2.5 revealed that adherence to traditional southern pattern was significantly associated with a decreased risk of hypertension in males (P < 0.05), while no significant association was observed among females. CONCLUSIONS: Our findings suggested that sex differences existed in the association between dietary patterns, air pollutants and hypertension. Furthermore, we found that adherence to traditional southern pattern may mitigate the risk of long-term PM2.5 exposure-induced hypertension in males.
Subject(s)
Air Pollutants , Hypertension , Ozone , Particulate Matter , Humans , Male , Female , Hypertension/epidemiology , China/epidemiology , Middle Aged , Air Pollutants/analysis , Air Pollutants/adverse effects , Particulate Matter/analysis , Particulate Matter/adverse effects , Adult , Ozone/analysis , Ozone/adverse effects , Sex Factors , Diet/statistics & numerical data , Aged , Environmental Exposure/adverse effects , Dietary PatternsABSTRACT
Bacterial infection is the most common risk factor that causes the failure of implantation surgery. Therefore, the development of biocompatible implants with excellent antibacterial properties is of utmost importance. In this study, NIR light-driven AgBiS2@ZIF-8 hybrid photocatalysts for rapid bacteria-killing were prepared. AgBiS2@ZIF-8 exhibited excellent photocatalytic activity due to the rapid transfer of photoelectrons from AgBiS2 to ZIF-8, resulting in abundant reactive oxygen species (ROS) to kill bacteria. Meanwhile, AgBiS2@ZIF-8 exhibited a noteworthy photothermal effect, which could effectively convert NIR light into heat. Subsequently, the NIR light-driven antibacterial activity of AgBiS2@ZIF-8/Ti against S. aureus and E. coli was studied. The experimental results showed that AgBiS2@ZIF-8 displayed enhanced photodynamic therapy (PDT) and photothermal therapy (PTT) performance. Under irradiation with 808 nm NIR light for 10 min, AgBiS2@ZIF-8/Ti could effectively eliminate 98.55% of S. aureus in vitro, 99.34% of E. coli in vitro and 95% S. aureus in vivo. At the same time, AgBiS2@ZIF-8/Ti had good biocompatibility. Therefore, AgBiS2@ZIF-8/Ti showed potential as an antibacterial material, which provided a strategy to fight polymicrobial infections.
Subject(s)
Photochemotherapy , Staphylococcus aureus , Escherichia coli , Reactive Oxygen Species , Anti-Bacterial Agents/pharmacologyABSTRACT
Acylcarnitines are metabolic intermediates of fatty acids and branched-chain amino acids having vital biofunctions and pathophysiological significances. Here, we developed a high-throughput method for quantifying hundreds of acylcarnitines in one run using ultrahigh performance liquid chromatography and tandem mass spectrometry (UPLC-MS/MS). This enabled simultaneous quantification of 1136 acylcarnitines (C0-C26) within 10-min with good sensitivity (limit of detection < 0.7 fmol), linearity (correlation coefficient > 0.992), accuracy (relative error < 20%), precision (coefficient of variation (CV), CV < 15%), stability (CV < 15%), and inter-technician consistency (CV < 20%, n = 6). We also established a quantitative structure-retention relationship (goodness of fit > 0.998) for predicting retention time (tR) of acylcarnitines with no standards and built a database of their multiple reaction monitoring parameters (tR, ion-pairs, and collision energy). Furthermore, we quantified 514 acylcarnitines in human plasma and urine, mouse kidney, liver, heart, lung, and muscle. This provides a rapid method for quantifying acylcarnitines in multiple biological matrices.
ABSTRACT
Semantic processing, a core of language comprehension, involves the activation of brain regions dispersed extensively across the frontal, temporal, and parietal cortices that compose the semantic network. To comprehend the functional structure of this semantic network and how it prepares for semantic processing, we investigated its intrinsic functional connectivity (FC) and the relation between this pattern and semantic processing ability in a large sample from the Human Connectome Project (HCP) dataset. We first defined a well-studied brain network for semantic processing, and then we characterized the within-network connectivity (WNC) and the between-network connectivity (BNC) within this network using a voxel-based global brain connectivity (GBC) method based on resting-state functional magnetic resonance imaging (fMRI). The results showed that 97.73% of the voxels in the semantic network displayed considerably greater WNC than BNC, demonstrating that the semantic network is a fairly encapsulated network. Moreover, multiple connector hubs in the semantic network were identified after applying the criterion of WNC > 1 SD above the mean WNC of the semantic network. More importantly, three of these connector hubs (i.e., the left anterior temporal lobe, angular gyrus, and orbital part of the inferior frontal gyrus) were reliably associated with semantic processing ability. Our findings suggest that the three identified regions use WNC as the central mechanism for supporting semantic processing and that task-independent spontaneous connectivity in the semantic network is essential for semantic processing.
