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Background: Cell-based transplantation, tissue engineering and gene therapy are important therapeutic strategies for present and future regenerative medicine. One challenge is to present the target cells in a suitable matrix to allow the cells to survive the wound contraction, tissue repair, and remodeling in certain tissues. Recently, functional biomaterial research has been directed towards the development of improved scaffolds and new drug delivery systems for regenerative medicine. Materials and methods: A literature survey was performed in basic and clinic publications relevant to the therapeutic potential of chitosan and its derivatives in regenerative medicine. In this review the functional properties and potential applications of chitosan and its derivatives in regenerative medicine are presented and discussed. Results: Chitosan can be obtained by alkaline deacetylation of chitin and is found to be a natural-based nontoxic, biocompatible, and biodegradable polymer with anti-microbial activity. Chitosan and its derivatives could accelerate wound healing by enhancing the functions of inflammatory cells and repairing cells. Recent studies further indicated that chitosan and its derivatives also are novel scaffold materials for tissue engineering and are-promising non-viral vectors for gene delivery. Conclusions: Regenerative medicine has entered a new era with the development of modern science and technology. The novel properties of chitosan make it a versatile biomaterial for cell therapy, tissue engineering and gene therapy. It is hoped that these diverse approaches for regenerative medicine will translate from “bench to bedside” in the future. [Copyright &y& Elsevier]

Background: The human positive cofactor 4 (PC4) is initially identified as a transcriptional cofactor and has an important role in embryonic development and malignant transformation. However, the clinical significance and the molecular mechanisms of PC4 in breast cancer development and progression are still unknown. Methods: We investigated PC4 expression in 114 cases of primary breast cancer and matched normal breast tissue specimens, and studied the impact of PC4 expression as well as the molecular mechanisms of this altered expression on breast cancer growth and metastasis both in vitro and in vivo. Results: PC4 was significantly upregulated in breast cancer and high PC4 expression was positively correlated with metastasis and poor prognosis of patients. Gene set enrichment analysis (GSEA) demonstrated that the gene sets of cell proliferation and Epithelial-Mesenchymal Transition (EMT) were positively correlated with elevated PC4 expression. Consistently, loss of PC4 markedly inhibited the growth and metastasis of breast cancer both in vitro and in vivo. Mechanistically, PC4 exerted its oncogenic functions by directly binding to c-Myc promoters and inducing Warburg effect. Conclusions: Our study reveals for the first time that PC4 promotes breast cancer progression by directly regulating c-Myc transcription to promote Warburg effect, implying a novel therapeutic target for breast cancer. [ABSTRACT FROM AUTHOR]

Background: Radiotherapy to cancer patients is inevitably accompanied by normal tissue injury, and the bone is one of the most commonly damaged tissues. Damage to bone marrow mesenchymal stem cells (BM-MSCs) induced by radiation is thought to be a major cause of radiation-induced bone loss. Exosomes exhibit great therapeutic potential in the treatment of osteoporosis, but whether exosomes are involved in radiation-induced bone loss has not been thoroughly elucidated to date. The main purpose of this study is to investigate the role of exosomes derived from BM-MSCs in restoring recipient BM-MSC function and alleviating radiation-induced bone loss. Methods: BM-MSC-derived exosomes were intravenously injected to rats immediately after irradiation. After 28 days, the left tibiae were harvested for micro-CT and histomorphometric analysis. The effects of exosomes on antioxidant capacity, DNA damage repair, proliferation, and cell senescence of recipient BM-MSCs were determined. Osteogenic and adipogenic differentiation assays were used to detect the effects of exosomes on the differentiation potential of recipient BM-MSCs, and related genes were measured by qRT-PCR and Western blot analysis. β-Catenin expression was detected at histological and cytological levels. Results: BM-MSC-derived exosomes can attenuate radiation-induced bone loss in a rat model that is similar to mesenchymal stem cell transplantation. Exosome-treated BM-MSCs exhibit reduced oxidative stress, accelerated DNA damage repair, and reduced proliferation inhibition and cell senescence-associate protein expression compared with BM-MSCs that exclusively received irradiation. Following irradiation, exosomes promote β-catenin expression in BM-MSCs and restore the balance between adipogenic and osteogenic differentiation. Conclusions: Our findings indicate that BM-MSC-derived exosomes take effects by restoring the function of recipient BM-MSCs. Therefore, exosomes may represent a promising cell-free therapeutic approach for the treatment of radiation-induced bone loss. [ABSTRACT FROM AUTHOR]

