RNase P: Beyond Precursor tRNA Processing.

Ribonuclease P (RNase P) was first described in the 1970's as an endoribonuclease acting in the maturation of precursor transfer RNAs (tRNAs). More recent studies, however, have uncovered non-canonical roles for RNase P and its components. Here, we review the recent progress of its involvement in chromatin assembly, DNA damage response, and maintenance of genome stability with implications in tumorigenesis. The possibility of RNase P as a therapeutic target in cancer is also discussed.

Itaconate protects ferroptotic neurons by alkylating GPx4 post stroke.

Neuronal ferroptosis plays a key role in neurologic deficits post intracerebral hemorrhage (ICH). However, the endogenous regulation of rescuing ferroptotic neurons is largely unexplored. Here, we analyzed the integrated alteration of metabolomic landscape after ICH using LC-MS and MALDI-TOF/TOF MS, and demonstrated that aconitate decarboxylase 1 (Irg1) and its product itaconate, a derivative of the tricarboxylic acid cycle, were protectively upregulated. Deficiency of Irg1 or depletion of neuronal Irg1 in striatal neurons was shown to exaggerate neuronal loss and behavioral dysfunction in an ICH mouse model using transgenic mice. Administration of 4-Octyl itaconate (4-OI), a cell-permeable itaconate derivative, and neuronal Irg1 overexpression protected neurons in vivo. In addition, itaconate inhibited ferroptosis in cortical neurons derived from mouse and human induced pluripotent stem cells in vitro. Mechanistically, we demonstrated that itaconate alkylated glutathione peroxidase 4 (GPx4) on its cysteine 66 and the modification allosterically enhanced GPx4's enzymatic activity by using a bioorthogonal probe, itaconate-alkyne (ITalk), and a GPx4 activity assay using phosphatidylcholine hydroperoxide. Altogether, our research suggested that Irg1/itaconate-GPx4 axis may be a future therapeutic strategy for protecting neurons from ferroptosis post ICH.

Discovery of potent small molecule ubiquitin-specific protease 10 inhibitors with anti-hepatocellular carcinoma activity through regulating YAP expression.

High expression of ubiquitin-specific protease 10 (USP10) promote the proliferation of hepatocellular carcinoma (HCC), thus the development of USP10 inhibitors holds promise as a novel therapeutic approach for HCC treatment. However, the development of selective USP10 inhibitor is still limited. In this study, we developed a novel USP10 inhibitor for investigating the feasibility of targeting USP10 for the treatment of HCC. Due to high USP10 inhibition potency and prominent selectivity, compound D1 bearing quinolin-4(1H)-one scaffold was identified as a lead compound. Subsequent research revealed that D1 significantly inhibits cell proliferation and clone formation in HCC cells. Mechanistic insights indicated that D1 targets the ubiquitin pathway, facilitating the degradation of YAP (Yes-associated protein), thereby triggering the downregulation of p53 and its downstream protein p21. Ultimately, this cascade leads to S-phase arrest in HCC cells, followed by cell apoptosis. Collectively, our findings highlight D1 as a promising starting point for USP10-positive HCC treatment, underscoring its potential as a vital tool for unraveling the functional intricacies of USP10.

18 F-MFBG PET/CT and MRI in Identifying Brain Metastases in a Posttreatment Neuroblastoma Patient.

ABSTRACT: A 7-year-old girl with known brain metastasis from neuroblastoma developed new onset of severe headache. A brain MRI confirmed known metastasis in the right frontal lobe of the brain without new abnormalities. The patient was enrolled in a clinical trial using 18 F-MFBG PET/CT to evaluate patients with neuroblastoma. The images confirmed abnormal activity in the known lesion in the right frontal lobe. In addition, the PET showed additional foci of abnormal activity in the left cerebellopontine region. A follow-up brain MRI study acquired 4 months later revealed abnormal signals in the same region.

Olesoxime protects against cisplatin-induced acute kidney injury by attenuating mitochondrial dysfunction.

