Synergistic Machine Learning Accelerated Discovery of Nanoporous Inorganic Crystals as Non-Absorbable Oral Drugs.

Machine learning (ML) has taken drug discovery to new heights, where effective ML training requires vast quantities of high-quality experimental data as input. Non-absorbable oral drugs (NODs) have unique safety advantage for chronic diseases due to their zero systemic exposure, but their empirical discovery is still time-consuming and costly. Here, a synergistic ML method, integrating small data-driven multi-layer unsupervised learning, in silico quantum-mechanical computations, and minimal wet-lab experiments was devised to identify the finest NODs from massive inorganic materials to achieve multi-objective function (high selectivity, large capacity and stability). Based on this method, a NH4-form nanoporous zeolite with MER framework (NH4-MER) was discovered for the treatment of hyperkalemia. In 3 different animal models, NH4-MER showed a superior safety and efficacy profile in reducing blood K+ without Na+ release, which is an unmet clinical need in chronic kidney disease and Gordon's syndrome. Our work provides a synergistic ML method to accelerate the discovery of NODs and other shape-selective materials. This article is protected by copyright. All rights reserved.

The facilitative effect of the keyword mnemonic on L2 vocabulary retrieval practice.

Keyword mnemonics and retrieval practice are two learning strategies that facilitate foreign language vocabulary learning. This study examined the combination of these strategies for learning English L2 vocabulary with a limited retrieval time. We recruited 110 Chinese college students studying English as a foreign language to investigate the effects of four learning strategies on the retention of English-Chinese word pairs: restudy, retrieval practice, imposed keyword mnemonic combined with retrieval practice, and induced keyword mnemonic combined with retrieval practice. The results revealed that when retrieval practice was constrained to two times, the final performance of the retrieval practice group did not exceed that of the restudy group; however, the combined keyword-retrieval group outperformed the restudy group, regardless of whether the keyword was imposed or induced. Furthermore, there was no significant difference in memory retention performance between the induced and imposed keyword-retrieval combinations. The findings suggest that when retrieval practice is constrained to two times, the keyword-retrieval strategy combination significantly enhances English L2 vocabulary learning compared to restudy or retrieval practice alone, and both the imposed and induced keyword mnemonics can strengthen its efficiency.

Ca & Mn dual-ion hybrid nanostimulator boosting anti-tumor immunity via ferroptosis and innate immunity awakening.

Limited by low tumor immunogenicity and the immunosuppressive tumor microenvironment (TME), triple-negative breast cancer (TNBC) has been poorly responsive to immunotherapy so far. Herein, a Ca & Mn dual-ion hybrid nanostimulator (CMS) is constructed to enhance anti-tumor immunity through ferroptosis inducing and innate immunity awakening, which can serve as a ferroptosis inducer and immunoadjuvant for TNBC concurrently. On one hand, glutathione (GSH) depletion and reactive oxygen species (ROS) generation can be achieved due to the mixed valence state of Mn in CMS. On the other hand, as an exotic Ca2+ supplier, CMS causes mitochondrial Ca2+ overload, which further amplifies the oxidative stress. Significantly, tumor cells undergo ferroptosis because of the inactivation of glutathione peroxidase 4 (GPX4) and accumulation of lipid peroxidation (LPO). More impressively, CMS can act as an immunoadjuvant to awaken innate immunity by alleviating intra-tumor hypoxia and Mn2+-induced activation of the STING signaling pathway, which promotes polarization of tumor-associated macrophages (TAMs) and activation of dendritic cells (DCs) for antigen presentation and subsequent infiltration of tumor-specific cytotoxic T lymphocytes (CTLs) into tumor tissues. Taken together, this work demonstrates a novel strategy of simultaneously inducing ferroptosis and awakening innate immunity, offering a new perspective for effective tumor immunotherapy of TNBC.

Investigation of Gut Microbiota Disorders in Sepsis and Sepsis Complicated with Acute Gastrointestinal Injury Based on 16S rRNA Genes Illumina Sequencing.

