Heavy Atom-Free, Mitochondria-Targeted, and Activatable Photosensitizers for Photodynamic Therapy with Real-Time In-Situ Therapeutic Monitoring.

Based on spin-orbit charge transfer intersystem crossing mechanism, two heavy-atom-free photosensitizers (PSs) BDP1/BDP2 with absorption maxima at 506 nm/660 nm were constructed for photodynamic therapy (PDT). The long triplet state lifetimes and large singlet oxygen quantum yields, coupled with the mitochondria-targeted feature, made them highly phototoxic toward cancer cells. Moreover, the PDT-promoted cell apoptosis could be monitored by an obvious fluorescence off-on response of the two PSs due to the concomitant activation of extensive mitophagy, thus facilitating timely therapeutic feedback to avoid under- or over-treatment. Importantly, such design allows the activatable PSs Glu-BDP1/Glu-BDP2 to be fabricated by attaching γ-glutamyl, a substrate of γ-glutamyltranspeptidase, to the alkoxyaniline unit of BDP1/BDP2, and their ability in either selectively killing cancer cells over normal cells or in ablating implanted tumour without damage to healthy tissue was demonstrated.

Constructing Heavy-Atom-Free Photosensitizers for Hypoxic Tumor Phototherapy Based on Donor-Excited Photoinduced Electron-Transfer-Driven Type-I and Type-II Mechanisms.

The spin-orbit charge transfer intersystem crossing (SOCT-ISC) photophysical process has shown great potential for constructing heavy-atom-free photosensitizers (PSs) for photodynamic therapy (PDT) of tumors. However, for almost all such PSs reported to date, the SOCT-ISC is driven by the acceptor-excited photoinduced electron transfer (a-PeT). In this work, for the first time the donor-excited photoinduced electron transfer (d-PeT)-driven SOCT-ISC mechanism is utilized to construct the heavy-atom-free PSs for PDT of tumors by directly installing the electron-deficient N-alkylquinolinium unit (as an electron acceptor) into the meso-position of the near-infrared (NIR) distyryl Bodipy chromophore (as an electron donor). In the less polar environment, the PSs exist as the monomer and promote the production of singlet oxygen (1O2) (Type-II) relying on the d-PeT-driven population of the triplet excited state via SOCT-ISC, whereas in the aqueous environment, they exist as nanoaggregates and induce the generation of superoxides (O2-•) and hydroxyl radicals (HO•) (Type-I) via the d-PeT-driven formation of the delocalized charge-separated state. The PSs could rapidly be internalized into cancer cells and induce the simultaneous production of intracellular 1O2, O2-•, and HO• upon NIR light irradiation, endowing the PSs with superb photocytotoxicity with IC50 values up to submicromolar levels whether under normoxia or under hypoxia. Based on the PSs platform, a tumor-targetable PS is developed, and its abilities in killing cancer cells and in ablating tumors without damage to normal cells/tissues under NIR light irradiation are verified in vitro and in vivo. The study expands the design scope of PSs by introducing the d-PeT conception, thus being highly valuable for achieving novel PSs in the realm of tumor PDT.

The effect of probiotics on severe oral mucositis in cancer patients undergoing chemotherapy and/or radiotherapy: A meta-analysis.

PURPOSE: Oral mucositis is a frequent adverse reaction in cancer treatment. Probiotics exhibit anti-inflammatory and immunomodulatory properties that could prevent the occurrence of severe oral mucositis (SOM) induced by chemotherapy or radiation therapy in patients. This meta-analysis aimed to investigate the influence of probiotics on the incidence of SOM in cancer patients undergoing chemotherapy and/or radiotherapy. METHODS: We conducted a comprehensive search in PubMed, Embase, the Cochrane Library, and the China National Knowledge Infrastructure (CNKI) from their inception to September 2023. Dichotomous variables are analyzed with odds ratios (ORs) with 95% CIs, and statistical significance was set at a two-tailed P <0 .05. The primary outcome indicator was the effect of probiotics on SOM. Secondary outcome indicators included the effect of probiotics on oral mucositis and the ratio of diarrhoea. Statistical analysis was conducted using RevMan (5.4) and Stata 17.0 software. RESULTS: The study included a total of 12 articles and involved 1055 patients. All patients had undergone either radiotherapy or chemotherapy. Our findings revealed that the experimental group, which received probiotics for treatment, exhibited a lower ratio of SOM compared to the control group that received traditional placebo treatment (OR=0.37, 95%CI [0.28, 0.50], P<0.01). Subgroup analysis revealed variations in the ratio of SOM based on therapeutic regimen, tumor type, and region. The overall ratio of oral mucositis was significantly lower in the experimental group compared to the control group (OR=0.19, 95%CI [0.09-0.39], P<0.01). The ratio of diarrhea in the two patient groups showed no significant difference (OR=0.85, 95%CI [0.24, 3.01], P>0.05). CONCLUSION: The results of this meta-analysis suggest that probiotics could decrease the occurrence of SOM.

