Exploring the Complexity and Promise of Tumor Immunotherapy in Drug Development.

Cancer represents a significant threat to human health, and traditional chemotherapy or cytotoxic therapy is no longer the sole or preferred approach for managing malignant tumors. With advanced research into the immunogenicity of tumor cells and the growing elderly population, tumor immunotherapy has emerged as a prominent therapeutic option. Its significance in treating elderly cancer patients is increasingly recognized. In this study, we review the conceptual classifications and benefits of immunotherapy, and discuss recent developments in new drugs and clinical progress in cancer treatment through various immunotherapeutic modalities with different mechanisms. Additionally, we explore the impact of immunosenescence on the effectiveness of cancer immunotherapy and propose innovative and effective strategies to rejuvenate senescent T cells.

An Advanced Molecularly Imprinted Photochemical Sensor Based Carbon Quantum dots for Highly Sensitive Detection of Chloramphenicol in Food.

A facile method which combines the advantages of carbon quantum dots and molecular imprinting technology to design a fluorescence molecular imprinting sensor for the high sensitivity and selective detection of chloramphenicol. The fluorescent molecule imprinted polymers are synthesized by sol-gel polymerization using carbon quantum dots as functional monomers and fluorescent sources, TEOS as crosslinkers, breaking with the traditional understanding of an additional functional monomer. Under optimal experimental, as the concentration of chloramphenicol increases, the fluorescence intensity of the fluorescence molecule imprinting sensor gradually decreases. The concentration of chloramphenicol is linear in the range of 5-100 µg/L and the detection limit is 1 µg/L (N/S = 3). The sensor is able to detect chloramphenicol in milk, enabling the application of real samples. The results show that this work provides an easy method to preparing fluorescent molecular imprinting sensors for the detection of chloramphenicol in milk.

A Durable Ni-Zn Microbattery with Ultrahigh-Rate Capability Enabled by In Situ Reconstructed Nanoporous Nickel with Epitaxial Phase.

Powering device for miniaturized electronics is highly desired with well-maintained capacity and high-rate performance. Though Ni-Zn microbattery can meet the demand to some extent with intrinsic fast kinetic, it still suffers irreversible structure degradation due to the repeated lattice strain. Herein, a stable Ni-Zn microbattery with ultrahigh-rate performance is rationally constructed through in situ electrochemical approaches, including the reconstruction of nanoporous nickel and the introduction of epitaxial Zn(OH)2 nanophase. With the enhanced ionic adsorption effect, the superior reactivity of the superficial nickel-based nanostructure is well stabilized. Based on facile miniaturization and electrochemical techniques, the fabricated nickel microelectrode exhibits 63.8% capacity retention when the current density is 500 times folded, and the modified hydroxides contribute to the great stability of the porous structure (92% capacity retention after 10 000 cycles). Furthermore, when the constructed Ni-Zn microbattery is measured in a practical metric, excellent power density (320.17 mW cm-2 ) and stable fast-charging performance (over 90% capacity retention in 3500 cycles) are obtained. This surface reconstruction strategy for nanostructure provides a new direction for the optimization of electrode structure and enriches high-performance output units for integrated microelectronics.

Micrometer-Sized Porous Fe2 N/C Bulk for High-Areal-Capacity and Stable Lithium Storage.

High-capacity anodes of lithium-ion batteries generally suffer from poor electrical conductivity, large volume variation, and low tap density caused by prepared nanostructures, which make it an obstacle to achieve both high-areal capacity and stable cycling performance for practical applications. Herein, micrometer-sized porous Fe2 N/C bulk is prepared to tackle the aforementioned issues, and thus realize both high-areal capacity and stable cycling performance at high mass loading. The porous structure in Fe2 N/C bulk is beneficial to alleviate the volumetric change. In addition, the N-doped carbon conducting networks with high electrical conductivity provide a fast charge transfer pathway. Meanwhile, the micrometer-sized Fe2 N/C bulk exhibits a higher tap density than that of commercial graphite powder (1.03 g cm-3 ), which facilitates the preparation of thinner electrode at high mass loadings. As a result, a high-areal capacity of above 4.2 mA h cm-2 at 0.45 mA cm-2 is obtained at a high mass loading of 7.0 mg cm-2 for LIBs, which still maintains at 2.59 mA h cm-2 after 200 cycles with a capacity retention of 98.8% at 0.89 mA cm-2 .

