Cathepsin B: The dawn of tumor therapy.

Cathepsin B (CTSB) is a key lysosomal protease that plays a crucial role in the development of cancer. This article elucidates the relationship between CTSB and cancer from the perspectives of its structure, function, and role in tumor growth, migration, invasion, metastasis, angiogenesis and autophagy. Further, we summarized the research progress of cancer treatment related drugs targeting CTSB, as well as the potential and advantages of Traditional Chinese medicine in treating tumors by regulating the expression of CTSB.

Ononin promotes radiosensitivity in lung cancer by inhibiting HIF-1α/VEGF pathway.

BACKGROUND: In our previous study, we provided evidence that Astragalus mongholicus Bunge(AM) and its extracts possess a protective capability against radiation-induced damage, potentially mediated through the reduction of reactive oxygen species (ROS) and nitric oxide (NO). However, we were pleasantly surprised to discover during our experimentation that AM not only offers protection against radiation damage but also exhibits a radiation sensitization effect. This effect may be attributed to a specific small molecule present in AM known as ononin. Currently, radiation sensitizers are predominantly found in nitrazole drugs and nanomaterials, with no existing reports on the radiation sensitization properties of ononin, nor its underlying mechanism. PURPOSE: This study aims to investigate the sensitization effect of the small molecule ononin derived from AM on lung cancer radiotherapy, elucidating its specific molecular mechanism of action. Additionally, the safety profile of combining astragalus small molecule ononin with radiation therapy will be evaluated. METHODS: The effective concentration of ononin was determined through cell survival experiments, and the impact of ononin combined with varying doses of radiation on lung cancer cells was observed using CCK-8 and cell cloning experiments. The apoptotic effect of ononin combined with radiation on lung cancer cells was assessed using Hochester staining, flow cytometry, and WB assay. Additionally, WB and immunofluorescence analysis were conducted to investigate the influence of ononin on HIF-1α/VEGF pathway. Furthermore, Molecular Dynamics Simulation was employed to validate the targeted binding ability of ononin and HIF-1α. A lung cancer cell line was established to investigate the effects of knockdown and overexpression of HIF-1α. Subsequently, the experiment was repeated using tumor bearing nude mice and C57BL/6 mouse models in an in vivo study. Tumor volume was measured using a vernier caliper, while HE, immunohistochemistry, and immunofluorescence techniques were employed to observe the effects of ononin combined with radiation on tumor morphology, proliferation, and apoptosis. Additionally, Immunofluorescence was employed to examine the impact of ononin on HIF-1α/VEGF pathway in vivo, and its effect on liver function in mice was assessed through biochemistry analysis. RESULTS: At a concentration of 25 µM, ononin did not affect the proliferation of lung epithelial cells but inhibited the survival of lung cancer cells. In vitro experiments demonstrated that the combination of ononin and radiation could effectively inhibit the growth of lung cancer cells, induce apoptosis, and suppress the excessive activation of the Hypoxia inducible factor 1 alpha/Vascular endothelial growth factor pathway. In vivo experiments showed that the combination of ononin and radiation reduced the size and proliferation of lung cancer tumors, promoted cancer cell apoptosis, mitigated abnormal activation of the Hypoxia inducible factor 1 alpha pathway, and protected against liver function damage. CONCLUSION: This study provides evidence that the combination of AM and its small molecule ononin can enhance the sensitivity of lung cancer to radiation. Additionally, it has been observed that this combination can specifically target HIF-1α and exert its effects. Notably, ononin exhibits the unique ability to protect liver function from damage while simultaneously enhancing the tumor-killing effects of radiation, thereby demonstrating a synergistic and detoxifying role in tumor radiotherapy. These findings contribute to the establishment of a solid basis for the development of novel radiation sensitizers derived from traditional Chinese medicine.

A potential marker of radiation based on 16S rDNA in the rat model: Intestinal flora.