To rescue ischemic myocardium from progressing to myocardial infarction, timely identification of the infarct size and reperfusion is crucial. However, fast and accurate identification, as well as the targeted protection of injured cardiomyocytes following ischemia/reperfusion (I/R) injury, remain significantly challenging. Here, a near infrared heptamethine dye IR‐780 is shown that has the potential to quickly monitor the area at risk following I/R injury by selectively entering the cardiomyocytes of the at‐risk heart tissues. Preconditioning with IR‐780 or timely IR‐780 administration before reperfusion significantly protects the heart from ischemia and oxidative stress‐induced cell death, myocardial remodeling, and heart failure in both rat and pig models. Furthermore, IR‐780 can directly bind to F0F1‐ATP synthase of cardiomyocytes, rapidly decrease the mitochondrial membrane potential, and subsequently slow down the mitochondrial energy metabolism, which induces the mitochondria into a "quiescent state" and results in mitochondrial permeability transition pore inhibition by preventing mitochondrial calcium overload. Collectively, the findings show the feasibility of IR‐780‐based imaging and protection strategy for I/R injury in a preclinical context and indicate that moderate mitochondrial function depression is a mode of action that can be targeted in the development of cardioprotective reagents. [ABSTRACT FROM AUTHOR]

Background: The need for radiotherapy among the elderly rises with increasing life expectancy and a corresponding increase of elderly cancer patients. Radiation-induced skin injury is one of the most frequent adverse effects in radiotherapy patients, severely limiting their life quality. Re-epithelialization and collagen deposition have essential roles in the recovery of skin injuries induced by high doses of ionizing radiation. At the same time, radiation-induced senescent cells accumulate in irradiated tissues. However, the effects and mechanisms of senescent cells on re-epithelialization and collagen deposition in radiation-induced skin injury have not been fully elucidated. Results: Here, we identified a role for a population of senescent cells expressing p16 in promoting re-epithelialization and collagen deposition in radiation-induced skin injury. Targeted ablation of p16+ senescent cells or treatment with Senolytics resulted in the disruption of collagen structure and the retardation of epidermal coverage. By analyzing a publicly available single-cell sequencing dataset, we identified fibroblasts as a major contributor to the promotion of re-epithelialization and collagen deposition in senescent cells. Notably, our analysis of publicly available transcriptome sequencing data highlighted IL-33 as a key senescence-associated secretory phenotype produced by senescent fibroblasts. Neutralizing IL-33 significantly impedes the healing process. Finally, we found that the effect of IL-33 was partly due to the modulation of macrophage polarization. Conclusions: In conclusion, our data suggested that senescent fibroblasts accumulated in radiation-induced skin injury sites participated in wound healing mainly by secreting IL-33. This secretion regulated the local immune microenvironment and macrophage polarization, thus emphasizing the importance of precise regulation of senescent cells in a phased manner. [ABSTRACT FROM AUTHOR]

Examines the effects of nerve growth factor (NGF) on the skin wound healing and blood recovery in mice after total body irradiation. Isolation of NGF from human placenta by gel-filtration and ion-affinity chromatography; Molecular weight of glycoproteins; Survival rate.

Currently, there is no effective treatment for chronic skin radiation injury, which burdens patients significantly. Previous studies have shown that cold atmospheric plasma has an apparent therapeutic effect on acute and chronic skin injuries in clinical. However, whether CAP is effective for radiation-induced skin injury has not been reported. We created 35Gy X-ray radiation exposure within 3 * 3 cm2 region of the left leg of rats and applied CAP to the wound bed. Wound healing, cell proliferation and apoptosis were examined in vivo or vitro. CAP alleviated radiation-induced skin injury by enhancing proliferation and migration and cellular antioxidant stress and promoting DNA damage repair through regulated nuclear translocation of NRF2. In addition, CAP inhibited the proinflammatory factors' expression of IL-1β, TNF-α and temporarily increased the pro repair factor's expression of IL-6 in irradiated tissues. At the same time, CAP also changed the polarity of macrophages to a repair-promoting phenotype. Our finding suggested that CAP ameliorated radiation-induced skin injury by activating NRF2 and ameliorating the inflammatory response. Our work provided a preliminary theoretical foundation for the clinical administration of CAP in high-dose irradiated skin injury. [Display omitted] • CAP alleviates radiation-induced skin injury. • CAP increased antioxidants through nuclear translocation of NRF2. • CAP ameliorates the inflammatory in irradiated skin. [ABSTRACT FROM AUTHOR]