The Shigella type three secretion system effector OspF invades host nucleus by binding host importin α1.

Shigella type III effector OspF, a nuclear translocation protein, has been showed to have an essential role in Shigella flexneri infection and virulence; OspF increases inflammation and induces bacterial invasion by down-regulating MAPK kinases pathway. Nevertheless, the exact mechanisms underlying its nuclear translocation and signaling remain unclear. In the following study, we constructed series of OspF truncated mutants to identify the OspF nuclear localization signals which mapped to the amino acids 209-239. Moreover, we found that this sequence was essential to bind the canonical nuclear import adaptor importin α1. Additionally, the 209-239 residues deletion mutant could not bind the importin α1. Consistent with this observation, our results revealed that OspF can inhibit the MAPK signals in the nucleus. Moreover, OspF translocate to the nucleus through Ran-GTPase and importin α1-dependent manner. These results can provide new avenues for depicting the biological functions of OspF during Shigella infection.

High-throughput, one-step screening, cloning and expression based on the lethality of DpnI in Escherichia coli.

The manipulation of recombinant DNA has been an integral step in molecular biology to date. A number of strategies have been developed over the years, as traditional cloning methods are time consuming, have high backgrounds and low efficiency and are often limited by the number of suitable restriction sites available. Here, we constructed a series of new positive-selection-based cloning vectors that overcome most of the above mentioned drawbacks and can be applied in both eukaryotic and prokaryotic systems. This strategy is based on the extreme toxicity of DpnI in wild-type E. coli and the inactivation of this lethality by the introduction of target gene within multiple cloning sites. There are no rapid approaches for identifying soluble proteins for high-throughput screening. In this study, we combined this highly efficient cloning strategy with rapid identification of soluble proteins to construct vectors with multiple fusion tags, such as MBP, GST, CBD, NusA, and Sumo, to generate enzymes with potential diagnostic, industrial or therapeutic applications. Thus, this versatile positive-selection-based technology is appropriate for routine cloning, DNA library construction, and high-throughput screening for the expression of proteins of interest.

TMT-based proteomics analysis identifies the interventional mechanisms of Qijia Rougan decoction in improving hepatic fibrosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Qijia Rougan decoction (QJ), consisting of eight herbs and two animal drugs, is an effective traditional Chinese medicine with hepatoprotective and antifibrotic effects. However, its underlying action mechanism remains unclear. AIM OF THE STUDY: To explore the mechanism underlying the treatment of liver fibrosis in rats by QJ. MATERIALS AND METHODS: Rats with fibrosis were constructed using carbon tetrachloride (CCl4). The QJ was orally administered to fibrotic rats. Hepatic pathological changes were evaluated using hematoxylin and eosin and Masson's trichrome staining. The differentially expressed proteins (DEPs) in QJ were analyzed using quantitative proteomics. Subsequently, the underlying mechanisms in liver fibrosis after QJ treatment were validated using Western blotting. RESULTS: The QJ markedly improved liver function and attenuated fibrotic progression. Based on the tandem mass-tag based (TMT) proteomics, we identified 818 common DEPs between QJ vs Model and Model vs Control, including 296 upregulated and 522 downregulated DEPs, which mostly participate in metabolic pathways, oxidation-reduction reactions, and collagen biosynthetic processes. In addition, we found that QJ reduced hepatocellular death by inhibiting the expression of caspase proteins, repressing pro-apoptotic proteins, and promoting anti-apoptotic proteins. We further demonstrated that QJ suppressed the Akt/mTOR pathway. CONCLUSION: QJ exerted hepatoprotective effects in CCl4-induced rats through multi-pathway regulation. This study provides protein information on liver fibrosis treated with QJ.

Gradient Pores Enhance Charge Storage Density of Carbonaceous Cathodes for Zn-Ion Capacitor.