The gastrointestinal microbiota plays an important role in the function of the host intestine. However, little is currently known about the effects of irradiation on the microorganisms colonizing the mucosal surfaces of the gastrointestinal tract. The aim of this study was to investigate the effects of X-ray irradiation on the compositions of the large intestinal Microbiotas of the rat. The gut microbiotas in control mice and mice receiving irradiation with different dose treatment were characterized by high-throughput sequencing of the bacterial 16S rDNA gene and their metabolites were detected by gas chromatography-mass spectrometry. Unexpectedly, the diversity was increased mildly at 2Gy irradiation, and dose dependent decreased at 4Gy, 6Gy, 8Gy irradiation. The phyla with large changes in phylum level are Firmicutes, Bacteroides and Proteobacteria; the abundance ratio of Firmicutes/Bacteroides is inverted; and when 8Gy is irradiated, the phylum abundance level was significantly increased. At the genus level, the abundance levels of Phascolarctobacterium, Ruminococcaceae and Lachnospiraceae increased at 2Gy irradiation, and significantly decreased at 4Gy, 6Gy, and 8Gy irradiation; the abundance level of Prevotellaceae diminished at 2Gy irradiation, and enhanced at 4Gy, 6Gy, 8Gy irradiation; The abundance level of Violet bacteria (Christenellaceae) and Lactobacillus attenuated in a dose-dependent manner; Lachnoclostridium enhanced in a dose-dependent manner; Bacteroides was in 4Gy, 6Gy, 8Gy The abundance level increased significantly during irradiation; the abundance level of Shigella (Escherichia-Shigella) only increased significantly during 8Gy irradiation. Lefse predicts that the biomarker at 0Gy group is Veillonellaceae, the biomarker at 2Gy group is Firmicutes, the biomarkers at 4Gy group are Dehalobacterium and Dehalobacteriaceae, the biomarkers at 6Gy group are Odoribacter, and the biomarkers at 8Gy group are Anaerotruncus, Holdemania, Proteus, Bilophila, Desufovibrionales and Deltaproteobacteria. Overall, the data presented here reveal that X-ray irradiation can cause imbalance of the intestinal flora in rats; different doses of irradiation can cause different types of bacteria change. Representative bacteria can be selected as biomarkers for radiation damage and repair.This may contribute to the development of radiation resistance in the future.

Protective effect of quercetin on lung epithelial cell bystander-effect in the conditioned medium model of lung cancer metastasis induced by radiation.

To investigate the protective effect of Quercetin (Que) on lung epithelial cells (BEAS-2B) induced bystander effect (RIBE) after heavy ion irradiation of A549 cells. A549 cells were irradiated with 2 Gy X heavy ion rays to obtain a conditioned medium. BEAS-2B was incubated with a conditioned medium or Que. CCK-8 assay was used to screen the optimal effective concentration of Que and detect cell proliferation. Cell number was measured by cell counter and apoptosis rate was measured by flow cytometry. HMGB1 and ROS levels were measured by ELISA. Western blot was used to detect the protein expression of HMGB1, TLR4, p65, Bcl-2, Bax, Caspase3 and Cleaved Caspase3. The growth and proliferation rate of BEAS-2B decreased while the apoptosis rate increased after conditioned medium stimulation, and Que intervention inhibited this effect. The expression of HMGB1 and ROS increased after conditioned medium stimulation, and this effect was inhibited by Que intervention. In addition, the conditioned medium increased the levels of proteins of HMGB1, TLR4, p65, Bax, Caspase3 and Cleaved Caspase 3, and decreased levels of Bcl-2 protein, but Que intervention decreased the levels of HMGB1, TLR4, p65, Bax, Caspase3 and Cleaved Caspase 3proteins, and increased levels of Bcl-2 protein. The RIBE of BEAS-2B induced by irradiation of A549 is associated with HMGB1TLR4/NF-κB signaling pathway in conditioned medium inducing apoptosis by activating ROS, and Que may block RIBE-induced apoptosis by regulating HMGB1/TLR4/NF-κB pathway.

Review: Mechanisms and perspective treatment of radioresistance in non-small cell lung cancer.