Subject(s)
Brain , Comprehension , Connectome , Magnetic Resonance Imaging , Nerve Net , Neural Pathways , Semantics , Humans , Magnetic Resonance Imaging/methods , Connectome/methods , Brain/physiology , Brain/diagnostic imaging , Adult , Nerve Net/physiology , Nerve Net/diagnostic imaging , Male , Comprehension/physiology , Neural Pathways/physiology , Female , Young Adult , Brain Mapping/methodsABSTRACT
Chronic wounds cause a number of unnecessary amputations due to a delay in proper treatment. To expedite timely treatment, this paper presents an algorithm which uses a logistic regression classifier to predict whether the wound will heal or not within a specified time. The prediction is made at three time-points: one month, three months, and six months from the first visit of the patient to the healthcare facility. This prediction is made using a systematically collected chronic wound registry and is based entirely on data collected during patients' first visit. The algorithm achieves an area under the receiver operating characteristic curve (AUC) of 0.75, 0.72, and 0.71 for the prediction at the three time-points, respectively.Clinical relevance- Using the proposed prediction model, the clinicians will have an early estimate of the time taken to heal thereby providing appropriate treatments. We hope this will ensure timely treatments and reduce the number of unnecessary amputations.
Subject(s)
Algorithms , Wound Healing , Humans , Time Factors , Registries , Databases, FactualABSTRACT
OBJECTIVE: This study aimed to investigate vitamin A and vitamin D conditions and related factors among children and adolescents aged 6-17 years in Jiangsu Province of China. METHODS: All the data were derived from China Nutrition and Health Surveillance of Children and Lactating Mothers in 2016-2017. By applying multiple stage stratified cluster random sampling method, 3244 children aged 6-17 years were selected from 12 survey sites in Jiangsu Province. Face to face interview, physical measurements and 6 mL blood sample were used to collect the general information, anthropometric information and blood nutritional indexes of the participants. Multivariate Logistic analysis was used for vitamin A and vitamin D conditions to test related factors. RESULTS: The prevalence of vitamin A deficiency and marginal deficiency was 0.8% and 15.8%, respectively.23.2% of the participants had vitamin D deficiency, 54.2% had vitamin D insufficiency and 4.8% had vitamin A insufficiency combined with vitamin D deficiency. Age group, weight levels, screen time and mother's education levels are the relevant factors of vitamin A insufficiency in children and adolescents. The related factors of vitamin D deficiency among children and adolescents are gender, age group, residence, physical activity level, screen time and mother's education levels. Gender, residence, weight levels, screen time and mother's education levels are the related factors of vitamin A insufficiency combined with vitamin D deficiency. CONCLUSION: Vitamin A insufficiency and vitamin D deficiency are at high epidemic levels among children and adolescents in Jiangsu Province in 2016-2017.
Subject(s)
Vitamin D Deficiency , Vitamin D , Child , Female , Humans , Adolescent , Vitamin A , Nutritional Status , Lactation , Vitamins , Vitamin D Deficiency/epidemiology , PrevalenceABSTRACT
BACKGROUND: Chinese/Mandarin language instruction to undergraduate students from non-Chinese speaking countries has become a topic of increasing interest, driven by China's influential role in global political and economic dynamics. With Mandarin being the language spoken by approximately 70% of Chinese speakers, it is not only taught within China but also in institutions around the world. While teaching any second or foreign language presents unique challenges, the specific challenges faced in Mandarin language education have not received comprehensive scrutiny, prompting the need for further investigation. OBJECTIVES: The primary objective of this study was to explore the challenges associated with teaching and learning Mandarin from the perspectives of non-native Mandarin language teachers. By adopting a qualitative (phenomenological) research approach, we aimed to uncover the multifaceted challenges that confront both educators and learners in the context of Mandarin language instruction. METHODOLOGY: The research methodology employed for this study involved the use of semi-structured interviews conducted with 15 Mandarin language teachers, who were chosen through theoretical sampling. These interviews were transcribed into text files and subsequently subjected to qualitative data analysis, which was facilitated by the use of MAQDA software. This approach allowed us to identify and categorize the various challenges and problems encountered in the teaching and learning of Mandarin. FINDINGS: The research findings revealed a range of challenges and problems experienced in Mandarin language education. These challenges were grouped into two primary thematic categories: psycho-linguistic and educational challenges. The linguistic challenges are deeply rooted in the distinctive features of the Mandarin language, presenting obstacles that necessitate innovative teaching strategies and materials. Educational challenges extend beyond native speaker proficiency, emphasizing the requirement for a comprehensive pedagogical skill set among instructors. IMPLICATIONS: The implications of this research extend to various stakeholders in the field of Chinese/Mandarin language education, including policymakers, educators, curriculum designers, and learners. Understanding the linguistic, educational, and psychological challenges can inform the development of more effective teaching methods, curriculum design, and motivation-enhancing strategies, ultimately promoting a more successful and engaging Mandarin language learning experience for non-native speakers.
