Photothermal "nano-dot" reactivate "immune-hot" for tumor treatment via reprogramming cancer cells metabolism.

Cancer immunotherapy, despite its enormous application prospect, is trapped in the abnormal lactic acid metabolism of tumor cells that usually causes an immunosuppressive tumor microenvironment (ITM). Inducing immunogenic cell death (ICD) not only sensitizes cancer cells to carcer immunity, but also leads to a great increase in tumor-specific antigens. It improves tumor condition from "immune-cold" to "immune-hot". Herein, a near-infrared photothermal agent NR840 was developed and encapsulated into tumor-targeted polymer DSPE-PEG-cRGD and carried lactate oxidase (LOX) by electrostatic interaction, forming self-assembling "nano-dot" PLNR840 with high loading capacity for synergistic antitumor photo-immunotherapy. In this strategy, PLNR840 was swallowed by cancer cells, then dye NR840 was excited at 808 nm to generate heat inducing tumor cell necrosis, which further caused ICD. LOX could serve as a catalyst, reducing lactic acid efflux via regulation of cell metabolism. More importantly, the consumption of intratumoral lactic acid could substantially reverse ITM, including promoting the polarization of tumor-associated macrophages from M2 to M1 type, inhibiting the viability of regulatory T cells for sensitizing photothermal therapy (PTT). After the combination of αPD-L1 (programmed cell death protein ligand 1), PLNR840 restored CD8+ T-cell activity that thoroughly cleaned the pulmonary metastasis of breast cancer in 4T1 mouse model and cured hepatocellular carcinoma in Hepa1-6 mouse model. This study provided an effective PTT strategy to boost "immune-hot" and reprogrammed tumor metabolism for antitumor immunotherapy.

Oxidative stress induced by berberine-based mitochondria-targeted low temperature photothermal therapy.

Introduction: Mitochondria-targeted low-temperature photothermal therapy (LPTT) is a promising strategy that could maximize anticancer effects and overcome tumor thermal resistance. However, the successful synthesis of mitochondria-targeted nanodrug delivery system for LPTT still faces diverse challenges, such as laborious preparations processes, low drug-loading, and significant systemic toxicity from the carriers. Methods: In this study, we used the tumor-targeting folic acid (FA) and mitochondria-targeting berberine (BBR) derivatives (BD) co-modified polyethylene glycol (PEG)-decorated graphene oxide (GO) to synthesize a novel mitochondria-targeting nanocomposite (GO-PEG-FA/BD), which can effectively accumulate in mitochondria of the osteosarcoma (OS) cells and achieve enhanced mitochondria-targeted LPTT effects with minimal cell toxicity. The mitochondria-targeted LPTT effects were validated both in vitro and vivo. Results: In vitro experiments, the nanocomposites (GO-PEG-FA/BD) could eliminate membrane potential (ΔΨm), deprive the ATP of cancer cells, and increase the levels of reactive oxygen species (ROS), which ultimately induce oxidative stress damage. Furthermore, in vivo results showed that the enhanced mitochondria-targeted LPTT could exert an excellent anti-cancer effect with minimal toxicity. Discussion: Taken together, this study provides a practicable strategy to develop an ingenious nanoplatform for cancer synergetic therapy via mitochondria-targeted LPTT, which hold enormous potential for future clinical translation.

Blunted superior temporal gyrus activity to negative emotional expression after mindfulness-based cognitive therapy for late-life depression.

Facial emotion recognition plays an important role in social functioning. Patients with late-life depression (LLD) often have abnormal facial emotion recognition. Mindfulness-based cognitive therapy (MBCT) is beneficial in treating depression. This study examined whether MBCT can act as an effective augmentation of antidepressants and improve facial emotion recognition in patients with LLD and its underlying neural mechanism. Patients with LLD were randomized into two groups (n = 30 per group). The MBCT group received an eight-week MBCT in conjunction with stable medication treatment. The other group was treated as usual (TAU group) with stable medication treatment. The positive affect (PA) scale, negative affect (NA) scale, and facial emotion recognition task with an fMRI scan were performed before and after the trial. After eight weeks of treatment, the repeated ANOVA showed that the PA score in the MBCT group significantly increased [F (1,54) = 13.31, p = 0.001], but did not change significantly [F (1,54) = 0.58, p = 0.449] in the TAU group. The NA scores decreased significantly in both the MBCT group [F (1,54) = 19.01, p < 0.001] and the TAU group [F (1,54) = 16.16, p < 0.001]. Patients showed an increase in recognition accuracy and speed of angry and sad faces after 8 weeks of MBCT. No improvement was detected in the TAU group after treatment. A significant interaction effect was found in the change of activation of the left superior temporal gyrus (L-STG) to negative emotional expression between time and groups. Furthermore, a decrease in activation of L-STG to negative emotional expression was positively correlated with the increase in PA score. The MBCT is beneficial for improving affect status and facial emotion recognition in patients with LLD, and the L-STG is involved in this process.