Radiotherapy is the major treatment of non-small cell lung cancer (NSCLC). The radioresistance and toxicity are the main obstacles that leading to therapeutic failure and poor prognosis. Oncogenic mutation, cancer stem cells (CSCs), tumor hypoxia, DNA damage repair, epithelial-mesenchymal transition (EMT), and tumor microenvironment (TME) may dominate the occurrence of radioresistance at different stages of radiotherapy. Chemotherapy drugs, targeted drugs, and immune checkpoint inhibitors are combined with radiotherapy to treat NSCLC to improve the efficacy. This article reviews the potential mechanism of radioresistance in NSCLC, and discusses the current drug research to overcome radioresistance and the advantages of Traditional Chinese medicine (TCM) in improving the efficacy and reducing the toxicity of radiotherapy.

Radiation-Induced Bystander Effect on the Genome of Bone Marrow Mesenchymal Stem Cells in Lung Cancer.

Aims: Radiation by-radiation effect (RIBE) can induce the genomic instability of bone marrow mesenchymal stem cells (BMSCs) adjacent to lung cancer, and this effect not only exists in the short-term, but also accompanies it in the long-term, but its specific mechanism is not clear. Our goal is to explore the similarities and differences in the mechanism of genomic damage in tumor-associated BMSCs induced by short-term and long-term RIBE, and to provide a theoretical basis for adjuvant drugs for protection against RIBE at different clinical time periods. Results: We found that both short- and long-term RIBE induced genomic instability. We could show a high expression of TGF-ß1, TNF-α, and HIF-1α in tumor-associated BMSCs after short-term RIBE whereas only TNF-α and HIF-1α expression was increased in long-term RIBE. We further confirmed that genomic instability is associated with the activation of the HIF-1α pathway and that this is mediated by TNF-α and TGF-ß1. In addition, we found differences in the mechanisms of genomic instability in the considered RIBE windows of analysis. In short-term RIBE, both TNF-α and TGF-ß1 play a role, whereas only TNF-α plays a decisive role in long-term RIBE. In addition, there were differences in BMSC recruitment and genomic instability of different tissues with a more pronounced expression in tumor and bone marrow than compared to lung. Innovation and Conclusion: We could show dynamic changes in the expression of the cytokines TGF-ß1 and TNF-α during short- and long-term RIBE. The differential expression of the two is the key to causing the genomic damage of tumor-associated BMSCs in the considered windows of analysis. Therefore, these results may serve as a guideline for the administration of radiation protection adjuvant drugs at different clinical stages. Antioxid. Redox Signal. 38, 747-767.

Potential molecular mechanism of Guiqi Baizhu Decoction in radiation-induced intestinal edema by regulating HIF-1a, AQP4 and Na+/K+-ATPase.

BACKGROUND: Guiqi Baizhu Decoction (GQBZD) has a good protective effect on radiation-induced intestinal edema (RIIE). However, the underlying molecular mechanisms need further elucidation. PURPOSE: To reveal the potential mechanism of RIIE and GQBZD treatment. METHODS: SD rats were irradiated with 6Gy X-ray to establish RIIE model. The general condition of the rats was observed; the dry/wet weight ratio of colon tissue was detected; the morphological changes of colon tissue were observed by HE staining; the expressions of ROS, HIF-1α and AQP4 in colon tissue were detected by confocal laser scanning; the expression of edema-related proteins was detected by Western blot. In addition, human colon epithelial cells (NCM460) was irradiated with 2Gy X-ray, and HIF-1α expression in NCM460 was knocked down by small interfering RNA (siRNA) transfection, and the activity of Na+/K+-ATPase was detected by enzyme activity kit; the ROS expression was detected by flow cytometer; the AQP4 expression was detected by laser confocal microscopy; and the expression of edema-related proteins were detected by Western blot. RESULTS: We found that after irradiation, the colon tissue of rats was significantly edema, mainly manifested as mucosal and submucosal edema, and the ultrastructure was reflected in the structural damage of nucleus and mitochondria. ROS, HIF-1α and AQP4 were significantly expressed, and Na+/K+-ATPase expression/activity was decreased. After the intervention of GQBZD, the edema of the colon tissue of the rats was improved, the expressions of ROS, HIF-1α and AQP4 were decreased, and the expression/activity of Na+/K+-ATPase was increased. CONCLUSION: Ionizing radiation (IR) can cause significant intestinal edema. AQP4 and Na+/K+-ATPase are the key factors of RIIE, which are regulated by ROS and HIF-1α. GQBZD can improve hypoxia and oxidative stress, regulate the expression of AQP4 and Na+/K+-ATPase, and achieve a protective effect on RIIE. This study is the first to reveal the mechanism of RIIE.