Engineering carbonaceous cathode materials with adequately accessible active sites is crucial for unleashing their charge storage potential. Herein, activated meso-microporous shell carbon (MMSC-A) nanofibers are constructed to enhance the zinc ion storage density by forming a gradient-pore structure. A dominating pore size of 0.86 nm is tailored to cater for the solvated [Zn(H2O)6]2+. Moreover, these gradient porous nanofibers feature rapid ion/electron dual conduction pathways and offer abundant active surfaces with high affinity to electrolyte. When employed in Zn-ion capacitors (ZICs), the electrode delivers significantly enhanced capacity (257 mAh g-1), energy density (200 Wh kg-1 at 78 W kg-1), and cyclic stability (95% retention after 10 000 cycles) compared to nonactivated carbon nanofibers electrode. A series of in situ characterization techniques unveil that the improved Zn2+ storage capability stems from size compatibility between the pores and [Zn(H2O)6]2+, the co-adsorption of Zn2+, H+, and SO4 2-, as well as reversible surface chemical interaction. This work presents an effective method to engineering meso-microporous carbon materials toward high energy-density storage, and also offers insights into the Zn2+ storage mechanism in such gradient-pore structures.

The anti-cholestatic effects of Coptis chinensis Franch. alone and combined with Tetradium ruticarpum (A. Jussieu) T. G. Hartley: dual effects on fecal metabolism and microbial diversity.

Introduction: Drug dosages and combinations are the main factors that affect the efficacy of pleiotropic traditional Chinese medicine (TCM). Coptis chinensis Franch. (CF) is a representative TCM with multiple effects and is often combined with Tetradium ruticarpum (A. Jussieu) T. G. Hartley (TR) to treat cholestasis. The present study assessed the influence of CF dose and its combination with TR on the efficacy of CF in cholestasis treatment, including their effects on fecal metabolism and fecal microorganisms. Methods: Rats with α-naphthylisothiocyanate (ANIT, 50 mg/kg)-induced cholestasis were administered low (0.3 g/kg) and high (0.6 g/kg) doses of CF, as well as CF combined with TR at doses of 0.6 g/kg and 0.9 g/kg, respectively. The anti-cholestatic effects of these treatments were assessed by determining their anti-inflammatory, hypolipidemic, and anti-oxidative stress properties. Additionally, fecal metabolomics and fecal microorganisms were analyzed. Results: Low dose CF had a more potent hypolipidemic effect than high dose CF, whereas high dose CF had more potent anti-inflammatory and anti-oxidative stress effects. Combination with TR enhanced the hypolipidemic effect, but antagonized the anti-inflammatory effect, of CF. Analyses of fecal metabolomics and fecal microorganisms showed differences in the regulation of lipid- and amino acid metabolism-related pathways, including pathways of linoleic acid, tyrosine, and arachidonic acid metabolism, and amino acid biosynthesis between different doses of CF as well as between different doses of CF in combination with TR. These differences may contribute to differences in the anti-cholestatic effects of these preparations. Conclusion: CF dose influences its anti-cholestatic efficacy. The combination with TR had synergistic or antagonistic effects on the properties of CF, perhaps by altering fecal metabolism and fecal microbial homeostasis.

Cycle-level traffic conflict prediction at signalized intersections with LiDAR data and Bayesian deep learning.

Real-time safety prediction models are vital in proactive road safety management strategies. This study develops models to predict traffic conflicts at signalized intersections at the signal cycle level, using advanced Bayesian deep learning techniques and efficient LiDAR points. The modeling framework contains three phases, which are data preprocessing, base deep learning model development, and Bayesian deep learning model development. The core of the framework is the long short-term memory (LSTM) employed to predict the conflict frequency of a cycle by using traffic features of the previous five cycles (e.g., dynamic traffic parameters, traffic conflict frequency). Four Bayesian deep learning models were developed, including Bayesian-Standard LSTM, Bayesian-Hybrid-LSTM, Bayesian-Stacked-LSTM Encoder-Decoder, and Bayesian-Multi-head Stacked-LSTM Encoder-Decoder. The developed models were applied to traffic conflicts extracted from LiDAR points that were collected from a signalized intersection in Harbin, China with a total duration of seven days. Traffic conflicts, measured by the modified time-to-collision conflict indicator, were identified using the peak over threshold approach. The models were thoroughly evaluated from the aspects of reliability, transferability, sensitivity, and robustness. The results show that the developed four models can predict traffic conflict frequency per cycle per lane simultaneously with its uncertainty. Moreover, the two Bayesian encoder-decoder models perform better than Bayesian-Standard LSTM and Bayesian-Hybrid-LSTM in the four tests. Bayesian-Multi-head Stacked-LSTM Encoder-Decoder is suggested as the optimal model for its high reliability under uncertainty, good transferability in three scenarios, low sensitivity to different parameters, and sound robustness against small noise. The proposed framework could benefit studies on the state-of-the-art data-driven approach for real-time safety prediction.

