Development and validation of prognostic models for small cell lung cancer patients with liver metastasis: a SEER population-based study.

BACKGROUND: This study was to establish and validate prediction models to predict the cancer-specific survival (CSS) and overall survival (OS) of small-cell lung cancer (SCLC) patients with liver metastasis. METHODS: In the retrospective cohort study, SCLC patients with liver metastasis between 2010 and 2015 were retrospectively retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were randomly divided into the training group and testing group (3: 1 ratio). The Cox proportional hazards model was used to determine the predictive factors for CSS and OS in SCLC with liver metastasis. The prediction models were conducted based on the predictive factors. The performances of the prediction models were evaluated by concordance indexes (C-index), and calibration plots. The clinical value of the models was evaluated by decision curve analysis (DCA). RESULTS: In total, 8,587 patients were included, with 154 patients experiencing CSS and 154 patients experiencing OS. The median follow-up was 3 months. Age, gender, marital status, N stage, lung metastases, multiple metastases surgery of metastatic site, chemotherapy, and radiotherapy were independent predictive factors for the CSS and OS of SCLC patients with liver metastasis. The prediction models presented good performances of CSS and OS among patients with liver metastasis, with the C-index for CSS being 0.724, whereas the C-index for OS was 0.732, in the training set. The calibration curve showed a high degree of consistency between the actual and predicted CSS and OS. DCA suggested that the prediction models provided greater net clinical benefit to these patients. CONCLUSION: Our prediction models showed good predictive performance for the CSS and OS among SCLC patients with liver metastasis. Our developed nomograms may help clinicians predict CSS and OS in SCLC patients with liver metastasis.

[Evidence mapping of clinical studies on 23 commonly used Chinese patent medicines for treating insomnia].

Evidence mapping was performed to systematically search and review the clinical studies about the treatment of insomnia with Chinese patent medicines. The evidence distribution in this field was analyzed and the problems of the studies were summarized. Chinese-and English-language articles of the studies involving the Chinese patent medicines specified in three national drug catalogs for the treatment of insomnia were searched against the databases with the time interval from inception to August 2023. Figures and tables were established to present the results. Finally, 23 Chinese patent medicines were screened out, which were mentioned in 299 articles involving 236 randomized controlled trials(RCTs), 35 non-randomized controlled trials(non-RCTs), 7 retrospective studies, 17 systematic reviews/Meta-analysis, and 4 guidelines/expert recommendations or consensus. Bailemian Capsules, Wuling Capsules, and Yangxue Qingnao Granules were mentioned in a large proportion of articles. The outcome indicators included sleep rating scale, clinical response rate, safety indicators, and anxiety and depression scores. The results showed that the studies about the treatment of insomnia with Chinese patent medicines were growing. However, there was a scarcity of research evidence, and the available studies were single-center with small sample sizes and short periods. These studies spanned broad clinical scopes with inadequately emphasized advantages of TCM and insufficient outcome indicators about quality of life, follow-up, and recurrence rate. RCT exhibited a high risk of bias, and the systematic reviews/Meta-analysis demonstrated low overall quality. The retrospective studies received suboptimal scores, and the non-RCT failed to mention follow-up time, loss rate to follow-up, and sample size estimations, which compromised result reliability. It is recommended that the research protocol for Chinese patent medicines in treating insomnia should adhere to the clinical research standards of TCM. The TCM syndrome score can serves as a crucial outcome measure, and emphasis should be placed on patients' quality of life, follow-up, and recurrence prevention. Measures should be taken to enhance the accessibility and affordability of Chinese patent medicines and strengthen the connection between medical insurance policies and the policies pertaining to Chinese patent medicines. Furthermore, it is advisable to reasonably increase the inclusion of Chinese patent medicines with well-established efficacy and safety evidence in the category A list of medical insurance.

Metalearning Generalizable Dynamics from Trajectories.

