Enantioselectivity regulation of antibody against chiral herbicide metolachlor based on interaction at chiral center.

Enantioselective antibodies have emerged as great potential biomaterials in the fields of immunoassays and chiral separation. However, cross-reactivity of antibodies to the distomer may severely restrict the application. Comprehending the interaction mechanism between antibodies and enantiomers could be beneficial to produce superior enantioselective antibodies. In this study, a pair of recombinant antibodies (RAbs) against metolachlor enantiomers at chiral carbon (αSS-MET and αSR-MET) were generated and characterized. The αSS-MET-RAb and αSR-MET-RAb showed comparable sensitivity and specificity to the parental monoclonal antibodies by icELISA, with IC50 values of 3.45 and 223.77 ng/mL, respectively. Moreover, the complex structures of RAbs and corresponding eutomer were constructed and analyzed, and site-specific mutagenesis was utilized to verify the reliability of the enantioselective mechanism elucidated. It demonstrated that the strength of the interaction between the chiral center region of eutomer and the antibody was the key factor for the enantioselectivity of antibody. Increasing this interaction could limit the conformational adjustment of the distomer in a specific chiral recognition cavity, thus decreasing the affinity of the antibody to the distomer. This work provided the in-depth analysis of enantioselective mechanism for two RAbs and paved the way to regulate antibody enantioselective performance for immunoassays of chiral compounds.

Highly sensitive and selective fluorescent "turn-on" sensor for Ag+ detection using MAPbBr3@PCN-221(Fe): An efficient Ag+-bridged energy transfer from perovskite to MOF.

Metal ion-induced water pollution is attracting increasing public attention. Perovskite quantum dots and metal-organic frameworks (MOFs), owing to their outstanding properties, hold promise as ideal probes for detecting metal ions. In this study, a composite material, MAPbBr3@PCN-221(Fe), was prepared by encapsulating MAPbBr3 quantum dots with PCN-221(Fe), demonstrating high chemical stability and good reusability. The composite material shows a sensitive fluorescence turn-on signal in the presence of silver ions. The fluorescence intensity of the composite material exhibits a linear relationship with the concentration of Ag+ in the solution, with a low detection limit of 8.68 µM. Moreover, the fluorescence signal exhibits a strong selectivity for Ag+, enabling the detection of Ag+ concentration. This fluorescence turn-on signal originates from the Ag+-bridged energy transfer from the conductive band of MAPbBr3 to the excited state of the MOF, which is directly proportional to the concentration of silver ions. Simultaneously, this finding may open up a new possibility in artificial controlled energy transfer from perovskite to MOF for future development.

Integrated influence of sulfide modification on the reactivity of nanoscale zero-valent iron towards decabromodiphenyl ether under an electromagnetic field.

Individual application of sulfide modification and electromagnetic field (EMF) can enhance the reactivity of nanoscale zero-valent iron (nZVI), yet the potential of both in combination is not clear. This work found that the reactivity of nZVI towards decabromodiphenyl ether was significantly enhanced by the combined effect of sulfidation and EMF. The specific reaction rate constant of nZVI increased by 7 to 10 times. A series of characterization results revealed that the sulfidation level not only affects the inherent reactivity but also the magnetic-induced heating (MIH) and corrosion (MIC) of nZVI. These collectively influence the degradation efficiency of nZVI under EMF. Sulfidation generally diminished the MIH effect. The low degree of sulfidation (S/Fe = 0.1) slightly reduced the MIC effect by 21.4%. However, the high degree of sulfidation (S/Fe = 0.4) led to significantly enhanced MIC effect by 107.1%. For S/Fe = 0.1 and 0.4, the overall enhancement in the reactivity resulting from EMF was alternately dominated by the contributions of MIH and MIC. This work provides valuable insights into the MIH and MIC effects about the sulfidation level of nZVI, which is needed for further exploration and optimization of this combined technology.

Adaptive plasticity of natural interleukin-35-induced regulatory T cells (Tr35) that are required for T-cell immune regulation.