Background: Sepsis is a life-threatening organ dysfunction caused by the host's dysfunctional response to infection, which can cause acute gastrointestinal injury (AGI). The gut microbiota is dynamic and plays a role in the immune and metabolic. The aim of this study was to investigate the composition and function of gut microbiota in patients with sepsis, as well as the gut microbiome that may be involved in the occurrence of AGI. Methods: A total of 23 stool samples from healthy control individuals and 41 stool samples from sepsis patients were collected. Patients with sepsis were followed up for one week to observe whether AGI has occurred. Finally, 41 patients included 21 sepsis complicated with AGI (referred to as Com-AGI) and 20 sepsis without complicated with AGI (referred to as No-AGI). The gut microbiota was analyzed by 16S rRNA gene sequencing, followed by composition analysis, difference analysis, correlation analysis, functional prediction analysis. Results: The diversity and evenness of gut microbiota were decreased in patients with sepsis. Compared with No-AGI, the gut microbiota of Com-AGI has higher community diversity, richness, and phylogenetic diversity. Escherichia-Shigella, Blautia and Enterococcus may be important indicators of sepsis. The correlation analysis showed that aspartate aminotransferase (AST) and Barnesiella have the most significant positive correlation. Moreover, Clostridium_innocuum_group, Christensenellaceae_R-7_group and Eubacterium were all significantly correlated with LAC and DAO. Clostridium_innocuum_group, Barnesiella, Christensenellaceae_R-7_group and Eubacterium may play important roles in the occurrence of AGI in sepsis. PICRUSt analysis revealed multiple functional pathways involved in the relationship between gut microbiota and sepsis, including starch degradation V, glycogen degradation I (bacterial), Lipoic acid metabolism and Valine, leucine and isoleucine biosynthesis. BugBase analysis showed that the gut microbiota with Aerobic phenotype may play an important role in sepsis. Conclusion: Dysfunction of gut microbiota was associated with sepsis and AGI in patients with sepsis.

A Counterion-Free Strategy for Chronic Metabolic Acidosis Based on an Orally Administered Gut-Restricted Inorganic Adsorbent.

Chronic metabolic acidosis, arising as a complication of chronic kidney disease (CKD), not only reduces patients' quality of life but also aggravates renal impairment. The only available therapeutic modality, involving intravenous infusion of NaHCO3 , engenders undesirable sodium retention, thereby increasing hemodynamic load and seriously exacerbating the primary disease. This deleterious cascade extends to the development of cardiovascular diseases. Herein, an orally administered, gut-restricted inorganic adsorbent that can effectively alleviate chronic metabolic acidosis without causing any electrolytic derangement or superfluous cardiovascular strain is developed. The genesis of ABC-350 entails the engineering of bismuth subcarbonate via annealing, thereby yielding a partially ß-Bi2 O3 -doped (BiO)2 CO3 biphasic crystalline structure framework enriched with atomic vacancies. ABC-350 can selectively remove chloride ions and protons from the gastrointestinal tract, mimicking the physiological response to gastric acid removal and resulting in increased serum bicarbonate. Owing to its gut-restricted nature, ABC-350 exhibits commendable biosafety, averting undue systemic exposure. In two rat models of metabolic acidosis, ABC-350 emerges not only as a potent mitigator of acidosis but also effects discernible amelioration concerning proximal tubular morphology, interstitial fibrosis, and the incendiary cascades incited by metabolic acidosis. ABC-350, as the translationally relevant material, provides a promising strategy for the treatment of metabolic acidosis.

Antioxidant potential and in vitro inhibition of starch digestion of flavonoids from Crataegus pinnatifida.

Hawthorn flavonoids were extracted by enzymolysis associated ultrasonic procedure. Thirteen flavonoids were identified by HPLC/ESI-QTOF/MS, and the major components were procyanidin C1, rutin-rhamnoside, vitexin-rhamnoside, and catechin. Hawthorn flavonoids exhibited strong free radical scavenging activities against DPPH, ABTS, and hydroxyl radicals. Total and intercellular antioxidant experiments revealed that the free hydro-PSC value was 295.32 ± 12.20 µmol of VCE/g DW, and the free cellular antioxidant activity (CAA) values were 168.60 ± 4.87 µmol of QE/g DW in the no PBS wash protocol and 49.53 ± 1.75 µmol of QE/g DW in the PBS wash protocol. In addition, hawthorn flavonoids exhibited higher α-amylase and α-glucosidase inhibitory activities. The wheat starch digestibility was also reduced by hawthorn flavonoids as well. The results indicated that enzymolysis associated ultrasonic extraction was advisable for extracting flavonoids from hawthorn, and hawthorn flavonoids might be recommended as a potential food supplement with hypoglycemic activities.

Pectin oligosaccharides improved lipid metabolism in white adipose tissue of high-fat diet fed mice.