We present the interpretable meta neural ordinary differential equation (iMODE) method to rapidly learn generalizable (i.e., not parameter-specific) dynamics from trajectories of multiple dynamical systems that vary in their physical parameters. The iMODE method learns metaknowledge, the functional variations of the force field of dynamical system instances without knowing the physical parameters, by adopting a bilevel optimization framework: an outer level capturing the common force field form among studied dynamical system instances and an inner level adapting to individual system instances. A priori physical knowledge can be conveniently embedded in the neural network architecture as inductive bias, such as conservative force field and Euclidean symmetry. With the learned metaknowledge, iMODE can model an unseen system within seconds, and inversely reveal knowledge on the physical parameters of a system, or as a neural gauge to "measure" the physical parameters of an unseen system with observed trajectories. iMODE can be generally applied to a dynamical system of an arbitrary type or number of physical parameters and is validated on bistable, double pendulum, Van der Pol, Slinky, and reaction-diffusion systems.

Bayesian chemical reaction neural network for autonomous kinetic uncertainty quantification.

Chemical reaction neural network (CRNN), a recently developed tool for autonomous discovery of reaction models, has been successfully demonstrated on a variety of chemical engineering and biochemical systems. It leverages the extraordinary data-fitting capacity of modern deep neural networks (DNNs) while preserving high interpretability and robustness by embedding widely applicable physical laws such as the law of mass action and the Arrhenius law. In this paper, we further developed Bayesian CRNN to not only reconstruct but also quantify the uncertainty of chemical kinetic models from data. Two methods, the Markov chain Monte Carlo algorithm and variational inference, were used to perform the Bayesian CRNN, with the latter mainly adopted for its speed. We demonstrated the capability of Bayesian CRNN in the kinetic uncertainty quantification of different types of chemical systems and discussed the importance of embedding physical laws in data-driven modeling. Finally, we discussed the adaptation of Bayesian CRNN for incomplete measurements and model mixing for global uncertainty quantification.

Microfluidic Production of Zwitterion Coating Microcapsules with Low Foreign Body Reactions for Improved Islet Transplantation.

Islet transplantation is a promising strategy for type 1 diabetes mellitus (T1DM) treatment, whereas implanted-associated foreign body reaction (FBR) usually induces the necrosis of transplanted islets and leads to the failure of glycemic control. Benefiting from the excellent anti-biofouling property of zwitterionic materials and their successful application in macroscopic implanted devices, microcapsules with zwitterionic coatings may be promising candidates for islet encapsulation. Herein, a series of zwitterion-coated core-shell microcapsules is fabricated (including carboxybetaine methacrylate [CBMA]-coated gelatin methacrylate [GelMA] [CBMA-GelMA], sulfobetaine methacrylate [SBMA]-coated GelMA [SBMA-GelMA], and phosphorylcholine methacrylate [MPC]-coated GelMA [MPC-GelMA]) by one-step photopolymerization of inner GelMA and outer zwitterionic monomers via a handmade two-fluid microfluidic device and it is demonstrated that they can effectively prevent protein adsorption, cell adhesion, and inflammation in vitro. Interestingly, the zwitterionic microcapsules successfully resist FBR in C57BL/6 mice after intraperitoneal implantation for up to 4 months. After successfully encapsulating xenogeneic rat islets in the SBMA-GelMA microcapsules, sustained normoglycemia is further validated in streptozotocin (STZ)-induced mice for up to 3 months. The zwitterion-modified microcapsule using a microfluidic device may represent a platform for cell encapsulation treatment for T1DM and other hormone-deficient diseases.

Equipping Cancer Cell Membrane Vesicles with Functional DNA as a Targeted Vaccine for Cancer Immunotherapy.