Background: IL-35 potently inhibits immune responses both in vivo and in vitro. However, the specific characteristics of IL-35-producing cells, including their developmental origin, cellular phenotype, and function, are unknown. Methods: By using a novel IL-35 reporter mouse (Ebi3-Dre-Thy1.1) and double transgenic fate-mapping reporter mice (35EbiT-Rosa26-rox-tdTomato reporter mice or Foxp3 fate-mapping system), we tracked and analyzed the differentiation and developmental trajectories of Tr35 cells in vivo. And then we investigated the therapeutic effects of OVA-specific Tr35 cells in an OVA-induced allergic airway disease model. Results: We identified a subset of cells, denoted Tr35 cells, that secrete IL-35 but do not express Foxp3. These cells have high expression of molecules associated with T-cell activation and can inhibit T-cell proliferation in vitro. Our analyses showed that Tr35 cells are a distinct subpopulation of cells that are independent of Tr1 cells. Tr35 cells exhibit a unique gene expression profile and tissue distribution. The presence of Thy1.1 (Ebi3) expression in Tr35 cells indicates their active secretion of IL-35. However, the proportion of ex-Tr35 cells (Thy1.1-) is significantly higher compared to Tr35 cells (Thy1.1+). This suggests that Tr35 cells possess the ability to regulate IL-35 expression rapidly in vivo. Tr35 cells downregulated the expression of the inflammatory cytokines IL-4, IFN-γ and IL-17A. However, once Tr35 cells lost IL-35 expression and became exTr35 cells, the expression of inflammatory cytokines was upregulated. Importantly, our findings indicate that Tr35 cells have therapeutic potential. In an OVA-induced allergic airway disease mouse model, Tr35 cell reinfusion significantly reduced airway hyperresponsiveness and histopathological airway and lung inflammation. Conclusions: We have identified a subset of Tregs, Tr35 cells, that are distinct from Tr1 cells. Tr35 cells can dynamically regulate the secretion of inflammatory cytokines by controlling IL-35 expression to regulate inflammatory immune responses.

DDX39B protects against sorafenib-induced ferroptosis by facilitating the splicing and cytoplasmic export of GPX4 pre-mRNA in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the main histological subtype of primary liver cancer and remains one of the most common solid malignancies globally. Ferroptosis was recently defined as an iron-catalyzed form of regulated necrosis. Because cancer cells exhibit higher iron requirements than noncancer cells, treatment with ferroptosis-inducing compounds may be a feasible strategy for cancer therapy. However, cancer cells develop acquired resistance to evade ferroptosis, and the mechanisms responsible for ferroptosis resistance are not fully clarified. In the current study, we reported that DDX39B was downregulated during sorafenib-induced ferroptosis in a dose- and time-dependent manner. Exogenous introduction of DDX39B ensured the survival of HCC cells upon exposure to sorafenib, while the opposite phenomenon was observed in DDX39B-silenced HCC cells. Mechanistically, we demonstrated that DDX39B increased GPX4 levels by promoting the splicing and cytoplasmic translocation of GPX4 pre-mRNA, which was sufficient to detoxify sorafenib-triggered excess lipid ROS production, lipid peroxidation accumulation, ferrous iron levels, and mitochondrial damage. Inhibition of DDX39B ATPase activity by CCT018159 repressed the splicing and cytoplasmic export of GPX4 pre-mRNA and synergistically assisted sorafenib-induced ferroptotic cell death in HCC cells. Taken together, our data uncover a novel role for DDX39B in ferroptosis resistance by modulating the maturation of GPX4 mRNA via a posttranscriptional approach and suggest that DDX39B inhibition may be a promising therapeutic strategy to enhance the sensitivity and vulnerability of HCC cells to sorafenib.

Capsaicin reverses cisplatin resistance in tongue squamous cell carcinoma by inhibiting the Warburg effect and facilitating mitochondrial-dependent apoptosis via the AMPK/AKT/mTOR axis.