Optical amplification from high vibrational states of ionized nitrogen molecules generated by 800-nm femtosecond laser pulses.

We experimentally investigated the interaction between nitrogen molecules and intense femtosecond laser pulses. When irradiated by an 800-nm pump laser and a delayed 355-nm seed laser, the spectral lines around 353.3 nm and 353.8 nm are observed to be greatly amplified, no matter whether the pump laser is circularly or linearly polarized. The two spectral lines correspond to the transition of N2+ (B, ν' = 5 → X, ν = 4) and N2+ (B, ν' = 4 → X, ν = 3), respectively. In comparison with the spectral lines related with ground vibrational states of nitrogen molecular ion, the observed amplification exhibits different polarization dependence of the pump laser. This distinctive change can be explained by the population variation of high vibrational states caused by the pump laser with different polarizations.

Duality of Interactions Between TGF-ß and TNF-α During Tumor Formation.

The tumor microenvironment is essential for the formation and development of tumors. Cytokines in the microenvironment may affect the growth, metastasis and prognosis of tumors, and play different roles in different stages of tumors, of which transforming growth factor ß (TGF-ß) and tumor necrosis factor α (TNF-α) are critical. The two have synergistic and antagonistic effect on tumor regulation. The inhibition of TGF-ß can promote the formation rate of tumor, while TGF-ß can promote the malignancy of tumor. TNF-α was initially determined to be a natural immune serum mediator that can induce tumor hemorrhagic necrosis, it has a wide range of biological activities and can be used clinically as a target to immune diseases as well as tumors. However, there are few reports on the interaction between the two in the tumor microenvironment. This paper combs the biological effect of the two in different aspects of different tumors. We summarized the changes and clinical medication rules of the two in different tissue cells, hoping to provide a new idea for the clinical application of the two cytokines.

Ramsey interferometry through coherent A2Πu-X2Σg+-B2Σu+ coupling and population transfer in N2+ air laser.

Motivated by the hot debate on the mechanism of laser-like emission at 391 nm from N2 gas irradiated by a strong 800 nm pump laser and a weak 400 nm seed laser, we theoretically study the temporal profile, optical gain, and modulation of the 391 nm signal from N2+. Our calculation sheds light on the long standing controversy on whether population inversion is indispensable for optical gain and show the Ramsey fringes of the emission intensity at 391 nm formed by additionally injecting another 800 nm pump or 400 nm seed, which provides strong evidence for the coherence driven modulation of transition dipole moment and population transfer between the A2Πu(ν=2)-X2Σg+ states and the B2Σu+(ν=0)-X2Σg+ states. Our results show that the 391 nm optical gain is susceptible to the population inversion within N2+ states manipulated by the Ramsey technique and thus clearly reveal their symbiosis. This study reveals not only the physical picture of producing N2+ population inversion but also versatile control of the N2+ air laser.

Deubiquitinase PSMD7 regulates cell fate and is associated with disease progression in breast cancer.