By inducing tumor-specific immune responses, tumor vaccines have recently aroused great research interest. Herein, we design a targeted nanovaccine by equipping cell membrane vesicles (CMVs) harvested from tumor cells with functional DNA including CpG oligonucleotide, an agonist for toll-like receptor 9, as well as an aptamer targeting the dendritic cell (DC)-specific intercellular adhesion molecule (ICAM)-3 grabbing nonintegrin (DC-SIGN) receptor overexpressed on DCs. Such DNA-modified CMVs could target DCs and further stimulate their maturation. Notably, our nanovaccines could trigger robust antitumor immune responses to effective delay the tumor growth. Moreover, the combination of CMV-based nanovaccines with an immune checkpoint blockade could result in improved therapeutic responses by eliminating the majority of the tumors as well as long-term immune memory to prevent tumor recurrence. Therefore, by simply assembling functional DNA on CMVs harvested from tumor cells, we propose a general platform of DC-targeted personalized cancer vaccines for effective and specific cancer immunotherapy.

Ultrasensitive Detection of 17ß-Estradiol (E2) Based on Multistep Isothermal Amplification.

17ß-Estradiol (E2) can cause an adverse effect on the human endocrine system even at the nanomolar level. Measurements of very low levels of E2 remain a critical challenge due to insufficient sensitivity. In this study, a multistep isothermal amplification fluorescence strategy was constructed, which could realize the exponential amplification of target E2. Specifically, strand displacement reaction (SDA), rolling circle amplification (RCA), and multiprimed rolling circle amplification (MRCA) were combined in a series to quantify trace complementary strand of E2 (cDNA). The E2 aptamer and cDNA were hybridized and modified on the magnetic beads. E2 could bind to its aptamer and cause the release of the cDNA. Then, cDNA would combine with the template DNA, initiating the SDA-RCA-MRCA. The molecular beacons, possessing low background signal, whose fluorescence was quenched in the state of chain folding, could be specifically recognized by the long single-stranded DNA (L-ssDNA) generated by the multistep isothermal amplification triggered by cDNA, and then the fluorescence of the molecular beacons could be restored. Therefore, the E2 could be quantitatively detected by the recovery fluorescence intensity. The fluorescence value showed a good linear relationship with the concentration of E2 in the range of 0.001836-183.6 nM, and the limit of detection (LOD) was as low as 63.09 fM. In addition, the recovery rates of this method spiked in milk and water were 80.8-107.0%, respectively. This method has the advantage of multistep isothermal amplification to obtain abundant fluorescence signals, which may provide a new possibility for highly sensitive detection of other small-molecule targets.

A Colorimetric Strip for Rapid Detection and Real-Time Monitoring of Histamine in Fish Based on Self-Assembled Polydiacetylene Vesicles.

Self-assembled polydiacetylene (PDA) vesicles, with the distinct advantages of low-cost materials, simple preparation, and excellent chromatic properties, can be perfectly combined with a colorimetric strip for on-site inspection. Herein, without involving expensive reagents and instruments, a visual colorimetric strip based on well-prepared PDA vesicles was developed to analyze and monitor histamine in deep-sea fish and its canned food. The standard calorimetric card for semiquantitative detection of histamine was successfully prepared and the quantitative detection can be further realized by analyzing the gray value using ImageJ and "Color Grab" in a smart phone. After optimizing the assembly conditions, this assay exhibited a linear response to histamine within the range from 70 to 2240 ppm. With excellent stability and sensitivity, this strip can be used to monitor the quality change of canned fish at different temperatures, so that people can avoid suffering from histamine poisoning, suggesting that it holds great potential in the intelligent system for on-site detection and real-time monitoring.

An ultrasensitive sensor based on quantitatively modified upconversion particles for trace bisphenol A detection.

Bisphenol A (BPA) is one of the endocrine-disrupting chemicals which might cause reproductive and endocrine system diseases, and poses a serious threat to the ecosystem and human health. This paper reports an ultrasensitive sensor for trace BPA detection employing fluorescence resonance energy transfer (FRET) between modified upconversion nanoparticles (UCNPs) and tetramethylrhodamine. To circumvent the problems of low luminous efficiency of FRET and low sensitivity of sensor, the upconversion nanoparticles with very strong fluorescence efficiency were prepared and quantitatively modified. Results showed that the concentrations of amino groups and streptavidin were 43 nmol/mg and 6.12 µg/mg on the surface of the UCNPs, respectively. Under the optimal detection conditions, the peak intensity of UCNPs at 547 nm was linear with the logarithm of the BPA concentration with the detection limit of 0.05 ng/mL. Without complicated pre-processing, the recoveries were in general between 91.0 and 115.0% in tap water, river water, and disposable paper cup water. Therefore, the proposed sensor is suitable for effective sensing of trace BPA in water samples. Graphical abstract ᅟ.