Single-molecule photosensitizers for NIR-II fluorescence and photoacoustic imaging guided precise anticancer phototherapy.

It is ideal yet challenging to achieve precise tumor targeting and high-quality imaging guided combined photodynamic and photothermal therapy (PDT and PTT). In this study, we synthesized a series of D-π-A-type single-molecule photosensitizers (CyE-TT, CyQN-TT, and CyQN-BTT) based on quaternized 1,1,2-trimethyl-1H-benz[e]indoles as acceptors by introducing π-bridges to elongate their emission wavelength and triphenylamine as a donor to construct a twisted molecular conformation. We found that the 1O2 generation ability and the photothermal conversion efficiency (PCE) are directly correlated with the π-bridge between donors and acceptors in these molecules. When a 2,1,3-benzothiadiazole group as a π-bridge was introduced into CyQN-BTT, the singlet oxygen yield enhanced to 27.1%, PCE to 37.8%, and the emission wavelength was red-shifted to near-infrared II (NIR-II). Importantly, double-cationic CyQN-BTT displays structure-inherent cancer cell targeting ability instead of targeting normal cells. Consequently, relying on NIR-II fluorescence imaging (NIR-II FLI) and photoacoustic imaging (PAI) guided PDT and PTT, CyQN-BTT can accurately locate solid tumors in mice and effectively eliminate them with good biocompatibility and biosafety to normal tissues. This study provides insights into the design and development of a tumor-specific targeting multifunctional photosensitizer for precise cancer phototherapy.

Selenium Attenuates TBHP-Induced Apoptosis of Nucleus Pulposus Cells by Suppressing Mitochondrial Fission through Activating Nuclear Factor Erythroid 2-Related Factor 2.

Intervertebral disc (IVD) degeneration (IDD), the leading cause of low back pain (LBP), remains intractable due to a lack of effective therapeutic strategies. Several lines of studies have documented that nucleus pulposus cell (NPC) death induced by excessive oxidative stress is a crucial contributor to IDD. However, the concrete role and regulation mechanisms have not been fully clarified. Selenium (Se), a vital prosthetic group of antioxidant enzymes, is indispensable for maintaining redox homeostasis and promoting cell survival. However, no light was shed on the role of Se on IDD progression, especially regulation on mitochondrial dynamics and homeostasis. To fill this research gap, the current study focuses on the effects of Se, including sodium selenite (SS) and selenomethionine (Se-Met), on IDD progression and the underlying mechanisms. In vitro, we found that both SS and Se-Met alleviated tert-butyl hydroperoxide- (TBHP-) induced oxidative stress, protected mitochondrial function, and inhibited apoptosis of NPCs. Further experiments indicated that Se suppressed TBHP-induced mitochondrial fission and rescued the imbalance of mitochondrial dynamics. Promoting mitochondrial fission by carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP) partially counteracted the cytoprotective effects of Se. Moreover, blocking nuclear factor erythroid 2-related factor 2 (Nrf2) with ML385 proved that the effect of Se on regulating mitochondrial dynamics was attributed to the activation of the Nrf2 pathway. In the puncture-induced rat IDD model, a supplement of Se-Met ameliorated degenerative manifestations. Taken together, our results demonstrated that Se suppressed TBHP-induced oxidative stress and mitochondrial fission by activating the Nrf2 pathway, thereby inhibiting the apoptosis of NPCs and ameliorating IDD. Regulation of mitochondrial dynamics by Se may have a potential application value in attenuating the pathological process of IDD.

Organic Photo-antimicrobials: Principles, Molecule Design, and Applications.

The emergence of multi-drug-resistant pathogens threatens the healthcare systems world-wide. Recent advances in phototherapy (PT) approaches mediated by photo-antimicrobials (PAMs) provide new opportunities for the current serious antibiotic resistance. During the PT treatment, reactive oxygen species or heat produced by PAMs would react with the cell membrane, consequently leaking cytoplasm components and effectively eradicating different pathogens like bacteria, fungi, viruses, and even parasites. This Perspective will concentrate on the development of different organic photo-antimicrobials (OPAMs) and their application as practical therapeutic agents into therapy for local infections, wound dressings, and removal of biofilms from medical devices. We also discuss how to design highly efficient OPAMs by modifying the chemical structure or conjugating with a targeting component. Moreover, this Perspective provides a discussion of the general challenges and direction for OPAMs and what further needs to be done. It is hoped that through this overview, OPAMs can prosper and will be more widely used for microbial infections in the future, especially at a time when the global COVID-19 epidemic is getting more serious.

Amplification of oxidative stress with lycorine and gold-based nanocomposites for synergistic cascade cancer therapy.