Therapeutic potential and pharmacological significance of extracellular vesicles derived from traditional medicinal plants.

Medicinal plants are the primary sources for the discovery of novel medicines and the basis of ethnopharmacological research. While existing studies mainly focus on the chemical compounds, there is little research about the functions of other contents in medicinal plants. Extracellular vesicles (EVs) are functionally active, nanoscale, membrane-bound vesicles secreted by almost all eukaryotic cells. Intriguingly, plant-derived extracellular vesicles (PDEVs) also have been implicated to play an important role in therapeutic application. PDEVs were reported to have physical and chemical properties similar to mammalian EVs, which are rich in lipids, proteins, nucleic acids, and pharmacologically active compounds. Besides these properties, PDEVs also exhibit unique advantages, especially intrinsic bioactivity, high stability, and easy absorption. PDEVs were found to be transferred into recipient cells and significantly affect their biological process involved in many diseases, such as inflammation and tumors. PDEVs also could offer unique morphological and compositional characteristics as natural nanocarriers by innately shuttling bioactive lipids, RNA, proteins, and other pharmacologically active substances. In addition, PDEVs could effectively encapsulate hydrophobic and hydrophilic chemicals, remain stable, and cross stringent biological barriers. Thus, this study focuses on the pharmacological action and mechanisms of PDEVs in therapeutic applications. We also systemically deal with facets of PDEVs, ranging from their isolation to composition, biological functions, and biotherapeutic roles. Efforts are also made to elucidate recent advances in re-engineering PDEVs applied as stable, effective, and non-immunogenic therapeutic applications to meet the ever-stringent demands. Considering its unique advantages, these studies not only provide relevant scientific evidence on therapeutic applications but could also replenish and inherit precious cultural heritage.

Surmounting Cancer Drug Resistance: New Perspective on RNA-Binding Proteins.

RNA-binding proteins (RBPs), being pivotal elements in both physiological and pathological processes, possess the ability to directly impact RNA, thereby exerting a profound influence on cellular life. Furthermore, the dysregulation of RBPs not only induces alterations in the expression levels of genes associated with cancer but also impairs the occurrence of post-transcriptional regulatory mechanisms. Consequently, these circumstances can give rise to aberrations in cellular processes, ultimately resulting in alterations within the proteome. An aberrant proteome can disrupt the equilibrium between oncogenes and tumor suppressor genes, promoting cancer progression. Given their significant role in modulating gene expression and post-transcriptional regulation, directing therapeutic interventions towards RBPs represents a viable strategy for combating drug resistance in cancer treatment. RBPs possess significant potential as diagnostic and prognostic markers for diverse cancer types. Gaining comprehensive insights into the structure and functionality of RBPs, along with delving deeper into the molecular mechanisms underlying RBPs in tumor drug resistance, can enhance cancer treatment strategies and augment the prognostic outcomes for individuals afflicted with cancer.

The zhuyu pill relieves rat cholestasis by regulating the mRNA expression of lipid and bile metabolism associated genes.

Background: The Zhuyu pill (ZYP), composed of Coptis chinensis Franch. and Tetradium ruticarpum (A. Jussieu) T. G. Hartley, is an effective traditional Chinese medicine with potential anti-cholestatic effects. However, the underlying mechanisms of ZYP remain unknown. Objective: To investigate the mechanism underlying the interventional effect of ZYP on mRNA-seq analysis in cholestasis rat models. Materials and methods: This study tested the effects of a low-dose (0.6 g/kg) and high-dose (1.2 g/kg) of ZYP on a cholestasis rat model induced by α-naphthyl-isothiocyanate (ANIT, 50 mg/kg). Serum biochemistry and histopathology results were used to evaluate the therapeutic effect of ZYP, and mRNA-Seq analysis was performed and verified using real-time fluorescence quantitative PCR (qRT-PCR). GO, KEGG, and GSEA analyses were integrated to identify the mechanism by which ZYP impacted cholestatic rats. Results: ZYP was shown to significantly improve abnormal changes in the biochemical blood indexes and liver histopathology of cholestasis rats and regulate pathways related to bile and lipid metabolism, including fatty acid metabolism, retinol metabolism, and steroid hormone biosynthesis, to alleviate inflammation, cholestasis, and lipid metabolism disorders. Relative expression of the essential genes Cyp2a1, Ephx2, Acox2, Cyp1a2, Cyp2c11, and Sult2a1 was verified by qRT-PCR and showed the same trend as mRNA-seq analysis. Conclusion: ZYP has a significant anti-cholestatic effect by regulating bile metabolism and lipid metabolism related pathways. These findings indicate that ZYP is a novel and promising prospect for treating cholestasis.