Tuning the pH profile of ß-glucuronidase by rational site-directed mutagenesis for efficient transformation of glycyrrhizin.

In this study, we aimed to shift the optimal pH of acidic ß-glucuronidase from Aspergillus oryzae Li-3 (PGUS) to the neutral region by site-directed mutagenesis, thus allowing high efficient biotransformation of glycyrrhizin (GL) into glycyrrhetinic acid (GA) under higher pH where the solubility of GL could be greatly enhanced. Based on PGUS structure analysis, five critical aspartic acid and glutamic acid residues were replaced with arginine on the surface to generate a variant 5Rs with optimal pH shifting from 4.5 to 6.5. The catalytic efficiency (kcat /Km) value of 5Rs at pH 6.5 was 10.7-fold higher than that of PGUS wild-type at pH 6.5, even 1.4-fold higher than that of wild-type at pH 4.5. Molecular dynamics simulation was performed to explore the molecular mechanism for the shifted pH profile and enhanced pH stability of 5Rs.

Allelic diversity in an NLR gene BPH9 enables rice to combat planthopper variation.

Brown planthopper (BPH), Nilaparvata lugens Stål, is one of the most devastating insect pests of rice (Oryza sativa L.). Currently, 30 BPH-resistance genes have been genetically defined, most of which are clustered on specific chromosome regions. Here, we describe molecular cloning and characterization of a BPH-resistance gene, BPH9, mapped on the long arm of rice chromosome 12 (12L). BPH9 encodes a rare type of nucleotide-binding and leucine-rich repeat (NLR)-containing protein that localizes to the endomembrane system and causes a cell death phenotype. BPH9 activates salicylic acid- and jasmonic acid-signaling pathways in rice plants and confers both antixenosis and antibiosis to BPH. We further demonstrated that the eight BPH-resistance genes that are clustered on chromosome 12L, including the widely used BPH1, are allelic with each other. To honor the priority in the literature, we thus designated this locus as BPH1/9 These eight genes can be classified into four allelotypes, BPH1/9-1, -2, -7, and -9 These allelotypes confer varying levels of resistance to different biotypes of BPH. The coding region of BPH1/9 shows a high level of diversity in rice germplasm. Homologous fragments of the nucleotide-binding (NB) and leucine-rich repeat (LRR) domains exist, which might have served as a repository for generating allele diversity. Our findings reveal a rice plant strategy for modifying the genetic information to gain the upper hand in the struggle against insect herbivores. Further exploration of natural allelic variation and artificial shuffling within this gene may allow breeding to be tailored to control emerging biotypes of BPH.

Upconversion fluorescent aptasensor for bisphenol A and 17ß-estradiol based on a nanohybrid composed of black phosphorus and gold, and making use of signal amplification via DNA tetrahedrons.