Cisplatin is commonly used for the chemotherapy of tongue squamous cell carcinoma (TSCC); however, adverse side effects and drug resistance impact its therapeutic efficacy. Capsaicin is an active ingredient in chili peppers that exerts antitumor effects, whether it exerts antitumor effects on cisplatin-resistant cells remains unknown. Therefore, in this study, we investigated the effect of capsaicin on cisplatin resistance in TSCC cells and explored the underlying mechanisms. A cisplatin-resistant TSCC cell line was established by treated with increasing cisplatin concentrations. Combined treatment with cisplatin and capsaicin decreased the glucose consumption and lactate dehydrogenase activity and increased the adenosine triphosphate production both in vitro and in vivo, suggesting the inhibition of the Warburg effect. Moreover, this combined treatment induced cell apoptosis and significantly upregulated the levels of proapoptotic proteins, such as Bax, cleaved caspase-3, -7, and -9, and apoptosis-inducing factor. In contrast, levels of the antiapoptotic protein, Bcl-2, were downregulated. Additionally, LKB1 and AMPK activities were stimulated, whereas those of AKT and mTOR were suppressed. Notably, AMPK knockdown abolished the inhibitory effects of capsaicin and cisplatin on the AKT/mTOR signaling pathway and Warburg effect. Overall, combined treatment with capsaicin and cisplatin reversed cisplatin resistance by inhibiting the Warburg effect and facilitating mitochondrial-dependent apoptosis via the AMPK/AKT/mTOR axis. Our findings suggest combination therapy with capsaicin and cisplatin as a potentially novel strategy and highlight capsaicin as a promising adjuvant drug for TSCC treatment.

Circ_0006949 as a potential non-invasive diagnosis biomarker promotes the proliferation of NSCLC cells via miR-4673/GLUL axis.

The 5-year survival for non-small cell lung cancer (NSCLC) remains <20 %, primarily due to the early symptoms of lung cancer are inconspicuous. Prompt identification and medical intervention could serve as effective strategies for mitigating the death rate. We therefore set out to identify biomarkers to help diagnose NSCLC. CircRNA microarray and qRT-PCR reveal that sputum circ_0006949 is a potential biomarker for the early diagnosis and therapy of NSCLC, which can enhance the proliferation and clone formation, regulate the cell cycle, and accelerate the migration and invasion of NSCLC cells. Circ_0006949 and miR-4673 are predominantly co-localized in the cytoplasm of NSCLC cell lines and tissues; it upregulates GLUL by adsorption of miR-4673 through competing endogenous RNAs mechanism. The circ_0006949/miR-4673/GLUL axis exerts pro-cancer effects in vitro and in vivo. Circ_0006949 can boost GLUL catalytic activity, and they are highly expressed in NSCLC tissues and correlate with poor prognosis. In summary, circ_0006949 is a potential biomarker for the early diagnosis and therapy of NSCLC. This novel sputum circRNA is statistically more predictive than conventional serum markers for NSCLC diagnosis. Non-invasive detection of patients with early-stage NSCLC using sputum has shown good potential for routine diagnosis and possible screening.

Two-dimensional binary phase gratings for zero-order and high-order diffraction suppression.

A two-dimensional binary phase grating is proposed in this paper. Unlike a conventional transmission grating, in theory, the proposed phase grating can simultaneously eliminate the zero- and high-order diffraction along certain axes on the image plane, forming a pure sinusoidal transmission modulation that leaves only the first-order diffraction. The first-ever, to the best of our knowledge, theoretical model for achieving sinusoidal transmission modulation is suggested in this paper; then the theoretical calculation and experiment results are displayed to investigate the physical mechanism of the proposed grating. Moreover, the manipulation on the arrangement of grating design can disperse or concentrate the diffraction energy at a specific axis. Finally, almost first-order-only diffraction is achieved on a single axis by introducing random changes to certain geometrical parameters of the two-dimensional binary phase grating. Our work provides potential applications in optical science and engineering fields.

Stable Q-switched and femtosecond mode-locked erbium-doped fiber laser based on a CuSe nanosheets saturable absorber.