Carrier-Free Nanoplatform via Evoking Pyroptosis and Immune Response against Breast Cancer.

Pyroptosis, as a novel mode of cell death, has been proven to have impressive antitumor effects. Dying cells undergoing pyroptosis can elicit antitumor immunity by the release of tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs). Accordingly, developing an effective, stable, and controllable nanoplatform that can promote these two side effects is a promising option for cancer therapy. In this study, we designed a carrier-free chemo-photodynamic nanoplatform (A-C/NPs) using a co-assembly strategy with cytarabine (Ara-C) and chlorin e6 (Ce6) to induce pyroptosis and a subsequent immune response against breast cancer. Mechanistically, A-C/NPs can trigger GSDME-mediated pyroptosis in a controllable manner through reactive oxygen species (ROS) accumulation, causing immunogenic cell death (ICD), in which dying cells release high-mobility group box 1 (HMGB1), adenosine triphosphate (ATP), and calcitonin (CRT). Additionally, Ara-C can stimulate the maturation of cytotoxic T lymphocytes to act synergistically with Ce6-mediated immunogenic cell death (ICD), collectively augmenting the anticancer effect of A-C/NPs. The A-C/NPs showed excellent suppressive effects on the growth of orthotopic, abscopal, and recurrent tumors in a breast cancer mouse model. The chemo-photodynamic therapy (PDT) using the proposed nanomedicine strategy could be a novel strategy for triggering pyroptosis and improving the global anticancer immune response.

Identification of Six Genes as Diagnostic Markers for Colorectal Cancer Detection by Integrating Multiple Expression Profiles.

Background: Many studies have demonstrated the promising utility of DNA methylation and miRNA as biomarkers for colorectal cancer (CRC) early detection. However, mRNA is rarely reported. This study aimed to identify novel fecal-based mRNA signatures. Methods: The differentially expressed genes (DEGs) were first determined between CRCs and matched normal samples by integrating multiple datasets. Then, Least Absolute Shrinkage and Selection Operator (LASSO) regression was used to reduce the number of candidates of aberrantly expressed genes. Next, the potential functions were investigated for the candidate signatures and their ability to detect CRC and pan-cancers was comprehensively evaluated. Results: We identified 1841 common DEGs in two independent datasets. Functional enrichment analysis revealed they were mainly related to extracellular structure, biosynthesis, and cell adhesion. The CRC classifier was established based on six genes screened by LASSO regression. Sensitivity, specificity, and area under the ROC curve (AUC) for CRC detection were 79.30%, 80.40%, and 0.85 (0.76-0.92) in the training set, and these indexes achieved 93.20%, 41.80%, and 0.73 (0.65-0.83) in the testing set. For validation set, the sensitivity, specificity, and AUC were 98.90%, 98.00%, and 0.97 (0.94-0.99). The average sensitivities exceeded 90.00% for CRCs with different clinical features. For adenomas detection, the sensitivity and specificity were 74.50% and 64.00%. Besides, the six genes obtained an average AUC of 0.855 for pan-cancer detection. Conclusion: The six-gene signatures showed ability to detect CRC and pan-cancer samples, which could be served as potential diagnostic markers.

Temporal analysis of cellphone-use-involved crash injury severities: Calling for preventing cellphone-use-involved distracted driving.