BACKGROUND: Mitochondrial dysfunction is a critical factor in the pathogenesis of acute kidney injury (AKI). Agents that ameliorate mitochondrial dysfunction hold potential for AKI treatment. The objective of this study was to investigate the impact of olesoxime, a novel mitochondrial-targeted agent, on cisplatin-induced AKI. METHODS: In vivo, a cisplatin-induced AKI mouse model was established by administering a single intraperitoneal dose of cisplatin (25 mg/kg) to male C57BL/6 mice for 72 hours, followed by gavage of either olesoxime or a control solution. In vitro, human proximal tubular HK2 cells were cultured and subjected to treatments with cisplatin, either in the presence or absence of olesoxime. RESULTS: In vivo, our findings demonstrated that olesoxime administration significantly mitigated the nephrotoxic effects of cisplatin in mice, as evidenced by reduced blood urea nitrogen (BUN) and serum creatinine (SCr) levels, improved renal histopathology, and decreased expression of renal tubular injury markers such as kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Furthermore, olesoxime administration markedly reduced cisplatin-induced apoptosis, inflammation, and oxidative stress in the kidneys of AKI mice. Additionally, olesoxime treatment effectively restored mitochondrial function in the kidneys of AKI mice. In vitro, our results indicated that olesoxime treatment protected against cisplatin-induced apoptosis and mitochondrial dysfunction in cultured HK2 cells. Notably, cisplatin's anticancer effects were unaffected by olesoxime treatment in human cancer cells. CONCLUSION: The results of this study suggest that olesoxime is a viable and efficient therapeutic agent in the treatment of cisplatin-induced acute kidney injury presumably by alleviating mitochondrial dysfunction.

RN0D, a galactoglucan from Panax notoginseng flower induces cancer cell death via PINK1/Parkin mitophagy.

Metabolic alterations within mitochondria, encompassing processes such as autophagy and energy metabolism, play a pivotal role in facilitating the swift proliferation, invasion, and metastasis of cancer cells. Despite this, there is a scarcity of currently available medications with proven anticancer efficacy through the modulation of mitochondrial dysfunction in a clinical setting. Here, we introduce the structural characteristics of RN0D, a galactoglucan isolated and purified from Panax notoginseng flowers, mainly composed of ß-1,4-galactan and ß-1,3/1,6-glucan. RN0D demonstrates the capacity to induce mitochondrial impairment in cancer cells, leading to the accumulation of reactive oxygen species, initiation of mitophagy, and reduction in both mitochondrial number and size. This sequence of events ultimately results in the inhibition of mitochondrial and glycolytic bioenergetics, culminating in the demise of cancer cells due to adenosine triphosphate (ATP) deprivation. Notably, the observed bioactivity is attributed to RN0D's direct targeting of Galectin-3, as affirmed by surface plasmon resonance studies. Furthermore, RN0D is identified as an activator of the PTEN-induced kinase 1 (PINK1)/Parkin pathway, ultimately instigating cytotoxic mitophagy in tumor cells. This comprehensive study substantiates the rationale for advancing RN0D as a potentially efficacious anticancer therapeutic.

XQZ3, a Chlorella pyrenoidosa polysaccharide suppresses cancer progression by restraining mitochondrial bioenergetics via HSP90/AKT signaling pathway.

The mitochondria are known to exert significant influence on various aspects of cancer cell physiology. The suppression of mitochondrial function represents a novel avenue for the advancement of anti-cancer pharmaceuticals. The heat shock protein HSP90 functions as a versatile regulator of mitochondrial metabolism in cancer cells, rendering as a promising target for anticancer interventions. In this work, a novel acid polysaccharide named as XQZ3 was extracted from Chlorella pyrenoidosa and purified by DEAE-cellulose and gel-filtration chromatography. The structural characteristic of XQZ3 was evaluated by monosaccharides composition, methylation analysis, TEM, FT-IR, and 2D-NMR. It was found that XQZ3 with a molecular weight of 29.13 kDa was a complex branched polysaccharide with a backbone mainly composed of galactose and mannose. It exhibited good antitumor activity in vitro and in vivo by patient-derived 3D organoid models and patient-derived xenografts models. The mechanistic investigations revealed that XQZ3 specifically interacted with HSP90, impeding the activation of the HSP90/AKT/mTOR signaling cascade. This, in turn, led to the induction of mitochondrial dysfunction, autophagy, and apoptosis, ultimately resulting in the demise of cancer cells due to nutrient deprivation. This study offers a comprehensive theoretical foundation for the advancement of XQZ3, a novel polysaccharide inhibitor targeting HSP90, with potential as an effective therapeutic agent against cancer.