Stable Q-switched and femtosecond mode-locked erbium-doped fiber laser (EDFL) have been achieved using CuSe nanosheets as novel saturable absorber (SA), where the CuSe nanosheets were prepared by a hydrothermal method. The nonlinear optical properties of CuSe nanosheets were measured using an Z-scan setup, revealing nonlinear absorption coefficients of -3.67 ± 0.22 cm GW-1 at 1560 nm. The prepared CuSe nanosheets were mixed with polyvinyl alcohol (PVA) to obtain a CuSe-PVA SA with a modulation depth of 3.8 ± 0.13%, and it was utilized to realize a Q-switched EDFL, obtaining the narrowest pulse duration of 1.29 µs and the maximum output power of 5.96 mW, which corresponds to a pulse energy of up to 103.7 nJ. In addition, CuSe nanosheets were deposited on a D-shaped fiber (DSF) to fabricate a CuSe-DSF SA with a modulation depth of 5.6 ± 0.17%, and it was utilized to realize a mode-locked EDFL. The mode-locked EDFL demonstrated a low threshold of only 42 mW, a pulse duration of 740 fs, and a maximum output power of 9.7 mW. Meanwhile, it exhibited a high signal-to-noise ratio of 72 dB. To the best of our knowledge, this is the first time of CuSe nanosheets as SA in EDFL. The results demonstrate that CuSe nanosheets are a highly promising nonlinear optical material with great potential for applications in ultrafast photonics.

Optical feedback frequency locking: impact of directly reflected field and responding strategies.

The challenges presented by the directly reflected field in optical feedback cavity-enhanced spectroscopy systems serve as substantial obstacles, introducing additional complexity to existing systems and compromising their sensitivity, as the underlying mechanisms of its adverse effects remain not fully understood. This study aims to address this issue by introducing a comprehensive analytical model. Additionally, frequency locking can be achieved by decreasing the feedback rate, the laser's linewidth enhancement factor, and the directly reflected field, and by increasing the refractive index of the gain medium, the length of the laser's resonant cavity, the electric field reflectivity of the laser's output facet, and the resonant field. These parameters can affect the feedback coupling rate pre-factor, and for a resonant cavity with a length of 0.394 m, optical feedback can only be established when the feedback coupling rate pre-factor is less than 1.05 × 109. Through experimental validation, we successfully confirm the effectiveness of the proposed solution in eliminating the detrimental effects of the directly reflected field. Importantly, this suppression is achieved without compromising other aspects of the system's performance. The research findings not only offer the potential to optimize various cavity-enhanced spectroscopy systems that rely on optical feedback but also show promising applications in advancing the development of high-purity spectrum diode lasers utilizing optical feedback from an external high-finesse cavity.

Improving vitrification efficiency of human in vitro matured oocytes by the addition of LEA proteins.

