Infectious diseases are a global public health problem, with emerging and re-emerging infectious diseases on the rise worldwide. Therefore, their prevention and treatment are still major challenges. Bile acids are common metabolites in both hosts and microorganisms that play a significant role in controlling the metabolism of lipids, glucose, and energy. Bile acids have historically been utilized as first-line, valuable therapeutic agents for related metabolic and hepatobiliary diseases. Notably, bile acids are the major active ingredients of cow bezoar and bear bile, which are commonly used traditional Chinese medicines (TCMs) with the therapeutic effects of clearing heat, detoxification, and relieving wind and spasm. In recent years, the promising performance of bile acids against infectious diseases has attracted attention from the scientific community. This paper reviews for the first time the biological activities, possible mechanisms, production routes, and potential applications of bile acids in the treatment and prevention of infectious diseases. Compared with previous reviews, we comprehensively summarize existing studies on the use of bile acids against infectious diseases caused by pathogenic microorganisms that are leading causes of global morbidity and mortality. In addition, to ensure a stable supply of bile acids at affordable prices, it is necessary to clarify the biosynthesis of bile acids in vivo, which will assist scientists in elucidating the accumulation of bile acids and discovering how to engineer various bile acids by means of chemosynthesis, biosynthesis, and chemoenzymatic synthesis. Finally, we explore the current challenges in the field and recommend a development strategy for bile-acid-based drugs and the sustainable production of bile acids. The presented studies suggest that bile acids are potential novel therapeutic agents for managing infectious diseases and can be artificially synthesized in a sustainable way.
The anticancer potential of quassinoids has attracted a great deal of attention for decades, and scientific data revealing their possible applications in cancer management are continuously increasing in the literature. Aside from the potent cytotoxic and antitumor properties of these degraded triterpenes, several quassinoids have exhibited synergistic effects with anticancer drugs. This article provides an overview of the potential anticancer properties of quassinoids, including their cytotoxic and antitumor activities, mechanisms of action, safety evaluation, and potential benefits in combination with anticancer drugs.
DNA guanine (G)-quadruplexes (G4s) are unique secondary structures formed by two or more stacked G-tetrads in G-rich DNA sequences. These structures have been found to play a crucial role in highly transcribed genes, especially in cancer-related oncogenes, making them attractive targets for cancer therapeutics. Significantly, targeting oncogene promoter G4 structures has emerged as a promising strategy to address the challenge of undruggable and drug-resistant proteins, such as MYC, BCL2, KRAS, and EGFR. Natural products have long been an important source of drug discovery, particularly in the fields of cancer and infectious diseases. Noteworthy progress has recently been made in the discovery of naturally occurring DNA G4-targeting drugs. Numerous DNA G4s, such as MYC-G4, BCL2-G4, KRAS-G4, PDGFR-β-G4, VEGF-G4, and telomeric-G4, have been identified as potential targets of natural products, including berberine, telomestatin, quindoline, sanguinarine, isaindigotone, and many others. Herein, we summarize and evaluate recent advancements in natural and nature-derived DNA G4 binders, focusing on understanding the structural recognition of DNA G4s by small molecules derived from nature. We also discuss the challenges and opportunities associated with developing drugs that target DNA G4s.
Antibacterial resistance is a global health threat that requires further concrete action on the part of all countries. In this context, one of the biggest concerns is whether enough new antibacterial drugs are being discovered and developed. Although several high-quality reviews on clinical antibacterial drug pipelines from a global perspective were published recently, none provides comprehensive information on original antibacterial drugs at clinical stages in China. In this review, we summarize the latest progress of novel antibacterial drugs approved for marketing and under clinical evaluation in China since 2019. Information was obtained by consulting official websites, searching commercial databases, retrieving literature, asking personnel from institutions or companies, and other means, and a considerable part of the data covered here has not been included in other reviews. As of June 30, 2023, a total of 20 antibacterial projects from 17 Chinese pharmaceutical companies or developers were identified and updated. Among them, two new antibacterial drugs that belong to traditional antibiotic classes were approved by the National Medical Products Administration (NMPA) in China in 2019 and 2021, respectively, and 18 antibacterial agents are in clinical development, with one under regulatory evaluation, five in phase-3, six in phase-2, and six in phase-1. Most of the clinical candidates are new analogs or mono-components of traditional antibacterial pharmacophore types, including two dual-acting hybrid antibiotics and a recombinant antibacterial protein. Overall, despite there being 17 antibacterial clinical candidates, our analysis indicates that there are still relatively few clinically differentiated antibacterial agents in stages of clinical development in China. Hopefully, Chinese pharmaceutical companies and institutions will develop more innovative and clinically differentiated candidates with good market potential in the future research and development (R&D) of original antibacterial drugs.