Discovery of a selective TRF2 inhibitor FKB04 induced telomere shortening and senescence in liver cancer cells.

Telomere repeat binding factor 2 (TRF2), a critical element of the shelterin complex, plays a vital role in the maintenance of genome integrity. TRF2 overexpression is found in a wide range of malignant cancers, whereas its down-regulation could cause cell death. Despite its potential role, the selectively small-molecule inhibitors of TRF2 and its therapeutic effects on liver cancer remain largely unknown. Our clinical data combined with bioinformatic analysis demonstrated that TRF2 is overexpressed in liver cancer and that high expression is associated with poor prognosis. Flavokavain B derivative FKB04 potently inhibited TRF2 expression in liver cancer cells while having limited effects on the other five shelterin subunits. Moreover, FKB04 treatment induced telomere shortening and increased the amounts of telomere-free ends, leading to the destruction of T-loop structure. Consequently, FKB04 promoted liver cancer cell senescence without modulating apoptosis levels. In corroboration with these findings, FKB04 inhibited tumor cell growth by promoting telomeric TRF2 deficiency-induced telomere shortening in a mouse xenograft tumor model, with no obvious side effects. These results demonstrate that TRF2 is a potential therapeutic target for liver cancer and suggest that FKB04 may be a selective small-molecule inhibitor of TRF2, showing promise in the treatment of liver cancer.

Metagenomics and untargeted metabolomics analyses to unravel the formation mechanism of characteristic metabolites in Cantonese soy sauce during different fermentation stages.

Cantonese soy sauce (CSS) is an important Chinese condiment due to its distinctive flavor. Microorganisms play a significant role in the flavor formation of CSS during fermentation. However, the correlation between microbes and flavor compounds as well as the potential fermentation mechanism remained poorly uncovered. Here we revealed the dynamic changes of microbial structure and characteristics metabolites as well as their correlation of CSS during the fermentation process. Metagenomics sequencing analysis showed that Tetragenococcus halophilus, Weissella confusa, Weissella paramesenteroides, Aspergillus oryzae, Lactiplantibacillus plantarum, Weissella cibaria were top six dominant species from day 0 to day 120. Sixty compounds were either positively or tentatively identified through untargeted metabolomics profile and they were 27 peptides, amino acids and derivatives, 8 carbohydrates and conjugates, 14 organic acids and derivatives, 5 amide compounds, 3 flavonoids and 3 nucleosides. Spearman correlation coefficient indicated that Tetragenococcus halophilus, Zygosaccharomyces rouxii, Pediococcus pentosaceus and Aspergillus oryzae were significantly related with the formation of taste amino acids and derivatives, peptides and functional substances. Additionally, the metabolisms of flavor amino acids including 13 main free amino acids were also profiled. These results provided valuable information for the production practice in the soy sauce industry.

Role of interferon-induced transmembrane protein family in cancer progression: a special focus on pancreatic cancer.

Human interferon-induced transmembrane protein family (IFITMs) consists of five main proteins. IFITM1, IFITM2, and IFITM3 can be induced by interferon, while IFITM5 and IFITM10 are insensitive to interferon. IFITMs has various functions, including well-researched antiviral effects. As a molecule whose expression is significantly increased by interferon in the immune microenvironment, IFITMs has drawn growing interest in recent years for their role in the cancer progression. Unlike antiviral effects, the role and mechanism of IFITMs in cancer progression have not been clearly studied, especially the role and molecular mechanism of IFITMs in pancreatic cancer are rarely reported in the literature. This article focuses on the role and potential mechanism of IFITMs in pancreatic cancer progression by analyzing the function and mechanism of IFITM1-3 in other cancers and conducting bioinformatics analysis using the databases, so as to provide a new target for pancreatic cancer therapy.