STUDY QUESTION: Can the addition of late embryogenesis-abundant (LEA) proteins as a cryoprotective agent during the vitrification cryopreservation of in vitro matured oocytes enhance their developmental potential after fertilization? SUMMARY ANSWER: LEA proteins improve the developmental potential of human in vitro matured oocytes following cryopreservation, mostly by downregulating FOS genes, reducing oxidative stress, and inhibiting the formation of ice crystals. WHAT IS KNOWN ALREADY: Various factors in the vitrification process, including cryoprotectant toxicity, osmotic stress, and ice crystal formation during rewarming, can cause fatal damage to oocytes, thereby affecting the oocytes developmental potential and subsequent clinical outcomes. Recent studies have shown that LEA proteins possess high hydrophilicity and inherent stress tolerance, and can reduce low-temperature damage, although the molecular mechanism it exerts protective effects is still unclear. STUDY DESIGN, SIZE, DURATION: Two LEA proteins extracted and purified by us were added to solutions for vitrification-warming of oocytes at concentrations of 10, 100, and 200 µg/mL, to determine the optimal protective concentration for each protein. Individual oocyte samples were collected for transcriptomic analysis, with each group consisting of three sample replicates. PARTICIPANTS/MATERIALS, SETTING, METHODS: Immature oocytes were collected from patients who were undergoing combined in vitro fertilization (IVF) treatment and who had met the designated inclusion and exclusion criteria. These oocytes underwent in vitro maturation (IVM) culture for experimental research. A fluorescence microscope was used to detect the levels of mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and calcium in the mitochondria of vitrified-warmed human oocytes treated with different concentrations of LEA proteins, and the protective effect of the protein on mitochondrial function was assessed. The levels of intracellular ice recrystallization inhibition (IRI) in human oocytes after vitrification-warming were characterized by the cryomicroscope, to determine the LEA proteins inhibitory effect on recrystallization. By analyzing transcriptome sequencing data to investigate the potential mechanism through which LEA proteins exert their cryoprotective effects. MAIN RESULTS AND THE ROLE OF CHANCE: The secondary structures of AfrLEA2 and AfrLEA3m proteins were shown to consist of a large number of α-helices and the proteins were shown to be highly hydrophilic, in agreement with previous reports. Confocal microscopy results showed that the immunofluorescence of AfrLEA2-FITC and AfrLEA3m-FITC-labeled proteins appeared to be extracellular and did not penetrate the cell membrane compared with the fluorescein isothiocyanate (FITC) control group, indicating that both AfrLEA2 and AfrLEA3m proteins were extracellular. The group treated with 100 µg/mL AfrLEA2 or AfrLEA3m protein had more uniform cytoplasmic particles and fewer vacuoles compared to the 10 and 200 µg/mL groups and were closest to the fresh group. In the 100 µg/mL groups, MMPs were significantly higher while ROS and calcium levels were significantly lower than those in the control group and were closer to the levels observed in fresh oocytes. Meanwhile, 100 µg/mL of AfrLEA2 or AfrLEA3m protein caused smaller ice crystal formation in the IRI assay compared to the control group treated with dimethylsulphoxide (DMSO) and ethylene glycol (EG); thus, the recrystallization inhibition was superior to that with the conventional cryoprotectants DMSO and EG. Further results revealed that the proteins improved the developmental potential of human oocytes following cryopreservation, likely by downregulating FOS genes and reducing oxidative stress. LIMITATIONS, REASONS FOR CAUTION: The in vitro-matured metaphase II (IVM-MII) oocytes used in the study, due to ethical constraints, may not accurately reflect the condition of MII oocytes in general. The AfrLEA2 and AfrLEA3m proteins are recombinant proteins and their synthetic stability needs to be further explored. WIDER IMPLICATIONS OF THE FINDINGS: LEA proteins, as a non-toxic and effective cryoprotectant, can reduce the cryoinjury of oocytes during cryopreservation. It provides a new promising method for cryopreservation of various cell types. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Key Research and Development Program of China (2022YFC2703000) and the National Natural Science Foundation of China (52206064). The authors declare no competing interest. TRIAL REGISTRATION NUMBER: N/A.

Regulation of electron density redistribution for efficient alkaline hydrogen evolution reaction and overall water splitting.

The rational design of morphology and heterogeneous interfaces for non-precious metal electrocatalysts is crucial in electrochemical water decomposition. In this paper, a bifunctional electrocatalyst (Ni/NiFe LDH), which coupling nickel with nickel-iron layer double hydroxide (NiFe LDH), is synthesized on carbon cloth. At current density of 10 mA cm-2, the Ni/NiFe LDH exhibits a low hydrogen evolution reaction (HER) overpotential of only 36 mV due to the accelerated electrolyte penetration, which is caused by superhydrophilic interface. Moreover, an alkaline electrolyzer is formed and provide a current density of 10 mA cm-2 with a voltage of only 1.49 V. It is confirmed by the density functional theory (DFT) that electron from the Ni layer is transferred to NiFe LDH layer, redistributing the local electron density around the heterogeneous phase interface. Thus, the Gibbs free energy for hydrogen adsorption is optimized. This work provides a promising strategy for the rational regulation of electrons at heterogeneous interfaces and the synthesis of flexible electrocatalysts.

MXene/TPU Hybrid Fabrics Enable Smart Wound Management and Thermoresponsive Drug Delivery.