Postovulatory aging can trigger deterioration of oocyte quality and subsequent embryonic development, and thus reduce the success rates of assisted reproductive technology (ART). The molecular mechanisms underlying postovulatory aging, and preventative strategies, remain to be explored. The near‐infrared fluorophore IR‐61, a novel heptamethine cyanine dye, has the potential for mitochondrial targeting and cell protection. In this study, we found that IR‐61 accumulated in oocyte mitochondria and reduced the postovulatory aging‐induced decline in mitochondrial function, including mitochondrial distribution, membrane potential, mtDNA number, ATP levels, and mitochondrial ultrastructure. In addition, IR‐61 rescued postovulatory aging‐caused oocyte fragmentation, defects in spindle structure, and embryonic developmental potential. RNA sequencing analysis indicated that the postovulatory aging‐induced oxidative stress pathway might be inhibited by IR‐61. We then confirmed that IR‐61 decreased the levels of reactive oxygen species and MitoSOX, and increased GSH content in aged oocytes. Collectively, the results indicate that IR‐61 may prevent postovulatory aging by rescuing oocyte quality, promoting successful rate in ART procedure. [ABSTRACT FROM AUTHOR]

Objectives: Intestinal mucositis is the major side effect during abdominal or pelvic radiotherapy, but the underlying immunogen remains to be further characterised and few radioprotective agents are available. This study investigated the role of dsDNA‐triggered inflammasomes in intestinal mucositis during radiotherapy. Methods: Pro‐inflammatory cytokines were detected by ELISA. Radiation‐induced intestinal injury in mice was analyzed by means of survival curves, body weight, HE staining of intestines, and intestinal barrier integrity. Western blot, immunofluorescence staining, co‐immunoprecipitation assay and flow cytometry were used to investigate the regulatory role of dsDNA on inflammasomes. Results: Here, we show that a high level of IL‐1β and IL‐18 is associated with diarrhoea in colorectal cancer (CRC) patients during radiotherapy, which accounts for intestinal radiotoxicity. Subsequently, we found that the dose‐dependently released dsDNA from the intestinal epithelial cells (IECs) serves as the potential immunogenic molecule for radiation‐induced intestinal mucositis. Our results further indicate that the released dsDNA transfers into the macrophages in an HMGB1/RAGE‐dependent manner and then triggers absent in melanoma 2 (AIM2) inflammasome activation and the IL‐1β and IL‐18 secretion. Finally, we show that the FDA‐approved disulfiram (DSF), a newly identified inflammasome inhibitor, could mitigate intestinal radiotoxicity by controlling inflammasome. Conclusion: These findings indicate that the extracellular self‐dsDNA released from the irradiated IECs is a potential immunogen to stimulate immune cells and trigger the subsequent intestinal mucositis, while blunting the dsDNA‐triggered inflammasome in macrophages may represent an exciting therapeutic strategy for side effects control during abdominal radiotherapy. [ABSTRACT FROM AUTHOR]