Immune effector dysfunction signatures predict outcomes in patients with colorectal cancer.

BACKGROUND: Immune effector dysfunction (IED) is mainly manifested as immune exhaustion and senescence, which are the primary obstacles to the success of cancer immunotherapy. In the current study, we characterized the prognostic relevance of IED signatures in patients with colorectal cancer (CRC). METHODS: Immunohistochemistry (IHC) data of CRC tissue samples from 41 newly diagnosed patients in our clinical center (HDPH cohort) were used to investigate the prognostic importance of IED signatures. The results were validated by the RNA sequencing data of 372 CRC patients from the Cancer Genome Atlas (TCGA) database. RESULTS: In the HDPH cohorts, high Natural Killer (NK) and CD8+ tumor-infiltrating lymphocytes (TILs) were associated with poor overall survival (OS) and relapse-free survival (RFS) in CRC patients. Optimal IED signatures, including high expression of CCR9, ISG20, and low expression of ICOS, and CACNA2D2, predicted poor OS and RFS. Moreover, high-risk scores estimated by a weighted combination of these four IED genes were associated with poor OS and RFS. Notably, risk stratification was constructed by combining risk score and tumor node metastasis (TNM) stage better than TNM stage alone in predicting OS and RFS for CRC patients. The above results were confirmed in the TCGA cohort. CONCLUSION: CCR9, ISG20, ICOS, and CACNA2D2 were optimal IED signatures for predicting the outcomes of CRC patients, which might be a potential biomarker for prognostic stratification and designing novel CRC therapy.

Diterpenoid tanshinones inhibit gastric cancer angiogenesis through the PI3K/Akt/mTOR signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia miltiorrhiza Bunge is a kind of Chinese herbal medicine known for activating blood circulation and removing blood stasis, with the effect of cooling blood and eliminating carbuncles, and has been proven to have the effect of treating tumors. However, the inhibitory effect of Salvia miltiorrhiza Bunge extracts (Diterpenoid tanshinones) on tumors by inhibiting angiogenesis has not been studied in detail. AIM OF THE STUDY: This study aimed to investigate the anti-gastric cancer effect of diterpenoid tanshinones (DT) on angiogenesis, including the therapeutic effects and pathways. MATERIALS AND METHODS: This experiment utilized network pharmacology was used to identify relevant targets and pathways of Salvia miltiorrhiza Bunge-related components in the treatment of gastric cancer. The effects of DT on the proliferation and migration of human gastric cancer cell line SGC-7901 and human umbilical vein endothelial cell line HUVECs were evaluated, and changes in the expression of angiogenesis-related factors were measured. In vivo, experiments were conducted on nude mice to determine tumor activity, size, immunohistochemistry, and related proteins. RESULTS: The findings showed that DT could inhibit the development of gastric cancer by suppressing the proliferation of gastric cancer cells, inducing apoptosis, and inhibiting invasion and metastasis. In addition, the content of angiogenesis-related factors and proteins was significantly altered in DT-affected cells and animals. CONCLUSIONS: Results suggest that DT has potential as a therapeutic agent for the treatment of gastric cancer, as it can inhibit tumor growth and angiogenesis. It was also found that DT may affect the expression of the angiogenic factor VEGF through the PI3K/Akt/mTOR pathway, leading to the regulation of tumor angiogenesis. This study provides a new approach to the development of anti-tumor agents and has significant theoretical and clinical implications for the treatment of gastric cancer.

Clinicopathological, immunohistochemical and molecular features of acinic cell carcinoma of the breast.