Thermoresponsive wound dressings with real-time monitoring and on-demand drug delivery have gained significant attention recently. However, such smart systems with stable temperature adjustment and drug release control are still lacking. Here, a novel smart fabric is designed for wound management with thermoresponsive drug delivery and simultaneously temperature monitoring. The triple layers of the fabrics are composed of the drug-loaded thermoresponsive nanofiber film, the MXene-optimized joule heating film, and the FPCB control chip. The precise and stable temperature stimulation can be easily achieved by applying a low voltage (0-4 V) to the heating film, achieving the temperature control ranging from 25 to 130 °C. And the temperature of the wound region can be monitored and adjusted in real time, demonstrating an accurate and low-voltage joule heating capability. Based on that, the drug-loaded film achieved precise thermoresponsive drug release and obtained significant antibacterial effects in vitro. The in vivo experiments also proved the hybrid fabric system with a notable antibacterial effect and accelerated wound healing process (about 30% faster than the conventional gauze group).

The Identification of a Novel Nucleomodulin MbovP467 of Mycoplasmopsis bovis and Its Potential Contribution in Pathogenesis.

Mycoplasmopsis bovis is a causative agent of crucial diseases in both dairy and beef cattle leading to substantial economic losses. However, limited control measures for M. bovis-related diseases exist due to a lack of understanding about the virulence factors of this pathogen, a common challenge in mycoplasma research. Consequently, this study aimed to characterize a novel nucleomodulin as a virulence-related factor of M. bovis. Employing bioinformatic tools, we initially predicted MbovP467 to be a secreted protein with a nuclear localization signal based on SignalP scores and the cNLS (Nuclear Localization Signal) Mapper, respectively. Subsequently, the MbovP467 gene was synthesized and cloned into a pEGFP plasmid with EGFP labeling to obtain a recombinant plasmid (rpEGFP-MbovP467) and then was also cloned in pET-30a with a consideration for an Escherichia coli codon bias and expressed and purified for the production of polyclonal antibodies against the recombinant MbovP467 protein. Confocal microscopy and a Western blotting assay confirmed the nuclear location of MbovP467 in bovine macrophages (BoMacs). RNA-seq data revealed 220 up-regulated and 20 down-regulated genes in the rpEGFP-MbovP467-treated BoMac group compared to the control group (pEGFP). A GO- and KEGG-enrichment analysis identified associations with inflammatory responses, G protein-coupled receptor signaling pathways, nuclear receptor activity, sequence-specific DNA binding, the regulation of cell proliferation, IL-8, apoptotic processes, cell growth and death, the TNF signaling pathway, the NF-κB signaling pathway, pathways in cancer, and protein families of signaling and cellular processes among the differentially expressed up-regulated mRNAs. Further experiments, investigating cell viability and the inflammatory response, demonstrated that MbovP467 reduces BoMac cell viability and induces the mRNA expression of IL-1ß, IL-6, IL-8, TNF-α, and apoptosis in BoMac cells. Further, MbovP467 increased the promoter activity of TNF-α. In conclusion, this study identified a new nucleomodulin, MbovP467, for M. bovis, which might have an important role in M. bovis pathogenesis.

Discovery of Small Molecule Interleukin 17A Inhibitors with Novel Binding Mode and Stoichiometry: Optimization of DNA-Encoded Chemical Library Hits to In Vivo Active Compounds.

Dysregulation of IL17A drives numerous inflammatory and autoimmune disorders with inhibition of IL17A using antibodies proven as an effective treatment. Oral anti-IL17 therapies are an attractive alternative option, and several preclinical small molecule IL17 inhibitors have previously been described. Herein, we report the discovery of a novel class of small molecule IL17A inhibitors, identified via a DNA-encoded chemical library screen, and their subsequent optimization to provide in vivo efficacious inhibitors. These new protein-protein interaction (PPI) inhibitors bind in a previously undescribed mode in the IL17A protein with two copies binding symmetrically to the central cavities of the IL17A homodimer.

Low field controllable continuous spin switching in the thulium-ytterbium single crystal.