Subject(s)
East Asian People , Language , Humans , Curriculum , Linguistics , LearningABSTRACT
Environmental protection and social obligation fulfillment have become hot subjects as the "dual carbon" approach has been developed and deepened. The ESG system is consistent with China's current policies, abandoning the traditional business philosophy of economic supremacy in favor of comprehensively measuring corporate social responsibility and sustainable development capability across three dimensions: environmental (E), social (S), and corporate governance (G), which receive widespread attention from all sectors of society. Based on observational data from A-share listed businesses in Shanghai and Shenzhen from 2011 to 2020, this study empirically evaluates the influence and mechanism of ESG on government subsidies. The research results indicate that enterprises can receive more government subsidies by improving ESG performance. Mechanism analysis found that corporate transparency plays a positive mediating role in the process of ESG affecting government subsidies. Further research on political affiliation and property rights has found that companies without political affiliation are more inclined to receive more government subsidies by improving ESG performance, and the impact of political affiliation and ESG performance on government subsidies is mutually complementary. Enterprises with different property rights have different strengths of motivation to increase government subsidies by improving ESG performance. State owned enterprises (excluding central enterprises) are the strongest, followed by non-state-owned enterprises, and central enterprises are the weakest. Therefore, enterprises should be further encouraged to strengthen ESG construction, improve the quality of ESG information disclosure, improve resource allocation efficiency, and promote high-quality development of enterprises.
Subject(s)
Carbon , Chlorhexidine , Humans , China , Commerce , Disclosure , GovernmentABSTRACT
Pheretima, also called "earthworms", is a well-known animal-derived traditional Chinese medicine that is extensively used in over 50 Chinese patent medicines (CPMs) in Chinese Pharmacopoeia (2020 edition). However, its zoological origin is unclear, both in the herbal market and CPMs. In this study, a strategy for integrating in-house annotated protein databases constructed from close evolutionary relationship-sourced RNA sequencing data from public archival resources and various sequencing algorithms (restricted search, open search, and de novo) was developed to characterize the phenotype of natural peptides of three major commercial species of Pheretima, including Pheretima aspergillum (PA), Pheretima vulgaris (PV), and Metaphire magna (MM). We identified 10,477 natural peptides in the PA, 7,451 in PV, and 5,896 in MM samples. Five specific signature peptides were screened and then validated using synthetic peptides; these demonstrated robust specificity for the authentication of PA, PV, and MM. Finally, all marker peptides were successfully applied to identify the zoological origins of Brain Heart capsules and Xiaohuoluo pills, revealing the inconsistent Pheretima species used in these CPMs. In conclusion, our integrated strategy could be used for the in-depth characterization of natural peptides of other animal-derived traditional Chinese medicines, especially non-model species with poorly annotated protein databases.
ABSTRACT
Androst-4-ene-3,17-dione (AD) and 22-hydroxy-23,24-bisnorchol-4-ene-3-one (4-HBC) are important drug intermediates that can be biosynthesized from phytosterols. However, the C9 hydroxylation of steroids via 3-ketosteroid 9α-hydroxylase (KSH) limits AD and 4-HBC accumulation. Five active KshAs, the oxidation component of KSH, were identified in Mycobacterium fortuitum ATCC 35855 for the first time. The deletion of kshAs indicated that the five KshA genes were jointly responsible for C9 hydroxylation during phytosterol biotransformation. MFKDΔkshA, the five KshAs deficient strain, blocked C9 hydroxylation and produced 5.37 g/L AD and 0.55 g/L 4-HBC. The dual function reductase Opccr knockout and 17ß-hydroxysteroid dehydrogenase Hsd4A enhancement reduced 4-HBC content from 8.75 to 1.72% and increased AD content from 84.13 to 91.34%, with 8.24 g/L AD being accumulated from 15 g/L phytosterol. In contrast, hsd4A and thioesterase fadA5 knockout resulted in the accumulation of 5.36 g/L 4-HBC from 10 g/L phytosterol. We constructed efficient AD (MFKDΔkshAΔopccr_hsd4A) and 4-HBC (MFKDΔkshAΔhsd4AΔfadA5) producers and provided insights for further metabolic engineering of the M. fortuitum ATCC 35855 strain for steroid productions. KEY POINTS: ⢠Five active KshAs were first identified in M. fortuitum ATCC 35855. ⢠Deactivation of all five KshAs blocks the steroid C9 hydroxylation reaction. ⢠AD or 4-HBC production was improved by Hsd4A, FadA5, and Opccr modification.