Image recognition of traditional Chinese medicine based on deep learning.

Chinese herbal medicine is an essential part of traditional Chinese medicine and herbalism, and has important significance in the treatment combined with modern medicine. The correct use of Chinese herbal medicine, including identification and classification, is crucial to the life safety of patients. Recently, deep learning has achieved advanced performance in image classification, and researchers have applied this technology to carry out classification work on traditional Chinese medicine and its products. Therefore, this paper uses the improved ConvNeXt network to extract features and classify traditional Chinese medicine. Its structure is to fuse ConvNeXt with ACMix network to improve the performance of ConvNeXt feature extraction. Through using data processing and data augmentation techniques, the sample size is indirectly expanded, the generalization ability is enhanced, and the feature extraction ability is improved. A traditional Chinese medicine classification model is established, and the good recognition results are achieved. Finally, the effectiveness of traditional Chinese medicine identification is verified through the established classification model, and different depth of network models are compared to improve the efficiency and accuracy of the model.

Aromatic secondary amine-functionalized fluorescent NO probes: improved detection sensitivity for NO and potential applications in cancer immunotherapy studies.

Tumor-associated macrophages (TAMs), constituting up to 50% of the solid tumor mass and commonly having a pro-tumoral M2 phenotype, are closely associated with decreased survival in patients. Based on the highly dynamic properties of macrophages, in recent years the repolarization of TAMs from pro-tumoral M2 phenotype to anti-tumoral M1 phenotype by various strategies has emerged as a promising cancer immunotherapy approach for improving cancer therapy. Herein, we present an aromatic secondary amine-functionalized Bodipy dye 1 and its mitochondria-targetable derivative Mito1 as fluorescent NO probes for discriminating M1 macrophages from M2 macrophages in terms of their difference in inducible NO synthase (iNOS) levels. The two probes possess the unique ability to simultaneously respond to two secondary oxides of NO, i.e., N2O3 and ONOO-, thus being more sensitive and reliable for reflecting intracellular NO than most of the existing fluorescent NO probes that usually respond to N2O3 only. With 1 as a representative, the discrimination between M1 and M2 macrophages, evaluation of the repolarization of TAMs from pro-tumoral M2 phenotype to anti-tumoral M1 phenotype, and visualization of NO communication during the immune-mediated phagocytosis of cancer cells by M1 macrophages have been realized. These results indicate that our probes should hold great potential for imaging applications in cancer immunotherapy studies and relevant anti-cancer drug screening.

A Si-rhodamine-based near-infrared fluorescent probe for visualizing endogenous peroxynitrite in living cells, tissues, and animals.

Peroxynitrite (ONOO-) is an extremely powerful biological oxidant and it can react with a wide variety of molecular targets to result in a series of disease states, which has made ONOO- a central biological pathogenic factor. In order to disclose its various pathological events, a large number of fluorescent ONOO- probes have been developed in recent years. Nevertheless, some limitations still remain, such as short excitation and emission wavelengths, long fluorescence response times, and cross-interference caused by other reactive oxygen species (ROS). In this work, a new near-infrared (NIR) fluorescent probe, SiRTA, containing an aromatic tertiary amine functional group and a Si-rhodamine fluorophore, was developed for endogenous ONOO- detection and imaging. The probe exhibits not only a fast, sensitive, and specific fluorescence off-on response toward ONOO- in chemical systems but also excellent imaging ability for endogenous ONOO- in living cells. With the probe, the therapeutic effects of phenolic acid antioxidants in EA.hy926 endothelial cells suffering from ischemia-reperfusion injury and the pathogenesis of diabetes and diabetic nephropathy in pancreatic ß-cells and diabetic rats have successfully been evaluated. These results indicate that SiRTA is a potentially outstanding imaging tool for studying the physiological and pathological events of ONOO- and relevant drug therapies.

Aromatic primary monoamine-based fast-response and highly specific fluorescent probes for imaging the biological signaling molecule nitric oxide in living cells and organisms.

Nitric oxide (NO) is an important cellular signaling molecule involved in many physiological and pathological processes. To probe its spatiotemporal information in biosystems, a large number of NO fluorescent probes have been exploited in the past ten years. Among them, the o-phenylenediamine-based probes are the earliest developed and most versatile NO fluorescent probes to date. However, there are still limitations such as relatively long response time, possible interference by dehydroascorbic acid (DHA)/methylglyoxal (MGO), and pH-sensitivity of their fluorescence signals. In this work, we present two aromatic primary monoamine-based NO fluorescent probes, MA and NIR-MA, and explore the reductive deamination reaction of the electron-rich p-methoxyaniline group with NO under aerobic conditions. The superiority of both probes is illustrated by their quick, stable, sensitive, and specific fluorescence off-on responses for NO over a series of biologically relevant interfering species, including reactive oxygen species, DHA/MGO, biothiols, and metal ions. Coupled with good cell permeability and low cytotoxicity, the two probes have successfully been applied to imaging the endogenous NO in RAW 264.7 macrophages stimulated by LPS/IFN-γ. Moreover, the fluorescence response of NIR-MA for NO occurs in the physiologically favorable NIR region, enabling its further use to image endogenous NO in an inflamed mouse model.