Background: Bladder cancer has a high rate of recurrence and drug resistance due to the lack of effective therapies. IR-780 iodide, a near-infrared (NIR) mitochondria-targeting fluorescent agent, has been demonstrated to achieve higher selectivity than other drugs in different tumor types and exhibited tumor-killing effects in some cancers. However, this therapeutic strategy is rarely studied in bladder cancer. Material and methods: The accumulation of IR-780 in bladder cancer was measured by NIR imaging. Human bladder cell lines (T24, 5637, and TCCSUP) were treated with IR-780 or combined IR-780 and hyperbaric oxygen (HBO). Cell viability, cell apoptosis, cellular ATP production, mitochondrial reactive oxygen species (ROS), and plasma membrane potential were detected. Mitochondrial complex I protein NDUFS1 was measured by western blot. To confirm the anti-tumor efficacy of IR-780 + HBO, mouse bladder cell line (MB49) tumor-bearing mice were established and tumor size and weight were recorded. Besides, cell apoptosis and tumor size were assessed in drug-resistant bladder cancer cells (T24/DDP) and xenografts to evaluate the effect of IR-780 + HBO on drug-resistant bladder cancer. Results: IR-780 selectively accumulated in bladder cancer (bladder cancer cells, transplanted tumors, and bladder cancer tissue from patients) and could induce cancer cell apoptosis by targeting the mitochondrial complex I protein NDUFS1. The combination with HBO could significantly enhance the anti-tumor effect of IR-780 in vitro by promoting cancer cell uptake and inducing excessive mitochondrial ROS production, while suppressing tumor growth and recurrence in animal models without causing apparent toxicity. Moreover, this combination antitumor strategy was also demonstrated in drug-resistant bladder cancer cells (T24/DDP) and xenografts. Conclusion: We identified for the first time a combination of IR-780 and HBO (IR-780 + HBO), which exhibits mitochondria-targeting and therapeutic capabilities, as a novel treatment paradigm for bladder cancer. [ABSTRACT FROM AUTHOR]

Skin wound is an emerging health challenge on account of the high-frequency trauma, surgery and chronic refractory ulcer. Further study on the disease biology will help to develop new effective approaches for wound healing. Here, we identified a wound-stress responsive gene, activating transcription factor 3 (ATF3), and then investigated its biological action and mechanism in wound healing. In the full-thickness skin wound model, ATF3 was found to promote fibroblast activation and collagen production, resulted in accelerated wound healing. Mechanically, ATF3 transcriptionally activated TGF-β receptor Ⅱ via directly binding to its specific promoter motif, followed by the enhanced TGF-β/Smad pathway in fibroblasts. Moreover, the increased ATF3 upon skin injury was partly resulted from hypoxia stimulation with Hif-1α dependent manner. Altogether, this work gives novel insights into the biology and mechanism of stress-responsive gene ATF3 in wound healing, and provides a potential therapeutic target for treatment. Schematic diagram for the potential mechanism of ATF3 in wound healing. Upon skin injury, the increased ATF3 at early stage is partly resulted from hypoxia stimulation with Hif-1α dependent manner. And then ATF3 drives fibroblast activation, collagen production and wound closure through transcriptionally activating TGFBR2 and enhancing TGF-β/Smad pathway. [Display omitted] • ATF3 accelerates wound healing through increasing fibroblast activation and collagen production in mice. • As a key transcriptional regulator of TGFBR2, ATF3 directly binds to its specific promoter motifs and enhances TGF-β/Smad pathway in fibroblasts. • ATF3 can be induced by hypoxia signal in fibroblasts. [ABSTRACT FROM AUTHOR]

Bladder cancer is a common malignancy with a poor prognosis worldwide. Positive cofactor 4 (PC4) is widely reported to promote malignant phenotypes in various tumors. Nonetheless, the biological function and mechanism of PC4 in bladder cancer remain unclear. Here, for the first time, we report that PC4 is elevated in bladder cancer and is associated with patient survival. Moreover, PC4 deficiency obviously inhibited bladder cancer cell proliferation and metastasis by reducing the expression of genes related to cancer stemness (CD44, CD47, KLF4 and c-Myc). Through RNA-seq and experimental verification, we found that activation of the Wnt5a/β-catenin pathway is involved in the malignant function of PC4. Mechanistically, PC4 directly interacts with Sp1 to promote Wnt5a transcription. Thus, our study furthers our understanding of the role of PC4 in cancer stemness regulation and provides a promising strategy for bladder cancer therapy. [ABSTRACT FROM AUTHOR]