Breast cancer is the most common malignant tumor and the leading cause of cancer-related death in women. The ubiquitin-proteasome system regulates the stability of most proteins controlling various biological processes in human cells. PSMD7, as a core component of the 26S proteasome, is critical for the degradation of ubiquitinated proteins in the proteasome. Currently, PSMD7 expression and its roles in the progression of breast cancer remain largely unknown. In this study, we assessed the level of PSMD7 in breast cancer tissues and investigated the underlying molecular events by which PSMD7 could play a role in tumor progression. The results showed that the PSMD7 level was significantly upregulated in breast cancer tissues. PSMD7 expression was closely associated with tumor subtype, tumor size, lymph node invasion, and TNM stage. A high PSMD7 level predicted poor overall survival (OS) and disease-free survival (DFS) in breast cancer patients. Furthermore, univariate Cox regression analysis indicated that lymph node invasion, distant metastasis, and PSMD7 expression were associated with OS and DFS. Multivariate regression analysis indicated that PSMD7 was an independent predictor of OS (HR=1.310, 95% CI=1.038-1.652). Importantly, PSMD7 knockdown induced cell cycle arrest in the G0/G1 phase, leading to cell senescence and apoptosis. PSMD7 knockdown inhibited the expression of key cell cycle-related proteins and promoted the stability of p21 and p27 in breast cancer cells. PSMD7 may be a valuable prognostic indicator and potential therapeutic target for breast cancer.

Formation Mechanism of Excited Neutral Nitrogen Molecules Pumped by Intense Femtosecond Laser Pulses.

Backward amplified spontaneous emission of neutral nitrogen molecules has been reported from laser-induced plasma filaments. The cavity-free UV emission has great potential applications in remote atmospheric sensing. However, the formation mechanism for the excited nitrogen molecules inside filaments remains controversial. Here we study the formation mechanism of excited nitrogen molecules pumped by intense femtosecond laser pulses. After modification of the electron energy distribution by inclusion of the recollision between the electron and its parent ion as well as modification of the electron collision cross section by inclusion of the secondary electron contribution, the theoretical calculations reproduce the experimental observations very well. The results clearly demonstrate that excited nitrogen molecules are generated through collisions between energetic electrons and neutral nitrogen molecules.

Enhanced Coherent Emission from Ionized Nitrogen Molecules by Femtosecond Laser Pulses.

The forward emission spectra were experimentally measured for ionized nitrogen molecules by an 800 nm pump laser and a delayed seed laser. It was found that emission lines around both 428 and 391 nm are greatly enhanced upon use of a 391 or 428 nm seed laser. The emission lines around 391 and 428 nm can be assigned to the rotational transitions of N2+ [B2Σu+(v' = 0) → X2Σg+(v = 0)] and N2+ [B2Σu+(v' = 0) → X2Σg+(v = 1)], respectively. They originate from seed-induced superfluorescence and resonant stimulated Raman scattering. The genetic algorithm was utilized to simulate the experimental observations and determine the relative population of B2Σu+(v' = 0), X2Σg+(v = 1), and X2Σg+(v = 0). The result verifies that vibrational population inversion is achieved between B2Σu+(v' = 0) and X2Σg+(v = 0) by the 800 nm pump laser. Our finding provides new insights into controlling the coherent emission of ionized nitrogen molecules, which has promising application in filamentation-based remote atmospheric sensing.

Genome-Wide Analysis of the PvHsp20 Family in Switchgrass: Motif, Genomic Organization, and Identification of Stress or Developmental-Related Hsp20s.