Theβ-1-6 -linked poly- N -acetylglucosamine (PNAG) polymer is a conserved surface polysaccharide produced by many bacteria, fungi, and protozoan (and even filarial) parasites. This wide-ranging expression makes PNAG an attractive target for vaccine development, as it potentially encompasses a broad range of microorganisms. Significant progress has been made in discovering important properties of the biology of PNAG expression in recent years. The molecular characterization and regulation of operons for the production of PNAG biosynthetic proteins and enzymes have been studied in many bacteria. In addition, the physiological function of PNAG has been further elucidated. PNAG-based vaccines and PNAG-targeting antibodies have shown great efficacy in preclinical research. Furthermore, clinical tests for both vaccines and antibodies have been carried out in humans and economically important animals, and the results are promising. Although it is not destined to be a smooth road, we are optimistic about new vaccines and immunotherapeutics targeting PNAG becoming validated and eventually licensed for clinical use against multiple infectious agents.
Microcirculatory disturbances are complex processes caused by many factors, including abnormal vasomotor responses, decreased blood flow velocity, vascular endothelial cell injury, altered leukocyte and endothelial cell interactions, plasma albumin leakage, microvascular hemorrhage, and thrombosis. These disturbances involve multiple mechanisms and interactions among mechanisms that can include energy metabolism, the mitochondrial respiratory chain, oxidative stress, inflammatory factors, adhesion molecules, the cytoskeleton, vascular endothelial cells, caveolae, cell junctions, the vascular basement membrane, neutrophils, monocytes, and platelets. In clinical practice, aside from drugs that target abnormal vasomotor responses and platelet adhesion, there continues to be a lack of multi-target drugs that can regulate the complex mechanistic links and interactions underlying microcirculatory disturbances. Natural products have demonstrated obvious positive therapeutic effects in treating ischemia/reperfu-sion (I/R)- and lipopolysaccharide (LPS)-induced microcirculatory disturbances. In recent years, numerous research papers on the improvement of microcirculatory function by natural products have been published in international journals. In 2008 and 2017, the first listed author of this review was invited to publish reviews in the journal of Pharmacology Therapeutics on the improvement of microcirculatory disturbances and organ injury induced by I/R using Salvia miltiorrhiza ingredients and other natural components of compounded Chinese medicine, respectively. This review systematically summarizes the effects, targets of action, and mechanisms of natural products regarding improving I/R- and LPS-induced microcirculatory disturbances and tissue injury. Based on this summary, scientific proposals are suggested for the discovery of new drugs to improve microcirculatory disturbances in disease.
Bear bile has been a valuable and effective medicinal material in traditional Chinese medicine (TCM) for over 13 centuries. However, the current practice of obtaining it through bear farming is under scrutiny for its adverse impact on bear welfare. Here, we present a new approach for creating artificial bear bile (ABB) as a high-quality and sustainable alternative to natural bear bile. This study addresses the scientific challenges of creating bear bile alternatives through interdisciplinary collaborations across various fields, including resources, chemistry, biology, medicine, pharmacology, and TCM. A comprehensive efficacy assessment system that bridges the gap between TCM and modern medical terminology has been established, allowing for the systematic screening of therapeutic constituents. Through the utilization of chemical synthesis and enzyme engineering technologies, our research has achieved the environmentally friendly, large-scale production of bear bile therapeutic compounds, as well as the optimization and recomposition of ABB formulations. The resulting ABB not only closely resembles natural bear bile in its composition but also offers advantages such as consistent product quality, availability of raw materials, and independence from threatened or wild resources. Comprehensive preclinical efficacy evaluations have demonstrated the equivalence of the therapeutic effects from ABB and those from commercially available drained bear bile (DBB). Furthermore, preclinical toxicological assessment and phase I clinical trials show that the safety of ABB is on par with that of the currently used DBB. This innovative strategy can serve as a new research paradigm for developing alternatives for other endangered TCMs, thereby strengthening the integrity and sustainability of TCM.