Impacts of pectin oligosaccharide (POS) got from hawthorn fruitage on adiponectin signaling pathway and white adipose metabolism in mice fed with high-fat control. The results showed that POS significantly inhibited the levels of inflammatory cytokines TNF-α and IL-6, and down-regulated expression of CD68. POS dramatically reduced gene expression contents of fatty acid composite concerning enzymes ACC and FAS, as well as TG synthesis-related enzymes SCD-1 and DGAT1 as compared to a high-fat group (HFC). POS dramatically increased expression levels of oxidation-related enzymes of fatty acid ACO, CPT-1, and TG deposition-related enzymes ATGL and HSL as contrast to the high-fat control group. In addition, POS activated adiponectin-mediated AdipoR1/AMPK/PPARα signaling path by upregulating expression levels of AdipoR1, AMPK and PPARα. The results demonstrated that POS can improve lipid metabolism of adipose tissue, and contribute to the creation of functional foods to prevent and treat lipid metabolism disorders. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-022-01109-9.

Effect of pH value and the distance between the electrodes on physicochemical properties of chitosan under SPP treatment.

Solution plasma process (SPP) was employed to degrade chitosan. The effects of the initial pH value and the distance between the electrodes on the steady shear flow behavior, structural characterization, molecular conformation, and antioxidant activity of chitosan were investigated. The results revealed that a lower initial pH value and a narrower distance between the electrodes were beneficial to the decrease in viscosity and increase in shear-thinning capacity. Structural characterization of the chitosan by FT-IR and 1H NMR showed that chemical structure of chitosan was not destroyed at different process parameters. The results of XRD, HPSEC-MALLS, SEM, and AFM indicated that SPP degradation clearly decreased the crystallinity, molecular weight, molecular size, and molecular aggregation of chitosan. At initial pH values of 2.8 and 5.8, the molecular weight was 27.16 and 44.25 kDa, at the distance between the electrodes of 4 and 8 mm, it was 35.88 and 66.17 kDa, respectively. The results of DPPH and hydroxyl radical scavenging assays demonstrated that a lower initial pH value and a narrower distance between the electrodes enhanced the antioxidant activity.

Pectic Oligogalacturonide Facilitates the Synthesis and Activation of Adiponectin to Improve Hepatic Lipid Oxidation.

SCOPE: Adiponectin (ADPN), a kind of adipokines, plays an important role in the regulation of lipid metabolism. The objective of this study is focused on the ADPN to investigate the functional mechanisms of pectin oligosaccharide (POS) from hawthorn fruit in the improvement of hepatic fatty acid oxidation. METHOD AND RESULTS: High-fat fed mice are used in this experiment. POS is administrated with the doses of 0.25, 0.75, and 1.5 g kg-1 diet, respectively. The results demonstrate that gene and protein expressions of ADPN synthesis regulators involved in PKA/ERK/CREB and C/EBPα/PPARγ pathways are upregulated by POS administration. POS also activates the AdiopR1/AMPKα/PGC1 and AdipoR2/PPARα signaling pathways to improve the fatty acid oxidation in the liver, which is further accelerated by the enhancement of mitochondrial functions. CONCLUSION: POS can act as an ADPN activator to improve lipid metabolism, leading it to the applications of biomedical and functional foods for ameliorating chronic liver diseases resulted from a high-energy diet.

Fe3O4 Mesocrystals with Distinctive Magnetothermal and Nanoenzyme Activity Enabling Self-Reinforcing Synergistic Cancer Therapy.

Magnetite (Fe3O4) nanoparticles have been extensively used in noninvasive cancer treatment, for example, magnetic hyperthermia (MH) and chemodynamic therapy (CDT). However, how to achieve a highly efficient MH-CDT synergistic therapy based only on a single component of Fe3O4 still remains a challenge. Herein, hollow Fe3O4 mesocrystals (MCs) are constructed via a modified solvothermal method. Owing to the distinctive magnetic property of the mesocrystalline structure, Fe3O4 MCs show excellent magnetothermal conversion efficiency with a specific absorption rate of 722 w g-1 at a Fe concentration of 0.6 mg mL-1, much higher than that of Fe3O4 polycrystals (PCs). Moreover, Fe3O4 MCs also exhibit higher peroxidase-like activity than Fe3O4 PCs, which may be ascribed to the higher ratio of Fe2+/Fe3+ and more oxygen defects in the Fe3O4 MCs. Detailed in vivo results confirm that Fe3O4 MCs can instantly initiate CDT by producing the detrimental •OH, and such boosted reactive oxygen levels not only induces cell apoptosis but also reduces the expression of heat shock proteins, thus enabling low-temperature-mediated MH. More importantly, the in situ rising temperature resulted from MH in turn facilitates CDT, thus achieving a self-augmented synergistic effect between MH and CDT.