Selective and sensitive visualization of endogenous nitric oxide in living cells and animals by a Si-rhodamine deoxylactam-based near-infrared fluorescent probe.

Nitric oxide (NO) is a fundamental signaling molecule that regulates virtually every critical cellular function, and it is also a potent mediator of cellular damage in a wide range of conditions mainly via its secondary metabolite peroxynitrite (ONOO-). In this work, we present an o-phenylenediamine (OPD)-locked Si-rhodamine deoxylactam, i.e.deOxy-DALSiR, as a near-infrared fluorescent probe for the selective and sensitive detection of NO in living cells and bodies. Not only could the probe overcome the limitations suffered by widely used and commercialized OPD-type fluorescent NO probes, such as the possible interferences by dehydroascorbic acid/ascorbic acid/methylglyoxal (DHA/AA/MGO), pH-sensitive fluorescence output, and short excitation and emission wavelengths, but it can also avoid serious interference from cysteine (Cys) found in the rhodamine lactam-based fluorescent NO probes developed later. What's more, the probe is fairly sensitive for NO, as evidenced by its rapid fluorescence response rate (within seconds), huge fluorescence off-on ratio (6300-fold), and ultra-low detection limit (0.12 nM). Its effectiveness and practicability have been demonstrated by the successful imaging of endogenous NO in RAW 264.7 macrophages, pancreatic ß-cells, and endothelial EA.hy926 cells, as well as in inflamed and diabetic mouse models.

A new class of fast-response and highly selective fluorescent probes for visualizing peroxynitrite in live cells, subcellular organelles, and kidney tissue of diabetic rats.

Peroxynitrite (ONOO(-)) is an extremely powerful oxidant in biological systems, and can react with a wide variety of molecular targets including proteins, lipids, and nucleic acids, eventually resulting in a series of disease states such as diabetes, Alzheimer's disease, cancer, arthritis, autoimmune, and other disorders. In this work, we present a new class of ONOO(-) fluorescent probes by exploiting the ONOO(-)-triggered N-oxidation and N-nitrosation reactions of aromatic tertiary amine for the first time. The as-obtained fluorescent probe A2 could detect ONOO(-) with quite fast fluorescence off-on response (within seconds), ultrasensitivity (detection limit: <2 nM), and excellent selectivity over a series of biologically relevant reactive oxygen species as well as metal cations. With the probe, the endogenous ONOO(-) in activated RAW264.7 murine macrophage, EA.hy926 endothelial cells after oxygen glucose deprivation and reoxygenation (OGD/RO), and kidney tissue of diabetic rats has been successfully visualized. Based on the molecular platform of A2, we further develop its mitochondria- and lysosome-targetable fluorescent probes Mito-A2 and Lyso-A2 by installing the corresponding targeting groups to alkoxy unit of A2, and confirm their abilities to image ONOO(-) in mitochondria and lysosomes, respectively, by co-localization assays. It is greatly expected that these probes can serve as useful imaging tools for clarifying the distribution and pathophysiological functions of ONOO(-) in cells, subcellular organelles, and animal tissues.

Fast-response and highly selective fluorescent probes for biological signaling molecule NO based on N-nitrosation of electron-rich aromatic secondary amines.

Nitric oxide (NO) is a ubiquitous biological messenger molecule, and plays the active roles in the regulation of various physiological processes. Although numerous NO fluorescent probes have also been successfully developed in the past ten years, it still remains challenging to increase the response rate for NO while having the high selectivity and sensitivity. In this work, a simple N-nitrosation reaction of the electron-rich aromatic secondary amine with NO under aerobic condition has been utilized for the first time to construct fluorescent probe for NO. The resulting probe 1, containing a N-benzyl-4-hydroxyaniline moiety as reaction group and a BODIPY dye as fluorescence reporter, could detect NO with the fast fluorescence off-on response (within seconds), high sensitivity (nM level), and excellent selectivity over various reactive oxygen species (ROS) as well as dehydroascorbic acid (DHA), ascorbic acid (AA), and methylglyoxal (MGO). Even in the presence of glutathione (GSH, a high reactive biothiol for NO), the probe still works well for NO. Further, a mitochondria-targetable probe 2 was exploited by introducing a targeted triphenylphosphonium cation into probe 1 scaffold. It's excellent NO sensing performance as well as its ability to specifically target mitochondria and image NO there have been nicely demonstrated. With the two probes, the basal and stimulation-induced NO in RAW264.7 murine macrophages as well as the endogenous NO in endothelial cells after oxygen-glucose deprivation (OGD) have been successfully visualized.