This study describes an upconversion fluorescent aptasensor based on black phosphorus nanohybrids and self-assembled DNA tetrahedrons dual-amplification strategy for rapid detection of the environmental estrogens bisphenol A (BPA) and 17ß-estradiol (E2). Tetrahedron complementary DNAs (T-cDNAs) were self-assembled in an oriented fashion on a 2D nanohybrid composed of black phosphorus (BP) and gold to give a materials of architecture BP-Au@T-cDNAs. In parallel, core-shell upconversion nanoparticles were modified with aptamers (UCNPs@apts) and used as capture probes. On complementary pairing, the BP-Au@T-cDNA quench the fluorescence of UCNPs@apts (measured at an excitation wavelength 808 nm and at main emission peaks at 545 nm and 805 nm.) Compared with single-stranded probes based on black phosphorus and gold, the dual-amplification strategy increases quenching efficiency by nearly 25%-30% and reduces capture time to 10 min. This is due to the higher optical absorption of 2D nanohybrid and the reduction of steric hindrance by T-cDNAs. Exposure to BPA or E2 cause the release of UCNPs@apts from the BP-Au@T-cDNAs due to stronger binding between aptamer and analyte. Hence, fluorescence recovers at 545 nm for BPA and 805 nm for E2. Based on these findings, a dually amplified aptamer assay was constructed that covers the 0.01 to 100 ng mL-1 BPA concentration range, and the 0.1 to 100 ng mL-1 E2 concentration range. The detection limits are 7.8 pg mL-1 and 92 pg mL-1, respectively. This method was applied to the simultaneous determination of BPA and E2 in spiked samples of water, food, serum and urine. Graphical abstract Schematic presentation of novel quenching probes designed by tetrahedron complementary DNAs oriented self-assembled on the surface of black phosphorus/gold nanohybrids. Combined with aptamer-modified upconversion nanoparticles, a dual-amplification self-assembled fluorescence nanoprobe was constructed for simultaneous detection of BPA and E2.

Genes associated with thermosensitive genic male sterility in rice identified by comparative expression profiling.

BACKGROUND: Thermosensitive genic male sterile (TGMS) lines and photoperiod-sensitive genic male sterile (PGMS) lines have been successfully used in hybridization to improve rice yields. However, the molecular mechanisms underlying male sterility transitions in most PGMS/TGMS rice lines are unclear. In the recently developed TGMS-Co27 line, the male sterility is based on co-suppression of a UDP-glucose pyrophosphorylase gene (Ugp1), but further study is needed to fully elucidate the molecular mechanisms involved. RESULTS: Microarray-based transcriptome profiling of TGMS-Co27 and wild-type Hejiang 19 (H1493) plants grown at high and low temperatures revealed that 15462 probe sets representing 8303 genes were differentially expressed in the two lines, under the two conditions, or both. Environmental factors strongly affected global gene expression. Some genes important for pollen development were strongly repressed in TGMS-Co27 at high temperature. More significantly, series-cluster analysis of differentially expressed genes (DEGs) between TGMS-Co27 plants grown under the two conditions showed that low temperature induced the expression of a gene cluster. This cluster was found to be essential for sterility transition. It includes many meiosis stage-related genes that are probably important for thermosensitive male sterility in TGMS-Co27, inter alia: Arg/Ser-rich domain (RS)-containing zinc finger proteins, polypyrimidine tract-binding proteins (PTBs), DEAD/DEAH box RNA helicases, ZOS (C2H2 zinc finger proteins of Oryza sativa), at least one polyadenylate-binding protein and some other RNA recognition motif (RRM) domain-containing proteins involved in post-transcriptional processes, eukaryotic initiation factor 5B (eIF5B), ribosomal proteins (L37, L1p/L10e, L27 and L24), aminoacyl-tRNA synthetases (ARSs), eukaryotic elongation factor Tu (eEF-Tu) and a peptide chain release factor protein involved in translation. The differential expression of 12 DEGs that are important for pollen development, low temperature responses or TGMS was validated by quantitative RT-PCR (qRT-PCR). CONCLUSIONS: Temperature strongly affects global gene expression and may be the common regulator of fertility in PGMS/TGMS rice lines. The identified expression changes reflect perturbations in the transcriptomic regulation of pollen development networks in TGMS-Co27. Findings from this and previous studies indicate that sets of genes involved in post-transcriptional and translation processes are involved in thermosensitive male sterility transitions in TGMS-Co27.

Ultrasensitive Detection Strategy of Norovirus Based on a Dual Enhancement Strategy: CRISPR-Responsive Self-Assembled SNA and Isothermal Amplification.