Targeted Therapeutic-Immunomodulatory Nanoplatform Based on Noncrystalline Selenium.

Developing versatile nanomaterials has offered a myriad of opportunities to surmount cancer. In particular, the combination of therapy and immunomodulatory effect to further enhance immune response provides a new idea for effective tumor treatment. Herein, for the first time, an in situ growth strategy is developed to construct highly dispersed noncrystalline selenium nanoparticles (Se NPs) with thiolated cyclo(Arg-Gly-Asp-Phe-Lys-(mpa)) (RGD) peptide modification (R-Se@DMSND) for targeted cancer treatment. Se NPs could be homogeneously grown into the pore channels of dendritic mesoporous silica nanoparticles (DMSNs) since the DMSNs could stabilize Se NPs to prevent their aggregations. Moreover, Se NPs could not only act as a therapeutic agent, inducing ROS overproduction, to effectively suppress primary tumor but also as an immunomodulatory agent to simultaneously inhibit the growth of secondary tumors by enhancement of the immune response, as confirmed by the in vivo results. Such the therapeutic-immunomodulatory strategy for tumorous therapy combining with immunomodulation using one simple nanoplatform may pave a new avenue in the biomedical field.

Clearable Theranostic Platform with a pH-Independent Chemodynamic Therapy Enhancement Strategy for Synergetic Photothermal Tumor Therapy.

Chemodynamic therapy (CDT) is an emerging field, which utilizes intratumoral iron-mediated Fenton chemistry for cancer therapy. However, the slightly acidic tumor environment is improper for the classical Fenton reaction, which is generally energetic in a narrow pH range (e.g., pH = 3-4). Herein, a kind of ultrasmall bovine serum albumin (BSA)-modified chalcopyrite nanoparticles (BSA-CuFeS2 NPs) was synthesized via a facile aqueous biomineralization strategy, which shows high dispersity and biocompatibility. Interestingly, the obtained BSA-CuFeS2 shows a pH-independent Fenton-like reaction, which could exert Fenton-like activity to efficiently generate •OH under a weak acidic tumor environment. Combined with the extraordinarily high photothermal conversion (38.8%), BSA-CuFeS2 shows the synergistic function of high photothermal therapy (PTT) and enhanced CDT, that is, PTT/CDT. Importantly, such ultrasmall BSA-CuFeS2 NPs measuring around 4.9 nm can be quickly cleared out of the body through kidneys and liver, thus effectively avoiding long-term toxicity and systemic toxicity. Moreover, BSA-CuFeS2 NPs can act as an efficient T2-weighted magnetic resonance imaging (MRI) contrast agent to guide tumor ablation in vivo. This work offers a universal approach to boost production •OH by a pH-independent Fenton-like reaction strategy and achieves MRI-guided synergistic enhanced photothermal-CDT for highly efficient tumor treatment.

On-Demand Detaching Nanosystem for the Spatiotemporal Control of Cancer Theranostics.

Engineering multiple theranostic modalities into a single nanoscale entity holds great potential to rejuvenate cancer treatments; however, enabling the sophisticated spatiotemporal control of each component for maximizing theranostic improvement and minimizing side effects concurrently remains a challenge. Herein, an intelligent detachable "nanorocket" is developed to sequentially manipulate and optimize multitheranostic processes for magnetic resonance-assisted ultrasound-drug combined therapy (MR-HIFU-Drug). The "nanorocket" is constructed by integrating multicomponent (MnCO3, doxorubicin, silica) on the pH-sensitive CaCO3 nanoparticles step by step via cation exchange and controlled heterogeneous nucleation, in which doxorubicin is encapsulated in both carbonates and silica component. The "nanorocket" can initiate sequential detachment in the acidic tumor microenvironment. Specifically, carbonates decompose instantly, releasing Mn2+ as the MR contrast agent and leaving hollow silica nanostructure behind as the HIFU synergistic agent. Consequently, burst release of drug is also triggered, further triggering the degradation of silica, which in turn regulates the slow release of drug from the silica matrix. Thus, efficient tumor inhibition is achieved by enhanced HIFU ablation and biphase release of doxorubicin with a stepwise clearance of Mn and Si. This work establishes a system for the systematic spatiotemporal dispatch of diverse theranostic components for the balance of efficacy and safety in cancer theranostics.

Engineering graphene oxide with ultrasmall SPIONs and smart drug release for cancer theranostics.

A smart nanotheranostics nanoplatform was constructed using engineered graphene oxide and the in situ growth of ultrasmall superparamagnetic iron oxide particles (SPIONs). The construction of such a novel theranostics nanoplatform shows great potential in tumor theranostics, especially for T1-weighted magnetic resonance (T1-MR) imaging guided, pH-sensitive chemotherapy.

