Research progress in nano-drug delivery systems based on the characteristics of the liver cancer microenvironment.

The liver cancer has microenvironmental features such as low pH, M2 tumor-associated macrophage enrichment, low oxygen, rich blood supply and susceptibility to hematotropic metastasis, high chemokine expression, enzyme overexpression, high redox level, and strong immunosuppression, which not only promotes the progression of the disease, but also seriously affects the clinical effectiveness of traditional therapeutic approaches. However, nanotechnology, due to its unique advantages of size effect and functionalized modifiability, can be utilized to develop various responsive nano-drug delivery system (NDDS) by using these characteristic signals of the liver cancer microenvironment as a source of stimulation, which in turn can realize the intelligent release of the drug under the specific microenvironment, and significantly increase the concentration of the drug at the target site. Therefore, researchers have designed a series of stimuli-responsive NDDS based on the characteristics of the liver cancer microenvironment, such as hypoxia, weak acidity, and abnormal expression of proteases, and they have been widely investigated for improving anti-tumor therapeutic efficacy and reducing the related side effects. This paper provides a review of the current application and progress of NDDS developed based on the response and regulation of the microenvironment in the treatment of liver cancer, compares the effects of the microenvironment and the NDDS, and provides a reference for building more advanced NDDS.

High-responsivity and high-speed black phosphorus photodetectors integrated with proton exchanged thin-film lithium niobate waveguides.

We present a high-performance broadband (450-1550 nm) black phosphorus photodetector based on a thin-film lithium niobate waveguide. The waveguides are fabricated by the proton exchange method with flat surfaces, which reduces the stress and deformation of two-dimensional materials. At a wavelength of 1550 nm, the photodetector simultaneously achieves a high responsivity and wide bandwidth, with a responsivity as high as 147 A/W (at an optical power of 17 nW), a 3-dB bandwidth of 0.86 GHz, and a detectivity of 3.04 × 1013 Jones. Our photodetector exhibits one of the highest responsivity values among 2D material-integrated waveguide photodetectors.

Development of a UPLC-MS/MS method for simultaneous therapeutic drug monitoring of anti-hepatocellular carcinoma drugs and analgesics in human plasma.

In hepatocellular carcinoma treatment, sorafenib, oxaliplatin, 5-fluorouracil, capecitabine, lenvatinib, and donafenib are first-line drugs; regorafenib, apatinib, and cabozantinib are second-line drugs; and oxycodone, morphine, and fentanyl are commonly used analgesics. However, the high degree of inter- and intra-individual variability in the efficacy and toxicity of these drugs remains an urgent issue. Therapeutic drug monitoring (TDM) is the most reliable technical means for evaluating drug safety and efficacy. Therefore, we developed an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for simultaneous TDM of three chemotherapy drugs (5-fluorouracil, oxaliplatin, and capecitabin), six targeted drugs (sorafenib, donafenib, apatinib, cabozantinib, regorafenib, and lenvatinib), and three analgesics (morphine, fentanyl, and oxycodone). We extracted 12 analytes and isotope internal standards (ISs) from plasma samples by magnetic solid phase extraction (mSPE) and separated them using a ZORBAX Eclipse Plus C18 column with water containing 0.1% formic acid and methanol containing 0.1% formic acid as the mobile phase. The analytical performance of our method in terms of sensitivity, linearity, specificity, carryover, precision, limit of quantification, matrix effect, accuracy, dilution integrity, extraction recovery, stability, and crosstalk of all the analytes under different conditions met all the criteria stipulated by the guidelines of the Chinese Pharmacopoeia and U.S. Food and Drug Administration. The response function was estimated at 10.0-10 000.0 ng/mL for sorafenib, donafenib, apatinib, cabozantinib, regorafenib, and lenvatinib, and 20.0-20 000.0 ng/mL for 5-fluorouracil, oxaliplatin, capecitabin, morphine, fentanyl, and oxycodone, with a correlation of > 0.9956 for all compounds. The precision and accuracy of all analytes were < 7.21% and 5.62%, respectively. Our study provides empirical support for a simple, reliable, specific, and suitable technique for clinical TDM and pharmacokinetics.