Spherical nucleic acids (SNAs) have been used to construct various nanobiosensors with gold nanoparticles (AuNPs) as nuclei. The SNAs play a critical role in biosensing due to their various physical and chemical properties, programmability, and specificity recognition ability. In this study, CRISPR-responsive self-assembled spherical nucleic acid (CRISPR-rsSNA) detection probes were constructed by conjugating fluorescein-labeled probes to the surface of AuNPs to improve the sensing performance. Also, the mechanism of ssDNA and the role of different fluorescent groups in the self-assembly process of CRISPR-rsSNA were explored. Then, CRISPR-rsSNA and reverse transcription-recombinase polymerase amplification (RT-RPA) were combined to develop an ultrasensitive fluorescence-detection strategy for norovirus. In the presence of the virus, the target RNA sequence of the virus was transformed and amplified by RT-RPA. The resulting dsDNA activated the trans-cleavage activity of CRISPR cas12a, resulting in disintegrating the outer nucleic acid structure of the CRISPR-rsSNA at a diffusible rate, which released reporter molecules. Norovirus was quantitated by fluorescence detection. This strategy facilitated the detection of the norovirus at the attomolar level. An RT-RPA kit for norovirus detected would be developed based on this method. The proposed method would be used for the detection of different viruses just by changing the target RNA and crRNA of the CRISPR cas12a system which provided a foundation for high-throughput detection of various substances.

Sunlight-powered self-excited oscillators for sustainable autonomous soft robotics.

As the field of soft robotics advances, full autonomy becomes highly sought after, especially if robot motion can be powered by environmental energy. This would present a self-sustained approach in terms of both energy supply and motion control. Now, autonomous movement can be realized by leveraging out-of-equilibrium oscillatory motion of stimuli-responsive polymers under a constant light source. It would be more advantageous if environmental energy could be scavenged to power robots. However, generating oscillation becomes challenging under the limited power density of available environmental energy sources. Here, we developed fully autonomous soft robots with self-sustainability based on self-excited oscillation. Aided by modeling, we have successfully reduced the required input power density to around one-Sun level through a liquid crystal elastomer (LCE)-based bilayer structure. The autonomous motion of the low-intensity LCE/elastomer bilayer oscillator "LiLBot" under low energy supply was achieved by high photothermal conversion, low modulus, and high material responsiveness simultaneously. The LiLBot features tunable peak-to-peak amplitudes from 4 to 72 degrees and frequencies from 0.3 to 11 hertz. The oscillation approach offers a strategy for designing autonomous, untethered, and sustainable small-scale soft robots, such as a sailboat, walker, roller, and synchronized flapping wings.

Metformin-containing hydrogel scaffold to augment CAR-T therapy against post-surgical solid tumors.

Physiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. Herein, we discovered that metformin, a prescribed drug for type 2 diabetes, could up-regulate the oxidative phosphorylation of CAR-T cells, increase their energy metabolism, and further promote their proliferation. Inspired by this finding, we designed a hydrogel scaffold to co-deliver metformin and CAR-T cells by adding CAR-T cells into a lyophilized alginate hydrogel containing metformin. The obtained hydrogel scaffold after being implanted into the tumor resection cavity could act as a cell reservoir to sustainably release both CAR-T cells and metformin. While the released metformin could suppress oxidative and glycolytic metabolism of cancer cells and lead to decreased tumor hypoxia, CAR-T cells would respond to metformin by markedly up-regulating oxidative metabolism and adopting a long-lived, highly activated phenotype, contributing to elevated antitumor responses. As demonstrated in several post-surgical tumor models, the proliferation and tumor-infiltration of CAR-T cells were significantly enhanced and the treatment efficacy of CAR-T cells was augmented, against both local tumors and distant abscopal tumors, while showing reduced systemic immune-related adverse effects. Our work presents a new strategy to achieve effective yet safe CAR-T therapy against solid tumors using a cell-delivery scaffold based on clinically validated drugs and biomaterials.

Sensitive colorimetric detection of antibiotic resistant Staphylococcus aureus on dairy farms using LAMP with pH-responsive polydiacetylene.