Hsp20 proteins exist in all plant species and represent the most abundant small heat shock proteins (sHSPs) in plants. Hsp20s were known as chaperones maintaining cellular homeostasis during heat or other kinds of abiotic stresses. The objective of this study was to understand the phylogenetic relationship, genomic organization, diversification of motif modules, genome localization, expression profiles, and interaction networks of switchgrass (Panicum virgatum L.) Hsp20s (PvHsp20s). A total of 63 PvHsp20s were identified with their consensus as well as unique ACD motifs and gene structures analyzed. Most PvHsp20s (87%) were responsive to heat and other kinds of abiotic stresses. When under optimum growth condition, 38 of them displayed relative higher expression levels in inflorescence and seeds, suggesting their protective roles in the stress-sensitive reproductive organs. An in silico analysis of interaction network of PvHsp20 proteins further revealed potential interactive proteins, including stress-inducible ones in the network. Furthermore, PvHsp20 genes unevenly distributed in two sets of homeologous chromosomes, and only segmental duplication was found among the paralogous gene pairs, reflecting that the allotetraploidization of switchgrass allowed the accumulation of PvHsp20s that in turn facilitated its successful adaptation in hot and dry plateaus of North America. The present results provided an insight into PvHsp20s with an emphasis on the uniqueness of this gene family in switchgrass. Such information shall also be useful in functional studies of PvHsp20 genes and molecular breeding of switchgrass.

HOTAIR overexpression correlated with worse survival in patients with solid tumors.

INTRODUCTION: HOX transcript antisense intergenic RNA (HOTAIR), a long non-coding RNA transcribed from the antisense strand of the HOXC gene locus, has been reported to be overexpressed in various carcinomas and is thought to be an indicator of poor prognosis. EVIDENCE ACQUISITION: We performed a meta-analysis using qualified relevant literatures to evaluate the prognostic significance of HOTAIR in various solid tumors. Eligible studies were identified from PubMed, EMBASE and ISI Web of Science through multiple search strategies. We extracted and estimated the hazard ratios (HRs) for overall survival (OS), which compared the high and low expression levels of HOTAIR in patients with a variety of solid carcinomas. HRs and 95% confidence intervals (95% CIs) were calculated to pool the effect size. EVIDENCE SYNTHESIS: A total of 2407 patients from 21 studies with various solid carcinomas were included. For OS, higher HOTAIR expression could significantly predict worse outcome with the pooled HR of 2.21 (95 % CI 1.77-2.74, P<0.00001). The subgroup analysis suggested that the elevated levels of HOTAIR appears to be worse OS in Asian population (HR=2.06, 95% CI 1.80-2.37, P<0.00001) and digestive system cancers (HR=2.27, 95% CI 1.93-2.67, P<0.00001) including esophageal squamous cell carcinoma (HR=2.27, 95% CI 1.62-3.18, P<0.00001) and colorectal cancer (HR=4.65, 95 % CI 2.39-9.05, P<0.00001). CONCLUSIONS: The present meta-analysis revealed that the high level of HOTAIR is associated with an adverse OS in numerous solid cancers, suggesting that HOTAIR may be a predictor of poor prognosis for the development of solid tumors.

Clinical experience with modified Miccoli's endoscopic thyroidectomy for treatment of thyroid carcinoma in 86 cases.

BACKGROUND: The main purpose of this study was to assess the feasibility and relevant applying techniques of total thyroidectomy for thyroid carcinoma with a modified Miccoli's approach. METHODS: Eighty-six patients with thyroid carcinoma consecutively received radical operation from October 2007 to June 2012. A cavity above the gland was constructed by a modified suspension method using the suspension retractor with suction catheter after the pathway making. Eighty-six cases underwent the modified Miccoli's endoscopic thyroidectomy using the ultrasonic scalpel and the space maintain-regulating device. Level VI lymph node dissection was performed using the method of inspection pit. RESULTS: All the procedures were completed successfully. The average detection rate of level VI lymph nodes, the average time of thyroidectomy and lymph nodes dissection were 7.27 ± 3.99 pieces per case, 51.32 ± 13.35 min, and 38.43 ± 15.24 min, respectively. With regard to postoperative complications, there were three cases of delayed transient hoarseness, two patients with transient numbness of hands and feet, one subject with chylous fistula, and no hemorrhage. CONCLUSION: Total thyroidectomy for thyroid carcinoma can be safely performed with the modified Miccoli's approach by using ultrasonic scalpel and the space maintain-regulating device. Application of these adaptive reforms can obviously reduce the difficulties in manipulation and have the advantages of minimal incisions, good cosmetic results, less bleeding, shorter hospital stay, and fewer complications.