A 61-kb biosynthetic gene cluster (BGC), which is accountable for the biosynthesis of hibarimicin (HBM) B from Microbispora rosea subsp. hibaria TP-A0121, was heterologously expressed in Streptomyces coeli-color M1154, which generated a trace of the target products but accumulated a large amount of shunt products. Based on rational analysis of the relevant secondary metabolism, directed engineering of the biosynthetic pathways resulted in the high production of HBM B, as well as new HBM derivates with improved antitumor activity. These results not only establish a biosynthetic system to effectively synthesize HBMs-a class of the largest and most complex Type-II polyketides, with a unique pseudo-dimeric structure-but also set the stage for further engineering and deep investigation of this complex biosynthetic pathway toward potent anticancer drugs.
This work explores the potential of a triple combination of meropenem (MEM), a novel metallo-βlactamase (MBL) inhibitor (indole-2-carboxylate 58 (InC58)), and a serine-β-lactamase (SBL) inhibitor (avibactam (AVI)) for broad-spectrum activity against carbapenemase-producing bacteria. A diverse panel comprising MBL- and SBL-producing strains was used for susceptibility testing of the triple combination using the agar dilution method. The frequency of resistance (FoR) to MEM combined with InC58 was investigated. Mutants were sequenced and tested for cross resistance, fitness, and the stability of the resistance phenotype. Compared with the double combinations of MEM plus an SBL or MBL inhibitor, the triple combination extended the spectrum of activity to most of the isolates bearing SBLs (oxacillinase-48 (OXA-48) and Klebsiella pneumoniae carbapenemase-2 (KPC-2)) and MBLs (New Delhi metallo-β- lactamases (NDMs)), although it was not effective against Verona integron-encoded metallo-βlactamase (VIM)-carrying Pseudomonas aeruginosa (P. aeruginosa) and OXA-23-carrying Acinetobacter baumannii (A. baumannii). The FoR to MEM plus InC58 ranged from 2.22×10-7 to 1.13×10-6. The resistance correlated with mutations to ompC and comR, affecting porin C and copper permeability, respectively. The mutants manifested a fitness cost, a decreased level of resistance during passage without antibiotic pressure, and cross resistance to another carbapenem (imipenem) and a β-lactamase inhibitor (taniborbactam). In conclusion, compared with the dual combinations, the triple combination of MEM with InC58 and AVI showed a much wider spectrum of activity against different carbapenemase-producing bacteria, revealing a new strategy to combat β-lactamase-mediated antimicrobial resistance.
Myocardial ischemia is a serious threat to human health, and vascular dysfunction is its main cause. Buxu Tongyu (BXTY) Granule is an effective traditional Chinese medicine (TCM) for treating myocardial ischemia. However, the underlying mechanism of BXTY is still unclear. In this study, we demonstrate that BXTY ameliorates myocardial ischemia by activating the soluble guanylate cyclase (sGC)-3′,5′-cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signaling pathway in vascular smooth muscle cells (VSMCs) to dilate the arteries. BXTY was given by gavage for ten consecutive days before establishing an animal model of acute myocardial ischemia in mice via the intraperitoneal injection of pituitrin. The results showed that BXTY alleviated the symptoms of myocardial ischemia induced by pituitrin in mice, including electrocardiogram abnormalities and changes in plasma enzymes. In addition, BXTY dilated pre-constricted blood vessels and inhibited the vasoconstriction of the superior mesenteric artery in a dose-dependent but endothelial-independent manner. These effects were eliminated by pre-incubating vascular rings with the sGC inhibitors NS 2028 or ODQ, or with the PKG inhibitor KT 5823. Moreover, BXTY increased the protein expression of sGC-β1 and the intracellular second messenger cGMP level in mouse aortic vascular smooth muscle cells (MOVAs). NS 2028 or ODQ reversed these effects of BXTY. The expression level of the cGMP downstream effector protein PKG-1 increased after treating MOVAs with BXTY. NS 2028, ODQ, or KT 5823 also reversed this effect of BXTY. In conclusion, BXTY can improve the symptoms of acute myocardial ischemia in mice, and activating the sGC-cGMP-PKG pathway in VSMCs to induce vasodilation is its key pharmacodynamic mechanism.