Rapidly and accurately detecting antibiotic-resistant pathogens in agriculture and husbandry is important since these represent a major threat to public health. While much attention has been dedicated to detecting now-common resistant bacteria, such as methicillin-resistant Staphylococcus aureus, fewer methods have been developed to assess resistance against macrolides in Staphylococcus aureus (SA). Here, we report a visual on-site detection system for macrolide resistant SA in dairy products. First, metagenomic sequencing in raw milk, cow manure, water and aerosol deposit collected from dairy farms around Tianjin was used to identify the most abundant macrolide resistance gene, which was found to be the macB gene. In parallel, SA housekeeping genes were screened to allow selective identification of SA, which resulted in the selection of the SAOUHSC_01275 gene. Next, LAMP assays targeting the above-mentioned genes were developed and interpreted by agarose gel electrophoresis. For on-site application, different pH-sensitive colorimetric LAMP indicators were compared, which resulted in selection of polydiacetylene (PDA) as the most sensitive candidate. Additionally, a semi-quantitative detection could be realized by analyzing the RGB information via smartphone with a LOD of 1.344 × 10-7 ng/µL of genomic DNA from a milk sample. Finally, the proposed method was successfully carried out at a real farm within 1 h from sample to result by using freeze-dried reagents and portable devices. This is the first instance in which PDA is used to detect LAMP products, and this generic read-out system can be expanded to other antibiotic resistant genes and bacteria.

Marsdenia tenacissima injection induces the apoptosis of prostate cancer by regulating the AKT/GSK3ß/STAT3 signaling axis.

Marsdenia tenacissima injection, a standard Marsdenia tenacissima extract (MTE), has been approved as an adjuvant therapeutic agent for various cancers. Our previous study showed that MTE inhibited the proliferation and metastasis of prostate cancer (PCa) cells. However, the underlying mechanisms and active ingredients of MTE against PCa were not completely understood. This study revealed that MTE induced significant decreases in cell viability and clonal growth in PCa cells. In addition, MTE induced the apoptosis of DU145 cells by reducing the mitochondrial membrane potential and increasing the expression of Cleaved Caspase 3/7, Cyt c, and Bax. In vivo, DU145 xenografted NOD-SCID mice treated with MTE showed significantly decreased tumor size. TUNEL staining and Western blot confirmed the pro-apoptotic effects of MTE. Network pharmacology analysis collected 196 ingredients of MTE linked to 655 potential targets, and 709 PCa-associated targets were retrieved, from which 149 overlapped targets were screened out. Pathway enrichment analysis showed that the HIF-1, PI3K-AKT, and ErbB signaling pathways were closely related to tumor apoptosis. Western blot results confirmed that MTE increased the expression of p-AKTSer473 and p-GSK3ßSer9, and decreased the expression of p-STAT3Tyr705in vitro and in vivo. A total of 13 compounds in MTE were identified by HPLC-CAD-QTOF-MS/MS and UPLC-QTOF-MS/MS. Molecular docking analysis indicated that six compounds may interact with AKT, GSK3ß, and STAT3. In conclusion, MTE induces the endogenous mitochondrial apoptosis of PCa by regulating the AKT/GSK3ß/STAT3 signaling axis, resulting in inhibition of PCa growth in vitro and in vivo.

Disulfiram loaded calcium phosphate nanoparticles for enhanced cancer immunotherapy.