Tunable Photoluminescence Properties of Cotton Fiber With Gradually Changing Crystallinity.

The alkali mercerizing process of semicrystalline cotton fiber (CF) is widely used in the printing and dyeing industry. The crystallinity change in the mercerizing process has been studied and certain laws have been obtained, but there is still a certain distance between the theoretical research results and the practical applications. CF is almost composed of cellulose, combined with the photoluminescence (PL) phenomenon of cellulose; herein, the varying crystallinity is correlated with its PL behavior after being treated with different concentrations of NaOH. In line with the characteristics of nonconventional luminogens, CF enjoys excitation-dependent emission and persistent room temperature phosphorescence (p-RTP) behavior. The emission spectra of all samples under the same excitation wavelength indicate that the change of CF crystallinity has a significant impact on its fluorescence and p-RTP emission. As the concentration of NaOH increases, the varying trend of quantum efficiency (QY) is consistent with the changed crystallinity of CF. Interestingly, the lifetime of p-RTP is exactly the opposite of the crystallinity change law. Clustering-triggered emission (CTE), crystallization-Induced Phosphorescence (CIP) mechanism, and the swelling due to hydrated sodium ions can reasonably explain these interesting photophysical processes, which also can be supported by theoretical calculations. The above studies have basically clarified the inherent law between the crystalline change of CF and the PL emission behavior during the alkali treatment process, which can be used as a theoretical reference for real-time monitoring of CF crystallinity changes using the spectral method in the actual cotton mercerizing process.

Tunable Photoluminescence Properties of Microcrystalline Cellulose with Gradually Changing Crystallinity and Crystal Form.

Nonconventional luminogens with persistent room temperature phosphoresce (p-RTP) are attracting increasing attention owing to their momentous significance and diverse technical applications in optoelectronic and biomedical. So far, the p-RTP emission of some amorphous powders or single crystals has been studied in depth. The p-RTP emission of amorphous and fully crystalline states and their emission properties are widely divergent, while the difference of their p-RTP emission mechanism is still controversial. The relevance between crystallinity change and p-RTP properties is rarely studied. Furthermore, there is almost no research on the photoluminescence (PL) property change and emission mechanism under the crystal form transformation of semi-crystalline polymer. Herein, microcrystalline cellulose (MCC) is chosen as a model compound to explore its crystallinity and the change in luminescence during the crystal form transformation to make up for this gap. By precisely adjusting the crystallinity and crystal cellulose conversion of MCC, the changing trend of quantum efficiency, and p-RTP lifetime is consistent with the change of crystallinity, and the cellulose I may be more beneficial to PL emission than cellulose II. Clustering-triggered emission mechanism can reasonably explain these interesting photophysical processes, which also can be supported by single-crystal analysis and theoretical calculations.

Lactobacillus delbrueckii subsp. bulgaricus KLDS 1.0207 Exerts Antimicrobial and Cytotoxic Effects in vitro and Improves Blood Biochemical Parameters in vivo Against Notable Foodborne Pathogens.