Four new norditerpenoid heterodimers with different dimerization patterns—namely, trigofragiloids A-C (denoted as compounds 1-3) and (+)- and (−)-trigofragiloid D (compound 4)—and three new phenanthrenone norditerpenoids—namely, trigofragiloids E-G (compounds 5-7)—were isolated from Trigonostemon fragilis. Compounds 1 and 2 feature a novel heterodimeric carbon skeleton formed by the conjugation of a tetra-norditerpenoid and an ennea-norditerpenoid; they have been identified as class 2 atropisomers by means of quantum chemical calculations. Compound 3 is an unprecedented phenylpropanoid-norditerpenoid adduct with a new dimerization pattern. Compounds (+)- and (−)-4 are the first example of S-shaped 1,4-dioxane-fused norditerpenoid dimers. Inspired by the structure elucidation of compound 4, two co-occurring analogues, actephilol A and epiactephilol A, were structurally revised as a pair of geometrical isomers and were identified as two pairs of enantiomers, (+)- and (−)-8 and (+)- and (−)-9, respectively. Their structures were characterized using a combined method. Notably, compound 7 exhibits remarkable adenosine triphosphate-citrate lyase (ACLY) inhibition with a half-maximal inhibition concentration (IC50) value of (0.46 ± 0.11) μmol∙L−1, as active as the positive control BMS-303141, and a molecular docking study offers deep insight into the interaction between compound 7 and ACLY.
In the microalgae harvesting process, which includes a step for dewatering the algal suspension, directly reusing extracted water in situ would decrease the freshwater footprint of cultivation systems. Among various algae harvesting techniques, membrane-based filtration has shown numerous advantages. This study evaluated the reuse of permeate streams derived from Scenedesmus obliquus (S. obliquus) biomass filtration under bench-scale and pilot-scale conditions. In particular, this study identified a series of challenges and mechanisms that influence the water reuse potential and the robustness of the membrane harvesting system. In a preliminary phase of this investigation, the health status of the initial biomass was found to have important implications for the harvesting performance and quality of the permeate stream to be reused; healthy biomass ensured better dewatering performance (i.e., higher water fluxes) and higher quality of the permeate water streams. A series of bench-scale filtration experiments with different combinations of cross-flow velocity and pressure values were performed to identify the operative conditions that would maximize water productivity. The selected conditions, 2.4 m·s−1 and 1.4 bar (1 bar = 105 Pa), respectively, were then applied to drive pilot-scale microfiltration tests to reuse the collected permeate as a new cultivation medium for S. obliquus growth in a pilot-scale photobioreactor. The investigation revealed key differences between the behavior of the membrane systems at the two scales (bench and pilot). It indicated the potential for beneficial reuse of the permeate stream as the pilot-scale experiments ensured high harvesting performance and growth rates of biomass in permeate water that were highly similar to those recorded in the ideal cultivation medium. Finally, different nutrient reintegration protocols were investigated, revealing that both macro- and micro-nutrient levels are critical for the success of the reuse approach.