Subject(s)
Mycobacterium fortuitum , Mycobacterium , Phytosterols , Mycobacterium fortuitum/metabolism , Mycobacterium/genetics , Mixed Function Oxygenases/metabolism , Steroids/metabolism , BiotransformationABSTRACT
Evaluating the consistency of herb injectable formulations could improve their product quality and clinical safety, particularly concerning the composition and content levels of trace ingredients. Panax notoginseng Saponins Injection (PNSI), widely used in China for treating acute cardiovascular diseases, contains low-abundance (10%-25%) and trace saponins in addition to its five main constituents (notoginsenoside R1, ginsenoside Rg1, ginsenoside Re, ginsenoside Rb1, and ginsenoside Rd). This study aimed to establish a robust analytical method and assess the variability in trace saponin levels within PNSI from different vendors and formulation types. To achieve this, a liquid chromatography-triple quadrupole mass spectrometry (LC-MS/MS) method employing multiple ions monitoring (MIM) was developed. A "post-column valve switching" strategy was implemented to eliminate highly abundant peaks (NR1, Rg1, and Re) at 26 min. A total of 51 saponins in PNSI were quantified or relatively quantified using 18 saponin standards, with digoxin as the internal standard. This study evaluated 119 batches of PNSI from seven vendors, revealing significant variability in trace saponin levels among different vendors and formulation types. These findings highlight the importance of consistent content in low-abundance and trace saponins to ensure product control and clinical safety. Standardization of these ingredients is crucial for maintaining the quality and effectiveness of PNSI in treating acute cardiovascular diseases.
Subject(s)
Cardiovascular Diseases , Ginsenosides , Panax notoginseng , Saponins , Chemometrics , Chromatography, Liquid , Tandem Mass SpectrometryABSTRACT
In China, the focus of drug research and development has gradually shifted from generic to innovative drugs. Using the Chinese Clinical Trials Registry and Information Transparency Platform, we retrospectively analyzed clinical trials of innovative pediatric drugs conducted in mainland China over the last decade. The goal of this work was to better understand the characteristics of and historical changes in innovative pediatric drug research and development (R&D) in China and to provide effective data support for policy makers and other stakeholders. This study included 198 innovative pediatric drug clinical trials. The data showed that, although some progress has been made in the R&D of innovative pediatric drugs in China, many factors limiting this progress still exist, such as concentrated R&D areas, inadequate pediatric participants, and unbalanced source distributions. The level of innovative pediatric drug R&D in China currently lags behind the global level and has not kept pace with anti-neoplastic drug R&D in China. To promote the innovative development of pediatric drugs in China, the Chinese government must develop an R&D supervision framework, improve the motivation and innovation capabilities of pharmaceutical companies, and optimize the source distribution between regions.
ABSTRACT
The implantation of medical devices is frequently accompanied by the invasion of bacteria, which may lead to implant failure. Therefore, an intelligent and responsive coating seems particularly essential in hindering implant-associated infections. Herein, a self-defensive antimicrobial coating, accompanied by silk fibroin as a valve, was successfully prepared on the titanium (Ti-Cu@SF) for pH-controlled release of Cu2+. The results showed that the layer could set free massive Cu2+ to strive against E. coli and S. aureus for self-defense when exposed to a slightly acidic condition. By contrary, a little Cu2+ was released in the physiological situation, which could avoid damage to the normal cells and showed excellent in vitro pH-dependent antibiosis. Besides, in vivo experiment confirmed that Ti-Cu@SF could work as an antibacterial material to kill S. aureus keenly and display negligible toxicity in vivo. Consequently, the design provided support for endowing the layer with outstanding biocompatibility and addressing the issue of bacterial infection during the implantation of Ti substrates.