We report the spin reorientation transition (SRT) and the low field controllable continuous spin switching (SSW) of the Tm0.75Yb0.25FeO3 (TYFO) single crystal in this study. The SRT, characterized by the transition from Γ2(Fx, Cy, Gz)-Γ4(Gx, Ay, Fz), occurs within the temperature range of 20-27 K. Under an external magnetic field of 50 Oe, the SSW occurs along the c-axis at approximately 98 K due to the reversal of Tm3+ magnetic moment induced by the magnetic coupling change between Tm3+ and Fe3+, transitioning from a parallel to an antiparallel alignment. Notably, a continuous SSW is observed along the a-axis at low temperatures, which has not been previously reported in rare earth orthoferrites. This unique behavior can be easily manipulated by low magnetic fields within the temperature range of 2-20 K. Both the spin reorientation transition and spin switching phenomena in the TYFO single crystal arise from interactions between rare earth ions and iron ions and can be effectively regulated by applied low magnetic fields, making it a promising material for low-field spin devices.

Nanomaterials in crossroad of autophagy control in human cancers: Amplification of cell death mechanisms.

Cancer is the result of genetic abnormalities that cause normal cells to grow into neoplastic cells. Cancer is characterized by several distinct features, such as uncontrolled cell growth, extensive spreading to other parts of the body, and the ability to resist treatment. The scientists have stressed the development of nanostructures as novel therapeutic options in suppressing cancer, in response to the emergence of resistance to standard medicines. One of the specific mechanisms with dysregulation during cancer is autophagy. Nanomaterials have the ability to specifically carry medications and genes, and they can also enhance the responsiveness of tumor cells to standard therapy while promoting drug sensitivity. The primary mechanism in this process relies on autophagosomes and their fusion with lysosomes to break down the components of the cytoplasm. While autophagy was initially described as a form of cellular demise, it has been demonstrated to play a crucial role in controlling metastasis, proliferation, and treatment resistance in human malignancies. The pharmacokinetic profile of autophagy modulators is poor, despite their development for use in cancer therapy. Consequently, nanoparticles have been developed for the purpose of delivering medications and autophagy modulators selectively and specifically to the cancer process. Furthermore, several categories of nanoparticles have demonstrated the ability to regulate autophagy, which plays a crucial role in defining the biological characteristics and response to therapy of tumor cells.

Chemo-Enzymatic Strategy for the Efficient Synthesis of Steroidal Drugs with 10α-Methyl Group and a Side Chain at C17-Position from Biorenewable Phytosterols.

Steroidal pharmaceuticals with a 10α-methyl group or without the methyl group at C10-position are important medicines, but their synthesis is quite challenging, due to that the natural steroidal starting materials usually have a 10ß-methyl group which is difficult to be inverted to 10α-methyl group. In this study, 3-((1R,3aS,4S,7aR)-1-((S)-1-hydroxypropan-2-yl)-7a-methyl-5-oxooctahydro-1H-inden-4-yl) propanoic acid (HIP-IPA, 2e) was demonstrated as a valuable intermediate for the synthesis of this kind of active pharmaceutical ingredients (APIs) with a side chain at C17-position. Knockout of a ß-hydroxyacyl-CoA dehydrogenase gene and introduction of a sterol aldolase gene into the genetically modified strains of Mycobacterium fortuitum (ATCC 6841) resulted in strains N13Δhsd4AΩthl and N33Δhsd4AΩthl, respectively. Both strains transformed phytosterols into 2e. Compound 2e was produced in 62% isolated yield (25 g) using strain N13Δhsd4AΩthl, and further converted to (3S,3aS,9aS,9bS)-3-acetyl-3a,6-dimethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-cyclopenta[a]naphthalen-7-one, which is the key intermediate for the synthesis of dydrogesterone. This study not only overcomes a challenging synthetic problem by enabling an efficient synthesis of dydrogesterone-like steroidal APIs from phytosterols, the well-recognized cheap and readily available biobased raw materials, but also provides insights for redesigning the metabolic pathway of phytosterols to produce other new compounds of relevance to the steroidal pharmaceutical industry.