With the popularity of smartphones and the increasing dependence on cellphones, cellphone-use-involved distracted driving has become a global traffic safety concern. Calling, texting, or watching videos while driving could have harmful impacts on driving abilities and increase crash-injury severities. To investigate the temporal stability and the heterogeneity of cellphone-involved crash injury severity determinants, a series of likelihood ratio tests and random parameters logit models with heterogeneity in means and variances are estimated. Cellphone-involved single-vehicle crash datasets of Pennsylvania from 2004 to 2019 are utilized. Marginal effects are also applied to investigate the impact of explanatory variables on injury severity outcomes. The results indicate an overall temporal instability of cellphone-involved crashes across different periods. However, driving without seatbelts and overturns are observed to produce relatively stable and positive influence on the increased injury severities of cellphone-involved crashes. Besides, it is noteworthy that a combination of cellphone usage with risky driving behaviors (aggressive driving, alcohol- or drug-related driving, speeding, or fatigue driving) significantly increase driver injury-severities. This finding highlights the necessity of identifying drivers with multiple risk-taking behaviors and enacting laws to prohibit these drivers from using cellphones while driving. Applications of smartphones provide another feasible approach to prevent using cellphones while driving. Insights and suggestions of this study would be valuable to mitigate the negative outcomes of cellphone-involved crashes and prevent the crashes caused by cellphone-involved distracted driving in the future.

Fuzheng Xiaozheng prescription exerts anti-hepatocellular carcinoma effects by improving lipid and glucose metabolisms via regulating circRNA-miRNA-mRNA networks.

BACKGROUND: Hepatocellular carcinoma (HCC) is a major threat to human health due to its high lethality. Our previous studies suggested that Fuzheng Xiaozheng prescription (FZXZP), an effective Chinese medicine, demonstrated significant suppressive effects on HCC. However, its underlying mechanism remains largely unclear. PURPOSE: This study aimed to investigate the anti-HCC mechanisms of FZXZP from transcriptomic sequencing based on a holistic perspective. METHODS: Rat HCC model was induced by diethylnitrosamine, and then the model was administered with two doses of FZXZP, high and low. Sodium demethylcantharidate was used as a positive control. Subsequently, microarrays of circRNA, miRNA and mRNA were performed on the blank, model, high and low dose groups, respectively, and the competitive binding mechanisms among them were further analyzed by bioinformatics. Then, the circRNA-miRNA-mRNA networks were constructed to mine the targeted-RNAs of FZXZP in HCC, as well as to explore their potential regulatory mechanisms. Finally, functions and pathways of the FZXZP targeted genes in rat HCC were annotated with GO and KEGG, and qRT-PCR was performed to validate the accuracy of the above analyses in this study. RESULTS: The results showed that FZXZP significantly inhibited the development and progression of HCC in rats, improved the pathological conditions and suppressed the proliferation of HCC cells. Subsequently, after a series of screening, the competing endogenous RNA networks (circRNA-miRNA-mRNA), consisting of 2 circRNAs, 7 miRNAs and 104 mRNAs, were finally established. KEGG and GO analyses of the networks revealed that lipid metabolism related pathways, such as fatty acid metabolism, bile secretion and PPAR pathway, were significantly enriched. In the further hubgene network analysis, in addition to lipid metabolism, aberrant glucose metabolism was found to be ameliorated by G6pc and Pklr in hubgenes. Finally, the qRT-PCR analyses confirmed that the expression tendencies of the above targeted genes were correct and believable in transcriptomic sequencings, and qRT-PCR results of the genes closely related to proliferation, invasion and apoptosis of HCC also indicated the inhibitory effects of FZXZP on HCC obviously. CONCLUSION: FZXZP demonstrated significant anti-HCC effects through improving lipid and glucose metabolism, restoring the metabolic homeostasis of the liver via circRNA-miRNA-mRNA networks.

Nanoparticle-Based Drug Delivery Systems Targeting Tumor Microenvironment for Cancer Immunotherapy Resistance: Current Advances and Applications.

Cancer immunotherapy has shown impressive anti-tumor activity in patients with advanced and early-stage malignant tumors, thus improving long-term survival. However, current cancer immunotherapy is limited by barriers such as low tumor specificity, poor response rate, and systemic toxicities, which result in the development of primary, adaptive, or acquired resistance. Immunotherapy resistance has complex mechanisms that depend on the interaction between tumor cells and the tumor microenvironment (TME). Therefore, targeting TME has recently received attention as a feasibility strategy for re-sensitizing resistant neoplastic niches to existing cancer immunotherapy. With the development of nanotechnology, nanoplatforms possess outstanding features, including high loading capacity, tunable porosity, and specific targeting to the desired locus. Therefore, nanoplatforms can significantly improve the effectiveness of immunotherapy while reducing its toxic and side effects on non-target cells that receive intense attention in cancer immunotherapy. This review explores the mechanisms of tumor microenvironment reprogramming in immunotherapy resistance, including TAMs, CAFs, vasculature, and hypoxia. We also examined whether the application of nano-drugs combined with current regimens is improving immunotherapy clinical outcomes in solid tumors.