Considering the huge cost and long test periods required for new drug development, repurposing drugs that have already been applied in the clinic as new cancer treatment candidates represents an attractive alternative. Disulfiram (DSF) was originally used to treat alcoholism and has proven to have anticancer effects with the coadministration of copper ions (Cu2+). However, the limited water-solubility of DSF and systemic toxicity induced by exogenous Cu2+ hinder its practical application. Herein, we constructed pH-responsive lipid-coated calcium phosphate nanoparticles (LCP NPs) co-loaded with Cu2+ and DSF. After intravenous injection, those nanoparticles with long blood half-life preferentially accumulate in tumors, followed by the degradation of nanoparticles in response to the acidic tumor microenvironment, subsequently releasing Cu2+ and DSF to generate cytotoxic metabolite DTC-Copper complex, bis(diethyldithiocarbamate)-copper (CuET) for tumor treatment. In addition to direct cytotoxicity, the active metabolite CuET could effectively induce immunogenic cell death (ICD) of cancer cells to regulate the immunosuppressive tumor microenvironment, contributing to enhanced immune checkpoint blockade (ICB) therapy in triggering systemic immune responses. This work thus demonstrates the great promises of repurposing the old drug DSF as a new ICD inducer with nano-formulation, to achieve improved synergetic tumor-responsive therapy with low side effects.

Proprietary Medicines Containing Bupleurum chinense DC. (Chaihu) for Depression: Network Meta-Analysis and Network Pharmacology Prediction.

Background and Aims: The rapid development of society has resulted in great competitive pressures, leading to the increase in suicide rates as well as incidence and recurrence of depression in recent years. Proprietary Chinese medicines containing Bupleurum chinense DC. (Chaihu) are widely used in clinical practice. This study aimed at evaluating the efficacy and safety of oral proprietary Chinese medicines containing Chaihu for treating depression by network meta-analysis (NMA) and exploring the potential pharmacological mechanisms of the optimal drugs obtained based on NMA. Methods: This study searched for clinical randomized controlled trial studies (RCTs) about Chaihu-containing products alone or in combination with selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), and cyclic antidepressants (CAS) for depression in eight databases. The search deadline is from data inception to April 2021. For efficacy assessment, the clinical response rate, the Hamilton Depression Scale-17 (HAMD-17), and adverse reactions were calculated. The methodological quality of the included studies was assessed for risk of bias following the Cochrane Handbook for Systematic Reviews of Interventions, and the data were subjected to NMA via the Stata version 16.0 software. Subsequently, the optimal drug obtained from the NMA results, Danzhi Xiaoyao pill (DZXY), was used to conduct network pharmacology analysis. We searched databases to acquire bioactive and potential targets of DZXY and depression-related targets. The protein-protein interaction (PPI) network, component-target network, the Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed by the STRING database, Cytoscape 3.9.0 software, and R version 4.1.2, respectively. Results: Thirty-seven RCTs, with a total of 3,263 patients, involving seven oral proprietary Chinese medicines containing Chaihu, were finally included. The results of the NMA demonstrated that the top four interventions with the best efficiency were Jiawei Xiaoyao + SSRI, DZXY + SNRI, Xiaoyao pill + SSRI, and Jieyu pill + SNRI; the top four interventions reducing HAMD score were DZXY + SNRI, Jiawei Xiaoyao, Jieyu pill, and Puyu pill + SNRI; the top four interventions with the least adverse effects were Jieyu pill, Anle pill + SSRI, DZXY + SNRI, and Puyu pill + SNRI. In the aspects above, DZXY + SNRI performed better than other treatments. After network meta-analysis, we conducted a network pharmacology-based strategy on the optimal drugs, DZXY, to provide the pharmacological basis for a conclusion. A total of 147 active compounds and 248 targets in DZXY were identified, of which 175 overlapping targets related to depression. Bioinformatics analysis revealed that MAPK3, JUN, MAPK14, MYC, MAPK1, etc. could become potential therapeutic targets. The MAPK signaling pathway might play an essential role in DZXY against depression. Conclusion: This is the very first systematic review and network meta-analysis evaluating different oral proprietary Chinese medicines containing Chaihu in depressive disorder. This study suggested that the combination of proprietary Chinese medicines containing Chaihu with antidepressants was generally better than antidepressant treatment. The incidence of adverse reactions with antidepressants alone was higher than that with proprietary Chinese medicines containing Chaihu alone or in combination with antidepressants. DZXY + SNRI showed significantly better results in efficacy, HAMD scores, and safety. The antidepressant effect of DZXY may be related to its regulation of neuroinflammation and apoptosis.