Perfluorooctyl bromide & indocyanine green co-loaded nanoliposomes for enhanced multimodal imaging-guided phototherapy.

As a highly biocompatible NIR dye, indocyanine green (ICG) has been widely explored for cancer treatment due to its various energy level transition pathways upon NIR light excitation simultaneously, which leads to different theranostic effects (eg. Photoacoustic (PA) and fluorescence imaging (FL), photodynamic and photothermal therapy (PDT&PTT)). However, the theranostic efficiency of ICG is restricted intrinsically, owing to the competitive relationship of its co-existing imaging and therapeutic effect. Moreover, the extrinsic hypoxia nature of tumor further limits its therapeutic effect, especially for the oxygen-dependent PDT. Herein, perfluorooctyl bromide (PFOB), another biocompatible chemical, was integrated with ICG in a nanoliposome structure via a facile two-step emulsion method. Such an ICG&PFOB co-loaded nanoliposomes (LIP-PFOB-ICG) realized computed tomography (CT) contrast imaging in vivo, providing better anatomical information of tumor in comparison to ICG enabled PA and FL imaging. More importantly, LIP-PFOB-ICG inhibited MDA-MB-231 tumor growth completely via intravenous injection through enhanced PDT&PTT synergistic therapy due to the excellent oxygen carrying ability of PFOB, which effectively attenuated tumor hypoxia, improved the efficiency of collisional energy transfer between ICG and oxygen and reduced the expression of heat shock protein (HSP). As expected, the introduction of PFOB within nanoliposomes with ICG has augmented the theranostic effect of ICG comprehensively, which makes this simple biocompatible liposome-based nanoagent a potential candidate for clinical imaging guided phototherapy of cancer.

Endogenous Catalytic Generation of O2 Bubbles for In Situ Ultrasound-Guided High Intensity Focused Ultrasound Ablation.

High intensity focused ultrasound (HIFU) surgery generally suffers from poor precision and low efficiency in clinical application, especially for cancer therapy. Herein, a multiscale hybrid catalytic nanoreactor (catalase@MONs, abbreviated as C@M) has been developed as a tumor-sensitive contrast and synergistic agent (C&SA) for ultrasound-guided HIFU cancer surgery, by integrating dendritic-structured mesoporous organosilica nanoparticles (MONs) and catalase immobilized in the large open pore channels of MONs. Such a hybrid nanoreactor exhibited sensitive catalytic activity toward H2O2, facilitating the continuous O2 gas generation in a relatively mild manner even if incubated with 10 µM H2O2, which finally led to enhanced ablation in the tissue-mimicking PAA gel model after HIFU exposure mainly resulting from intensified cavitation effect. The C@M nanoparticles could be accumulated within the H2O2-enriched tumor region through enhanced permeability and retention effect, enabling durable contrast enhancement of ultrasound imaging, and highly efficient tumor ablation under relatively low power of HIFU exposure in vivo. Very different from the traditional perfluorocarbon-based C&SA, such an on-demand catalytic nanoreactor could realize the accurate positioning of tumor without HIFU prestimulation and efficient HIFU ablation with a much safer power output, which is highly desired in clinical HIFU application.

Enabling Prussian Blue with Tunable Localized Surface Plasmon Resonances: Simultaneously Enhanced Dual-Mode Imaging and Tumor Photothermal Therapy.

Prussian blue (PB) has been used as a photothermal conversion agent to generate heat to induce localized damage to tumor. However, its therapeutic efficiency is far from satisfactory. One of the major obstacles is that the maximum NIR absorption peak of PB within 690-720 nm cannot be optimized near the wavelength of the laser to enhance its therapeutic efficiency. Herein, we report that the integration of Gd3+ into PB nanocrystals (GPB NCs) enables PB with tunable localized surface plasmon resonances (LSPRs) from 710 to 910 nm, achieving the maximum NIR peak near the wavelength of the laser. Concurrently, the efficiency of dual-mode imaging including photoacoustic imaging and magnetic resonance imaging has been greatly improved. These enhancements in dual-mode imaging and photothermal therapy enable PB with low nanomaterial dose and laser flux. Additionally, it is found that GPB NCs show the capability of not only acting as a chemical probe with tunable sensitivity but also scavenging reactive oxygen species. The integration of functional ions into a photothermal conversion agent is an efficient strategy to improve the synergy of nanoagent, enchancing tumor theranostic efficiency.