Anti-hepatocellular carcinoma efficacy of Fuzheng Xiaozheng prescription and its interventional mechanism studies.

ETHNOPHARMACOLOGICAL RELEVANCE: Fuzheng Xiaozheng prescription (FZXZP), a traditional Chinese medicine, which was derived from the famous decoction, Sanjiasan, in the book of "Wenyilun" in Ming dynasty. Due to its function of invigorating the circulation of blood in Chinese medicine, it was usually used for treating the liver cirrhosis, hepatocellular carcinoma (HCC), etc. Clinical application found that FZXZP exhibited satisfactory therapeutic effects in HCC treatments. However, we still know little about the underlying mechanisms. AIM OF STUDY: In this study, we aim to gain a deeper insight into the inhibiting effects of FZXZP on HCC rats and preliminarily elucidate the underlying intervention effects. MATERIALS AND METHODS: Two doses of FZXZP were adopted to evaluate the therapeutic effects on rat HCC, and then the intervention effects were evaluated from different aspects. High performance liquid chromatography (HPLC) was used for the active compounds prediction in FZXZP. Finally, the mRNA-Seq was conducted to reveal the intervention mechanisms and the mechanisms were further validated by quantitative Real-time PCR (qRT-PCR) and lipid contents analyses. RESULTS: The results showed that FZXZP significantly alleviated the serum biochemical indicators and improved the pathological characteristics of HCC rats. Mechanistically, FZXZP could regulate some lipid related metabolisms, including arachidonic acid, linoleic acid and retinol, as well as improving the steroid hormone biosynthesis, to improve the inflammatory statuses and restoring ability of HCC livers, and these were further confirmed by our following analyses on serum lipid contents and cytokine expressions. In addition, FZXZP could also negatively regulate four extracellular growth factors which could result in the blocking of two cancer-related signaling pathways, Ras/MAPK and Ras/PI3K-Akt. CONCLUSION: Our results suggested that FZXZP demonstrated significant inhibiting effects on rat HCC progresses, and these may be realized by improving the inflammatory statuses and blocking the Ras/MAPK and Ras/PI3K-Akt signaling pathways.

Fuzheng Xiaozheng prescription relieves rat hepatocellular carcinoma through improving anti-inflammation capacity and regulating lipid related metabolisms.

ETHNOPHARMACOLOGICAL RELEVANCE: Fuzheng Xiaozheng prescription (FZXZP) is a traditional Chinese medicine (TCM) that was derived from Sanjiasan, a famous decoction documented in the book of Wenyilun in Ming dynasty. Based on our years' clinic application, FZXZP demonstrated satisfactory therapeutic effects in cirrhosis and hepatocellular carcinoma (HCC) treatments. However, the underlying mechanisms are still largely unknown. AIM OF STUDY: In this study, we aim to systematically evaluate the intervention effects of FZXZP on rat HCC and deeply elucidate the underlying regulative mechanisms on rat HCC. MATERIALS AND METHODS: The HCC rats were induced by using diethylnitrosamine (DEN) and two doses of FZXZP were adopted to treat the HCC rats. Liver phenotype, blood chemistry and liver histopathology were used to evaluate the intervention effects. High performance liquid chromatography (HPLC) was conducted to analyze the components of FZXZP. Finally, miRNA-Seq and mRNA-Seq were performed to investigate the regulative mechanisms of FZXZP on rat HCC and qRT-PCR was carried out to verify the accuracies of the two RNA-Seqs. RESULTS: Results of liver phenotypes, blood chemistry and liver histopathology demonstrated that FZXZP significantly alleviated the liver damage, inhibited the progresses of HCC. Nine potential components were identified from FZXZP, and anti-cancer prediction suggested that almost all of them were reported to show an anti-cancer effect. Mechanistically, FZXZP was found to promote the lipid related metabolisms, improve the anti-inflammation ability by activating PPAR signaling pathway, arachidonic acid metabolism, bile secretion, etc. CONCLUSION: our results suggested that FZXZP significantly alleviated the rat HCC, mechanistically by improving the anti-inflammation ability and promoting the lipid related metabolisms.