The Advanced Geosynchronous Radiation Imager (AGRI) is a mission-critical instrument for the Fengyun series of satellites. AGRI acquires full-disk images every 15 min and views East Asia every 5 min through 14 spectral bands, enabling the detection of highly variable aerosol optical depth (AOD). Quantitative retrieval of AOD has hitherto been challenging, especially over land. In this study, an AOD retrieval algorithm is proposed that combines deep learning and transfer learning. The algorithm uses core concepts from both the Dark Target (DT) and Deep Blue (DB) algorithms to select features for the machine-learning (ML) algorithm, allowing for AOD retrieval at 550 nm over both dark and bright surfaces. The algorithm consists of two steps: ① A baseline deep neural network (DNN) with skip connections is developed using 10 min Advanced Himawari Imager (AHI) AODs as the target variable, and ② sunphotometer AODs from 89 ground-based stations are used to fine-tune the DNN parameters. Out-of-station validation shows that the retrieved AOD attains high accuracy, characterized by a coefficient of determination (R2) of 0.70, a mean bias error (MBE) of 0.03, and a percentage of data within the expected error (EE) of 70.7%. A sensitivity study reveals that the top-of-atmosphere reflectance at 650 and 470 nm, as well as the surface reflectance at 650 nm, are the two largest sources of uncertainty impacting the retrieval. In a case study of monitoring an extreme aerosol event, the AGRI AOD is found to be able to capture the detailed temporal evolution of the event. This work demonstrates the superiority of the transfer-learning technique in satellite AOD retrievals and the applicability of the retrieved AGRI AOD in monitoring extreme pollution events.
The availability of nitrogen (N) is crucial for both the productivity of terrestrial and aquatic ecosystems globally. However, the overuse of artificial fertilizers and the energy required to fix nitrogen have pushed the global nitrogen cycle (N-cycle) past its safe operating limits, leading to severe nitrogen pollution and the production of significant amounts of greenhouse gas nitrous oxide (N2O). The anaerobic ammonium oxidation (anammox) mechanism can counteract the release of ammonium and N2O in many oxygen-limited situations, assisting in the restoration of the homeostasis of the Earth’s N biogeochemistry. In this work, we looked into the characteristics of the anammox hotspots’ distribution across various types of ecosystems worldwide. Anammox hotspots are present at diverse oxic-anoxic interfaces in terrestrial systems, and they are most prevalent at the oxic-anoxic transition zone in aquatic ecosystems. Based on the discovery of an anammox hotspot capable of oxidizing ammonium anoxically into N2 without N2O by-product, we then designed an innovative concept and technical routes of nature-based anammox hotspot geoengineering for climate change, biodiversity loss, and efficient utilization of water resources. After 15 years of actual use, anammox hotspot geoengineering has proven to be effective in ensuring clean drinking water, regulating the climate, fostering plant and animal diversity, and enhancing long-term environmental quality. The sustainable biogeoengineering of anammox could be a workable natural remedy to resolve the conflicts between environmental pollution and food security connected to N management.
Efficient metal recovery from industrial wastewater facilitates addressing of the environmental hazards and resource requirements of heavy metals. The conventional electrodeposition recovery method is hampered by the limitations of interfacial ion transport in charge-transfer reactions, creating challenges for simultaneous rapid and high-quality metal recovery. Therefore, we proposed integrating a transient electric field (TE) and swirling flow (SF) to synchronously enhance bulk mass transfer and promote interfacial ion transport. We investigated the effects of the operation mode, transient frequency, and flow rate on metal recovery, enabling determination of the optimal operating conditions for rapid and efficient sequential recovery of Cu in TE&SF mode. These conditions included low and high electric levels of 0 and 4 V, a 50% duty cycle, 1 kHz frequency, and 400 L·h−1 flow rate. The kinetic coefficients of TE&SF electrodeposition were 3.5-4.3 and 1.37-1.97 times that of single TE and SF electrodeposition, respectively. Simulating the deposition process under TE and SF conditions confirmed the efficient concurrence of interfacial ion transport and charge transfer under TE and SF synergy, which achieved rapid and high-quality metal recovery. Therefore, the combined deposition strategy is considered an effective technique for reducing metal pollution and promoting resource recycling.
Metalenses with achromatic performance offer a new opportunity for high-quality imaging with an ultra-compact configuration; however, they suffer from complex fabrication processes and low focusing efficiency. In this study, we propose an efficient design method for achromatic microlenses on a wavelength scale using materials with low dispersion, an adequately designed convex surface, and a thickness profile distribution. By taking into account the absolute chromatic aberration, relative focal length shift (FLS), and numerical aperture (NA), microlens with a certain focal length can be realized through our realized map of geometric features. Accordingly, the designed achromatic microlenses with low-dispersion fused silica were fabricated using a focused ion beam, and precise surface profiles were obtained. The fabricated microlenses exhibited a high average focusing efficiency of 65% at visible wavelengths of 410-680 nm and excellent achromatic capability via white light imaging. Moreover, the design exhibited the advantages of being polarization-insensitive and near-diffraction-limited. These results demonstrate the effectiveness of our proposed achromatic microlens design approach, which expands the prospects of miniaturized optics such as virtual and augmented reality, ultracompact microscopes, and biological endoscopy.