Oxidative stress injury and subsequent inflammatory response are considered to play critical roles in radiation-induced lung injury (RILI). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that regulates oxidative stress response and represses inflammation, but its therapeutic value in RILI remains elusive. Our previous studies have shown that the near-infrared (NIR) IR-61 dye evokes intracellular antioxidant defense by enhancing Nrf2 signaling and promoting anti-inflammatory effects. We established a model of RILI in mice exposed to whole-thoracic irradiation. The results showed that IR-61 treatment notably improved pulmonary functions by decreasing lung density and diminishing airway resistance. In addition, IR-61 significantly ameliorated radiation-induced inflammatory cell infiltration and proinflammatory cytokine (IL-1β, IL-6, and TNF-α) release, thereby mitigating inflammatory response. Furthermore, IR-61 mitigated radiation-induced lung fibrosis by decreasing the collagen deposition and the levels of fibrogenesis-related factors (collagen I, collagen III, α-SMA, and fibronectin). More importantly, IR-61 was found to accumulate in the mitochondria of macrophages in irradiated lung tissues. Therefore, the functions of IR-61 in macrophages were further studied in irradiated macrophage cell lines, MH-s and RAW 264.7 in vitro. The results indicated that IR-61 upregulated the expression of Nrf2 and heme oxygenase-1 (HO-1) and decreased the levels of reactive oxygen species (ROS) and pro-inflammatory cytokines (IL-1β and IL-6) in macrophages after radiation. In summary, our study suggests that IR-61 effectively mitigates RILI by activating Nrf2 signaling in irradiated lung tissues. In particular, Nrf2-mediated anti-inflammatory and antioxidant effects in irradiated lung tissue macrophages play critical roles in protecting against RILI. [ABSTRACT FROM AUTHOR]

Summary: To explore the competence of near-infrared luminescent quantum dots for visual in vivo imaging on oral squamous carcinoma BcaCD885 cells. Peptide-conjugated near-infrared quantum dots, with an emission wavelength of 800nm (QD800), were used to label BcaCD885 cells by endocytosis. The QD800-labeled BcaCD885 cells were inoculated in the dorsum subcutaneous, back muscle and under the cheek oral mucosa of nude mice at cell counts of 1×103, 1×104, 1×105, and 1×106 respectively. At different time points, these mice were examined by an in vivo imaging system to investigate the sensitivity of QD800 to visual detection in BcaCD885 cells and the conditions of dynamic imaging. The minimum detectable counts of BcaCD885 cells for QD800-based in vivo imaging were 1×104 in the dorsum subcutaneous, back muscle and under the cheek oral mucosa. As tissue depth increased, the detectable fluorescence intensity dropped; as cell counts increased, the fluorescence intensity and the visual image duration also increased, especially for the QD800-labeled BcaCD885 cells in which counts of 1×106 were visual imaged in the dorsum subcutaneous, back muscle and under the cheek oral mucosa for 16d. Our study successfully used cell-penetrating peptides to conjugate near-infrared quantum dots for the first time and labeled oral squamous carcinoma cells with quantum dot conjugates by endocytosis for visual in vivo imaging. Because of the strong penetration power to tissues, near-infrared quantum dot technology exhibits great promise for the early diagnosis, visual observation and individualized treatment of oral cancer. [ABSTRACT FROM AUTHOR]

The immune microenvironment constructed by tumor-infiltrating immune cells and the molecular phenotype defined by hormone receptors (HRs) have been implicated as decisive factors in the regulation of breast cancer (BC) progression. Here, we found that the infiltration of mast cells (MCs) informed impaired prognoses in HR(+) BC but predicted improved prognoses in HR(−) BC. However, molecular features of MCs in different BC remain unclear. We next discovered that HR(−) BC cells were prone to apoptosis under the stimulation of MCs, whereas HR(+) BC cells exerted anti-apoptotic effects. Mechanistically, in HR(+) BC, the KIT ligand (KITLG), a major mast cell growth factor in recruiting and activating MCs, could be transcriptionally upregulated by the progesterone receptor (PGR), and elevate the production of MC-derived granulin (GRN). GRN attenuates TNFα-induced apoptosis in BC cells by competitively binding to TNFR1. Furthermore, disruption of PGR-KITLG signaling by knocking down PGR or using the specific KITLG-cKIT inhibitor iSCK03 potently enhanced the sensitivity of HR(+) BC cells to MC-induced apoptosis and exerted anti-tumor activity. Collectively, these results demonstrate that PGR-KITLG signaling in BC cells preferentially induces GRN expression in MCs to exert anti-apoptotic effects, with potential value in developing precision medicine approaches for diagnosis and treatment. • The infiltration of mast cells impaired prognoses in (HR) (+) BC but predicted improved prognoses in HR(−) BC. • HR(−) BC cells were prone to apoptosis under the stimulation of MCs, whereas HR(+) BC cells exerted anti-apoptotic effects. • PGR transcriptionally up regulates the expression of KITLG in HR(+) BC cells. • KITLG elevates the infiltration of MCs and stimulates GRN expression in MCs. • MC-derived GRN can competitively bind to TNFR1, thus inhibiting the TNF-α apoptotic pathway. [ABSTRACT FROM AUTHOR]