Breast acinic cell carcinoma (ACC) is a rare subtype of breast cancer. Accurate diagnosis of ACC using core needle biopsy (CNB) is pivotal for the use of effective treatments and patient prognosis. In the present study, a detailed analysis of the morphological, immunohistochemical and gene mutation features of 2 cases of ACC was performed. CNB was performed prior to surgical excision. The breast ACC in the present cases exhibited overt burrowing labyrinthine networks or 'hand-holding-hand' features. The tumor cells in both of the present cases expressed cytokeratin (CK)7, S100 and CK5/6, but were negative for p63, estrogen receptor and progesterone receptor. GATA binding protein 3 was positive in case 1 but negative in case 2. Fluorescence in situ hybridization indicated no ETS variant transcription factor 6 break-apart probe detection. Next-generation sequencing results revealed the same mutation and a similar abundance in exon 27 (NM_005120.2; c.3817G>T; p.A1273S) of the mediator of RNA polymerase II transcription, subunit 12 homolog (MED12) gene in both patients. To conclude, the findings of the present study suggested that recognition of this rare 'hand-holding-hand' structure could potentially be beneficial for avoiding patient misdiagnosis. In addition, it could be suggested that a mutation in the MED12 exon 27 was associated with the formation of a burrowing labyrinthine network or 'hand-holding-hand' feature.

Intravoxel Incoherent Motion Diffusion-weighted Magnetic Resonance Imaging combined with Texture Analysis in Predicting the Histological Grades of Rectal Adenocarcinoma.

PURPOSE: To evaluate the predictive value of 3.0T MRI Intravoxel Incoherent motion diffusion-weighted magnetic resonance imaging (IVIM-DWI) combined with texture analysis (TA) in the histological grade of rectal adenocarcinoma. METHODS: Seventy-one patients with rectal adenocarcinoma confirmed by pathology after surgical resection were collected retrospectively. According to pathology, they were divided into a poorly differentiated group (n=23) and a moderately differentiated group (n=48). The IVIM-DWI parameters and TA characteristics of the two groups were compared, and a prediction model was constructed by multivariate logistic regression analysis. ROC curves were plotted for each individual and combined parameter. RESULTS: There were statistically significant differences in D and D* values between the two groups (P < 0.05). The three texture parameters SmallAreaEmphasis, Median, and Maximum had statistically significant differences between groups (P = 0.01, 0.004, 0.009, respectively). The logistic regression prediction model showed that D*, the median, and the maximum value were significant independent predictors, and the AUC of the regression prediction model was 0.860, which was significantly higher than other single parameters. CONCLUSION: 3.0T MRI IVIM-DWI parameters combined with TA can provide valuable information for predicting the histological grades of rectal adenocarcinoma one week before the operation.

Targeted macrophage phagocytosis by Irg1/itaconate axis improves the prognosis of intracerebral hemorrhagic stroke and peritonitis.

BACKGROUND: Macrophages are innate immune cells whose phagocytosis function is critical to the prognosis of stroke and peritonitis. cis-aconitic decarboxylase immune-responsive gene 1 (Irg1) and its metabolic product itaconate inhibit bacterial infection, intracellular viral replication, and inflammation in macrophages. Here we explore whether itaconate regulates phagocytosis. METHODS: Phagocytosis of macrophages was investigated by time-lapse video recording, flow cytometry, and immunofluorescence staining in macrophage/microglia cultures isolated from mouse tissue. Unbiased RNA-sequencing and ChIP-sequencing assays were used to explore the underlying mechanisms. The effects of Irg1/itaconate axis on the prognosis of intracerebral hemorrhagic stroke (ICH) and peritonitis was observed in transgenic (Irg1flox/flox; Cx3cr1creERT/+, cKO) mice or control mice in vivo. FINDINGS: In a mouse model of ICH, depletion of Irg1 in macrophage/microglia decreased its phagocytosis of erythrocytes, thereby exacerbating outcomes (n = 10 animals/group, p < 0.05). Administration of sodium itaconate/4-octyl itaconate (4-OI) promoted macrophage phagocytosis (n = 7 animals/group, p < 0.05). In addition, in a mouse model of peritonitis, Irg1 deficiency in macrophages also inhibited phagocytosis of Staphylococcus aureus (n = 5 animals/group, p < 0.05) and aggravated outcomes (n = 9 animals/group, p < 0.05). Mechanistically, 4-OI alkylated cysteine 155 on the Kelch-like ECH-associated protein 1 (Keap1), consequent in nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and transcriptional activation of Cd36 gene. Blocking the function of CD36 completely abolished the phagocytosis-promoting effects of Irg1/itaconate axis in vitro and in vivo. INTERPRETATION: Our findings provide a potential therapeutic target for phagocytosis-deficiency disorders, supporting further development towards clinical application for the benefit of stroke and peritonitis patients. FUNDING: The National Natural Science Foundation of China (32070735, 82371321 to Q. Li, 82271240 to F. Yang) and the Beijing Natural Science Foundation Program and Scientific Research Key Program of Beijing Municipal Commission of Education (KZ202010025033 to Q. Li).