In three-dimensional (3D) stacking, the thermal stress of through-silicon via (TSV) has a significant influence on chip performance and reliability, and this problem is exacerbated in high-density TSV arrays. In this study, a novel hollow tungsten TSV (W-TSV) is presented and developed. The hollow structure provides space for the release of thermal stress. Simulation results showed that the hollow W-TSV structure can release 60.3% of thermal stress within the top 2 μm from the surface, and thermal stress can be decreased to less than 20 MPa in the radial area of 3 μm. The ultra-high-density (1600 TSV∙mm−2) TSV array with a size of 640 × 512, a pitch of 25 μm, and an aspect ratio of 20.3 was fabricated, and the test results demonstrated that the proposed TSV has excellent electrical and reliability performances. The average resistance of the TSV was 1.21 Ω. The leakage current was 643 pA and the breakdown voltage was greater than 100 V. The resistance change is less than 2% after 100 temperature cycles from −40 to 125 °C. Raman spectroscopy showed that the maximum stress on the wafer surface caused by the hollow W-TSV was 31.02 MPa, which means that there was no keep-out zone (KOZ) caused by the TSV array. These results indicate that this structure has great potential for applications in large-array photodetectors and 3D integrated circuits.
A substantial reduction in groundwater level, exacerbated by coal mining activities, is intensifying water scarcity in western China’s ecologically fragile coal mining areas. China’s national strategic goal of achieving a carbon peak and carbon neutrality has made eco-friendly mining that prioritizes the protection and efficient use of water resources essential. Based on the resource characteristics of mine water and heat hazards, an intensive coal-water-thermal collaborative co-mining paradigm for the duration of the mining process is proposed. An integrated system for the production, supply, and storage of mining companion resources is achieved through technologies such as roof water inrush prevention and control, hydrothermal quality improvement, and deep-injection geological storage. An active preventive and control system achieved by adjusting the mining technology and a passive system centered on multi-objective drainage and grouting treatment are suggested, in accordance with the original geological characteristics and dynamic process of water inrush. By implementing advanced multi-objective drainage, specifically designed to address the “skylight-type” water inrush mode in the Yulin mining area of Shaanxi Province, a substantial reduction of 50% in water drillings and inflow was achieved, leading to stabilized water conditions that effectively ensure subsequent safe coal mining. An integrated-energy complementary model that incorporates the clean production concept of heat utilization is also proposed. The findings indicate a potential saving of 8419 t of standard coal by using water and air heat as an alternative heating source for the Xiaojihan coalmine, resulting in an impressive energy conservation of 50.2% and a notable 24.2% reduction in carbon emissions. The ultra-deep sustained water injection of 100 m3·h−1 in a single well would not rupture the formation or cause water leakage, and 7.87 × 105 t of mine water could be effectively stored in the Liujiagou Formation, presenting a viable method for mine-water management in the Ordos Basin and providing insights for green and low-carbon mining.
In this paper, a hybrid integrated broadband Doherty power amplifier (DPA) based on a multi-chip module (MCM), whose active devices are fabricated using the gallium nitride (GaN) process and whose passive circuits are fabricated using the gallium arsenide (GaAs) integrated passive device (IPD) process, is proposed for 5G massive multiple-input multiple-output (MIMO) application. An inverted DPA structure with a low-Q output network is proposed to achieve better bandwidth performance, and a single-driver architecture is adopted for a chip with high gain and small area. The proposed DPA has a bandwidth of 4.4-5.0 GHz that can achieve a saturation of more than 45.0 dBm. The gain compression from 37 dBm to saturation power is less than 4 dB, and the average power-added efficiency (PAE) is 36.3% with an 8.5 dB peak-to-average power ratio (PAPR) in 4.5-5.0 GHz. The measured adjacent channel power ratio (ACPR) is better than −50 dBc after digital predistortion (DPD), exhibiting satisfactory linearity.