• Oxygen supplementation may disrupt virus replication. • Oxygen therapy can improve the antiviral immune response. • An oxygen-rich environment may down-regulate ACE2 expression. • Nocturnal oxygen therapy may delay the progression of COVID-19. There is currently no effective antiviral therapy or immune-based treatment for coronavirus disease (COVID-19). The urgent challenge is to prevent the transition of COVID-19 from mild to severe infection. This paper discussed nocturnal oxygen therapy as a new option for people with COVID-19 under home quarantine. It suggested that nocturnal oxygen therapy in the early stages may be helpful in preventing disease progression by inhibiting the rapid replication of the virus and improving the body's antiviral ability. [ABSTRACT FROM AUTHOR]

Maternal aging is associated with a decline in oocyte quality, which leads to the decreased fertility. Therefore, developing approaches to reduce aging-induced deterioration of oocyte quality in older women is important. Near-infrared cell protector-61 (IR-61), a novel heptamethine cyanine dye, has the potential for antioxidant effects. In this study, we found that IR-61 can accumulate in the ovaries and improved ovarian function of naturally aged mice; it also increased the oocyte maturation rate and quality by maintaining the integrity of the spindle/chromosomal structure and reducing the aneuploidy rate. In addition, the embryonic developmental competence of aged oocytes was improved. Finally, RNA-sequencing analysis indicated that IR-61 might perform the beneficial effects on aged oocytes by regulating mitochondrial function, this was confirmed by immunofluorescence analysis of mitochondrial distribution and reactive oxygen species. Taken together, our findings demonstrate that IR-61 supplementation in vivo can increase oocyte quality and protect oocytes from aging-induced mitochondrial dysfunction, and thus could improve the fertility of older women and efficiency of assisted reproductive technology. IR-61 can accumulate in the ovaries and improve the quality of aged oocytes by restoring mitochondrial function, enhancing meiotic competence, reducing the aneuploidy rate, and increasing embryonic development potential. These findings provide a theoretical basis for improving the reproductive outcomes of women of advanced maternal age. [Display omitted] • IR-61 accumulates in the ovaries and increases oocyte quantity in aged mice. • IR-61 supplementation enhances maturation competence and reduces the aneuploidy rate of aged oocytes. • IR-61 supplementation improves the developmental potential of aged oocytes. • IR-61 supplementation restores the mitochondrial function of aged oocytes. [ABSTRACT FROM AUTHOR]

[Display omitted] • A near-infrared dye IR-780 can accumulate in injured brain microvascular endothelial cells and decrease radiation-induced oxidative stress. • IR-780 protects the blood–brain barrier in radiation-induced brain injury. • IR-780 alleviates brain tissue inflammation following radiation. Radiation-induced brain injury (RIBI) is a common complication of radiation therapy for brain tumors. Vascular damage is one of the key factors closely related to the severity of the RIBI. However, effective vascular target treatment strategies are lacking. Previously, we have identified a fluorescent small molecule dye, IR-780, which shows the properties of injury tissue targeting and provided protection against various injuries by modulating oxidative stress. This study aims to validate the therapeutic effect of IR-780 on RIBI. The effectiveness of IR-780 against RIBI has been comprehensively evaluated through techniques such as behavior, immunofluorescence staining, quantitative real-time polymerase chain reaction, Evans Blue leakage experiments, electron microscopy, and flow cytometry. Results show that IR-780 improves cognitive dysfunction, reduces neuroinflammation, restores the expression of tight junction proteins in the blood–brain barrier (BBB), and promotes the recovery of BBB function after whole brain irradiation. IR-780 also accumulates in injured cerebral microvascular endothelial cells, and its subcellular location is in the mitochondria. More importantly, IR-780 can reduce the levels of cellular reactive oxygen species and apoptosis. Moreover, IR-780 has no significant toxic side effects. IR-780 alleviates RIBI by protecting vascular endothelial cells from oxidative stress, reducing neuroinflammation, and restoring BBB function, suggesting IR-780 as a promising treatment candidate for RIBI therapy. [ABSTRACT FROM AUTHOR]