BACKGROUND: Despite advances of surgery and neoadjuvant chemotherapy during the past few decades, the therapeutic efficacy of current therapeutic protocol for osteosarcoma (OS) is still seriously compromised by multi-drug resistance and severe side effects. Amplification of intracellular oxidative stress is considered as an effective strategy to induce cancer cell death. The purpose of this study was to develop a novel strategy that can amplify the intracellular oxidative stress for synergistic cascade cancer therapy. METHODS AND RESULTS: A novel nanocomposite, composed of folic acid (FA) modified mesoporous silica-coated gold nanostar (GNS@MSNs-FA) and traditional Chinese medicine lycorine (Ly), was rationally designed and developed. Under near-infrared (NIR) irradiation, the obtained GNS@MSNs-FA/Ly could promote a high level of ROS production via inducing mitochondrial dysfunction and potent endoplasmic reticulum (ER) stress. Moreover, glutathione (GSH) depletion during ER stress could reduce ROS scavenging and further enable efficient amplification of intracellular oxidative stress. Both in vitro and in vivo studies demonstrated that GNS@MSNs-FA/Ly coupled with NIR irradiation exhibited excellent antitumor efficacy without noticeable toxicity in MNNG/HOS tumor-bearing mice. CONCLUSION: All these results demonstrated that GNS@MSNs-FA/Ly coupled with NIR irradiation could dramatically amplify the intra-tumoral oxidative stress, exhibiting excellent antitumor ability without obvious systemic toxicity. Taken together, this promising strategy provides a new avenue for the effective cancer synergetic therapy and future clinical translation.

Promising application of Pulsed Electromagnetic Fields (PEMFs) in musculoskeletal disorders.

Increasing evidence suggests that an exogenous electromagnetic field might be involved in many biologic processes which are of great importance for therapeutic interventions. Pulsed electromagnetic fields (PEMFs) are known to be a noninvasive, safe and effective therapy agent without apparent side effects. Numerous studies have shown that PEMFs possess the potential to become a stand-alone or adjunctive treatment modality for treating musculoskeletal disorders. However, several issues remain unresolved. Prior to their widely clinical application, further researches from well-designed, high-quality studies are still required to standardize the treatment parameters and derive the optimal protocol for health-care decision making. In this review, we aim to provide current evidence on the mechanism of action, clinical applications, and controversies of PEMFs in musculoskeletal disorders.

Hybrid facial image feature extraction and recognition for non-invasive chronic fatigue syndrome diagnosis.

Due to an absence of reliable biochemical markers, the diagnosis of chronic fatigue syndrome (CFS) mainly relies on the clinical symptoms, and the experience and skill of the doctors currently. To improve objectivity and reduce work intensity, a hybrid facial feature is proposed. First, several kinds of appearance features are identified in different facial regions according to clinical observations of traditional Chinese medicine experts, including vertical striped wrinkles on the forehead, puffiness of the lower eyelid, the skin colour of the cheeks, nose and lips, and the shape of the mouth corner. Afterwards, such features are extracted and systematically combined to form a hybrid feature. We divide the face into several regions based on twelve active appearance model (AAM) feature points, and ten straight lines across them. Then, Gabor wavelet filtering, CIELab color components, threshold-based segmentation and curve fitting are applied to extract features, and Gabor features are reduced by a manifold preserving projection method. Finally, an AdaBoost based score level fusion of multi-modal features is performed after classification of each feature. Despite that the subjects involved in this trial are exclusively Chinese, the method achieves an average accuracy of 89.04% on the training set and 88.32% on the testing set based on the K-fold cross-validation. In addition, the method also possesses desirable sensitivity and specificity on CFS prediction.

The Neural Mechanism by Which the Dorsal Vagal Complex Mediates the Regulation of the Gastric Motility by Weishu (RN12) and Zhongwan (BL21) Stimulation.

A large number of studies have been conducted to explore the mechanism of Back-Shu and Front-Mu points. While several lines of evidence addressed the acupuncture information of Shu acupoints and Mu acupoints gathering in the spinal cord, whether the convergence is extended to the high centre still remains unclear. The study selected gastric Mu points (RN12) and gastric Shu points (BL21) regulating gastric motility and its central neural mechanisms as the breakthrough point, using the technique of immunochemistry, nuclei lesion, electrophysiology, and nerve transection. Here, we report that gastric motility regulation of gastric Shu and Mu acupoints and their synergistic effect and the signals induced by electroacupuncture (EA) stimulation of acupoints RN12 and RN12 gather in the dorsal vagal complex (DVC), increasing the levels of gastrointestinal hormones in the DVC to regulate gastric motility through the vagus. In sum, our data demonstrate an important role of DVC and vagus in the regulation of gastric motility by EA at gastric Shu and Mu points.