The relationship between trajectories of renal oxygen saturation and acute kidney injury: a prospective cohort study with a secondary analysis.

BACKGROUND: Acute kidney injury (AKI) is a major postoperative consequence, affecting prognosis of older patients. Effective prediction or intervention to predict or prevent the incidence of AKI is currently unavailable. AIMS: Dynamic changes of renal tissue oxygen saturation (RSO2) during surgery process are understudied and we intended to explore the distinct trajectories and associations with postoperative AKI. METHODS: This was a secondary analysis including data for older patients who underwent open hepatectomy surgery with informed consent. Latent class mixed models (LCMM) method was conducted to generate trajectories of intraoperative renal tissue RSO2 through different time points. The primary outcome was postoperative 7-day AKI. The univariate and multivariate regression analysis were performed to identify the relationship between distinct trajectories of renal tissue RSO2 and the risk of AKI. Meanwhile, the prediction efficacy of renal tissue RSO2 at different time points was compared to find potential intervention timing. RESULTS: Postoperative AKI occurred in 14 (15.2%) of 92 patients. There are two distinct renal tissue RSO2 trajectories, with 44.6% generating "high-downwards" trajectory and 55.4% generating "consistently-high" trajectory. Patients with "high-downwards" trajectory had significantly higher risk of postoperative AKI than another group (Unadjusted OR [Odds Ratio] = 3.790, 95% CI [Confidence Interval]: 1.091-13.164, p = 0.036; Adjusted OR = 3.973, 95% CI 1.020-15.478, p = 0.047, respectively). Predictive performance was 71.4% sensitivity and 60.3% specificity for "high-downwards" trajectory of renal tissue RSO2 to identify AKI. Furthermore, the renal tissue RSO2 exhibited the lowest level and the best results in terms of the sensitivity during the hepatic occlusion period, may be considered as a "time of concern". CONCLUSIONS: Older patients undergoing hepatectomy may show high-downwards trajectory of renal tissue RSO2, indicating a higher risk of AKI, and the lowest level was identified during the hepatic occlusion period. These findings may help to provide potential candidates for future early recognition of deterioration of kidney function and guide interventions.

Phase I, first-in-human study of XTR004, a novel 18F-labeled tracer for myocardial perfusion PET: Biodistribution, radiation dosimetry, pharmacokinetics, and safety after a single injection at rest.

OBJECTIVES: This study assessed the imaging characteristics, pharmacokinetics and safety of XTR004, a novel 18F-labeled Positron Emission Tomography (PET) myocardial perfusion imaging tracer, after a single injection at rest in humans. METHODS: Eleven healthy subjects (eight men and three women) received intravenous XTR004 (239-290 megabecquerel [MBq]). Safety profiles were monitored on the dosing day and three follow-up visits. Multiple whole-body PET scans were conducted over 4.7 h to evaluate biodistribution and radiation dosimetry. Blood and urine samples collected for 7.25 h were metabolically corrected to characterize pharmacokinetics. RESULTS: In the first 0-12 min PET images of ten subjects, liver (26.81 ± 4.01), kidney (11.43 ± 2.49), lung (6.75 ± 1.76), myocardium (4.72 ± 0.67) and spleen (3.1 ± 0.84) exhibited the highest percentage of the injected dose (%ID). Myocardial uptake of XTR004 in the myocardium initially reached 4.72 %ID and 7.06 g/mL, and negligibly changed within an hour (Δ: 7.20%, 5.95%). The metabolically corrected plasma peaked at 2.5 min (0.0013896 %ID/g) and halved at 45.2 min. Whole-body effective dose was 0.0165 millisievert (mSv)/MBq. Cumulative urine excretion was 8.18%. Treatment-related adverse events occurred in seven out of eleven subjects (63.6%), but no severe adverse event was reported. CONCLUSIONS: XTR004 demonstrated a favorable safety profile, rapid, high, and stable myocardial uptake and excellent potential for PET myocardial perfusion imaging (MPI). Further exploration of XTR004 PET MPI for detecting myocardial ischemia is warranted.