• PC4 is abnormally highly expressed in DLBCL and is positively correlated with c-Myc expression and is correlated with poor prognosis of patients. • Inhibition of PC4 induces autophagic cell death in MYC-expressing DLBCL cell lines. • PC4 exerts its oncogenic functions by directly binding to c-Myc promoters to improve cell glycolysis. • Knockdown of PC4 enhances the therapeutic effect of doxorubicin in MYC-expressing DLBCL. MYC-expressing diffuse large B-cell lymphoma (DLBCL) is one of the refractory lymphomas. Currently, the pathogenesis of MYC-expressing DLBCL is still unclear, and there is a lack of effective therapy. We characterized positive cofactor 4 (PC4) as an upstream regulator of c-Myc, and PC4 is overexpressed in DLBCL and is closely related to clinical staging, prognosis, and c-Myc expression. Furthermore, our in vivo and in vitro studies revealed that PC4 knockdown can induce autophagic cell death and enhance the therapeutic effect of doxorubicin in MYC-expressing DLBCL. Inhibition of c-Myc–mediated aerobic glycolysis and activation of the AMPK/mTOR signaling pathway are responsible for the autophagic cell death induced by PC4 knockdown in MYC-expressing DLBCL. Using dual-luciferase reporter assay and electrophoretic mobility shift assay assays, we also found that PC4 exerts its oncogenic functions by directly binding to c-Myc promoters. To sum up, our study provides novel insights into the functions and mechanisms of PC4 in MYC-expressing DLBCL and suggests that PC4 may be a promising therapeutic target for MYC-expressing DLBCL. . [Display omitted] [ABSTRACT FROM AUTHOR]

The development of chemoresistance to 5-fluorouracil (5-FU) is a major obstacle for sustained effective treatment of colorectal cancer (CRC), with the mechanisms being not fully understood. Here we demonstrated that tumor associated macrophages (TAMs) became activated during treatment with 5-FU and secreted factors that protected the CRC cells against chemotherapy with 5-FU. By performing metabolomics analysis, we identified putrescine, a member of polyamines, inducing resistance to 5-FU-triggered CRC apoptosis and tumor suppression via JNK-caspase-3 pathway. Noteworthily, either pharmacological or genetic blockage of ornithine decarboxylase (ODC) prevented TAMs-induced chemoresistance to 5-FU in vitro and in vivo. Our findings show that TAMs are potent mediators of resistance to 5-FU chemotherapy and uncover potential targets to enhance chemotherapy sensitivity in patients with CRC. [ABSTRACT FROM AUTHOR]

Abstract: Personalized oncology significantly relies on the development of theranostic agents to integrate cancer therapeutics and diagnostics. Current strategy for development of such multifunctional agents requires multistep chemical conjugation with cancer specific ligands, contrast agents and therapeutic drugs. In this study, we reported a near infrared (NIR) heptamethine indocyanine dye, IR-780, which selectively accumulated in the mitochondria of drug-resistant human lung cancer cells (A549/DR) and significantly inhibited cell growth, self-renewal and migration without the need of any chemical conjugation. IR-780 was also able to induce A549/DR cell apoptosis by disrupting the mitochondrial function. Furthermore, IR-780 dye exhibited remarkable tumoricidal activity and inhibited tumor recurrence in mouse syngeneic Lewis lung carcinoma xenograft model. With the unique properties of targeting, near infrared imaging and inhibitive effect to the drug-resistant cancer cells both in vitro and in vivo, IR-780 may represent a potential theranostic agent for tumor recurrence. [Copyright &y& Elsevier]