Globally, foodborne diseases (FBDs) result in millions of sicknesses and deaths annually. Cumulative evidence suggests that the use of probiotic lactic acid bacteria (LAB) strains could be a viable alternative in inhibiting the activities of foodborne pathogens. This study aims to evaluate the in vitro antimicrobial, cytotoxic, and tolerance levels of Lactobacillus bulgaricus KLDS 1.0207 against two notable foodborne pathogens - Escherichia coli ATCC25922 and Staphylococcus aureus ATCC25923. Afterward, a 48 BALB/c mice-trial was used to assess its ameliorative effects on weight and serum biochemical parameters. Results showed that the cell-free supernatant (CFS) of this strain significantly inhibited both pathogens, but these effects were abolished at pH 6.5 and 7.0 (P < 0.05). Also, 6.96 ± 0.02 log CFU mL-1 of L. bulgaricus KLDS 1.0207 was still viable after three hours in simulated gastric juice and at pH 3.0, indicating that this strain was a potential probiotic candidate. Also, inflammatory activities in RAW264.7 cells were significantly inhibited using 109 CFU mL-1 of L. bulgaricus KLDS 1.0207 cells (P < 0.05). Significant weight losses were also prevented in the T LBSA (from 19.42 ± 1.04 to 19.55 ± 0.55 g) and T LBEC (from 22.86 ± 0.90 to 14.77 ± 9.86 g) groups compared to their respective model groups (T SA - from 21.65 ± 1.80 to 20.14 ± 1.84, and T EC - from 21.45 ± 0.82 to 14.45 ± 9.70 g). Besides, there was a slight weight gain in the S. aureus prevention group (T LBSA ) compared to the model group (T SA ). Serum biochemical analyses revealed that the total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), and some mineral levels were markedly increased by S. aureus and E. coli administrations but were reversed to normalcy in both prevention groups (T LBSA and T LBEC ). Interestingly, high-density lipoprotein (HDL) levels, which were initially disrupted in the model groups, were restored in the prevention groups (T LBSA and T LBEC ). This study presents L. bulgaricus KLDS 1.0207 as a promising probiotic candidate with antimicrobial, anti-inflammatory, acid, and bile tolerant and lipid-regulating applications. It also gives valuable insights for targeted future in vivo treatment and prevention studies involving other probiotic LAB candidates. Future in vivo studies elucidating specific mechanisms behind the in vitro antimicrobial, cytotoxic, and in vivo ameliorative effects are warranted.

DNA methyltransferase expression in triple-negative breast cancer predicts sensitivity to decitabine.

Triple-negative breast cancer (TNBC) is a heterogeneous disease with poor prognosis that lacks targeted therapies, especially in patients with chemotherapy-resistant disease. Since DNA methylation-induced silencing of tumor suppressors is common in cancer, reversal of promoter DNA hypermethylation by 5-aza-2'-deoxycytidine (decitabine), an FDA-approved DNA methyltransferase (DNMT) inhibitor, has proven effective in treating hematological neoplasms. However, its antitumor effect varies in solid tumors, stressing the importance of identifying biomarkers predictive of therapeutic response. Here, we focused on the identification of biomarkers to select decitabine-sensitive TNBC through increasing our understanding of the mechanism of decitabine action. We showed that protein levels of DNMTs correlated with response to decitabine in patient-derived xenograft (PDX) organoids originating from chemotherapy-sensitive and -resistant TNBCs, suggesting DNMT levels as potential biomarkers of response. Furthermore, all 3 methytransferases, DNMT1, DNMT3A, and DNMT3B, were degraded following low-concentration, long-term decitabine treatment both in vitro and in vivo. The DNMT proteins could be ubiquitinated by the E3 ligase, TNF receptor-associated factor 6 (TRAF6), leading to lysosome-dependent protein degradation. Depletion of TRAF6 blocked decitabine-induced DNMT degradation, conferring resistance to decitabine. Our study suggests a potential mechanism of regulating DNMT protein degradation and DNMT levels as response biomarkers for DNMT inhibitors in TNBCs.

Backtracked and paused transcription initiation intermediate of Escherichia coli RNA polymerase.

Initiation is a highly regulated, rate-limiting step in transcription. We used a series of approaches to examine the kinetics of RNA polymerase (RNAP) transcription initiation in greater detail. Quenched kinetics assays, in combination with gel-based assays, showed that RNAP exit kinetics from complexes stalled at later stages of initiation (e.g., from a 7-base transcript) were markedly slower than from earlier stages (e.g., from a 2- or 4-base transcript). In addition, the RNAP-GreA endonuclease accelerated transcription kinetics from otherwise delayed initiation states. Further examination with magnetic tweezers transcription experiments showed that RNAP adopted a long-lived backtracked state during initiation and that the paused-backtracked initiation intermediate was populated abundantly at physiologically relevant nucleoside triphosphate (NTP) concentrations. The paused intermediate population was further increased when the NTP concentration was decreased and/or when an imbalance in NTP concentration was introduced (situations that mimic stress). Our results confirm the existence of a previously hypothesized paused and backtracked RNAP initiation intermediate and suggest it is biologically relevant; furthermore, such intermediates could be exploited for therapeutic purposes and may reflect a conserved state among paused, initiating eukaryotic RNA polymerase II enzymes.