Phytohemagglutinin from Phaseolus vulgaris enhances the lung cancer cell chemotherapy sensitivity by changing cell membrane permeability.

Chemotherapy is still a prevalent strategy for clinical lung cancer treatment. However, the inevitable emerged drug resistance has become a great hurdle to therapeutic effect. Studies have demonstrated that the primary cause of drug resistance is a decrease in the chemotherapeutic medicine concentration. Several lectins have been confirmed to be effective as chemotherapy adjuvants, enhancing the anti-tumor effects of chemotherapy drugs. Here, we combined phytohemagglutinin (PHA), which has been reported possess anti-tumor effects, with chemotherapy drugs Cisplatin (DDP) and Adriamycin (ADM) on lung cancer cells to detect the sensitivities of PHA as a chemotherapy adjuvant. Our results demonstrated that the PHA significantly enhanced the sensitivity of lung cancer cells to DDP and ADM, and Western blot showed that PHA combined with DDP or ADM enhance cytotoxic effects by inhibiting autophagy and promoting apoptosis. More importantly, we found PHA enhanced the chemotherapeutic drugs cytotoxicity by changing the cell membrane to increase the intracellular chemotherapeutic drugs concentration. Besides, the combination of PHA and ADM increased the ADM concentration in the multidrug-resistant strain A549-R cells and achieved the drug sensitization effect. Our results suggest that PHA combined with chemotherapy can be applied in the treatment of lung cancer cells and lung cancer multidrug-resistant strains, and provide a novel strategy for clinical tumor chemotherapy and a new idea to solve the problem of drug resistance in clinical lung cancer.

Jolkinolide B ameliorates rheumatoid arthritis by regulating the JAK2/STAT3 signaling pathway.

BACKGROUND: Jolkinolide B (JB), an ent­abietane-type diterpenoid in Euphorbia plants, has various pharmacological activities, including anticancer, anti-inflammatory, and anti-tuberculosis activities. However, no previous studies have proven whether JB can be regarded as a targeted drug for the treatment of rheumatoid arthritis (RA). PURPOSE: This study aimed to evaluate the anti-RA effects of JB and explore the potential mechanisms. METHODS: Components and targets of JB and RA were identified in different databases, and potential targets and pathways were predicted by protein-protein interaction (PPI) network analysis and pathway enrichment analysis. Then, molecular docking and surface-plasmon resonance (SPR) were used to confirm the predict. The anti-arthritic effects of JB were studied in vivo with collagen-induced arthritis (CIA) rat model and in vitro with lipopolysaccharide (LPS) and interleukin-6 (IL-6)-induced RAW264.7 macrophage. Potential mechanisms were further verified by in vivo and in vitro experiments. RESULTS: The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that Th17 cell differentiation, prolactin signaling pathway, and JAK/STAT signaling pathway might be associated with anti-RA effects of JB. Molecular docking and SPR results showed that JB bound effectively to JAK2. JB significantly decreased body weight loss, arthritis index, paw thickness, and synovial thickness in CIA rats. Histomorphological results suggested the protective effects of JB on CIA rats with ankle joint injury. Molecular biology analysis indicated that JB suppressed the mRNA expression of inflammatory factors in ankle joints for CIA rats and reduced the concentration of these factors in LPS- induced RAW264.7 macrophage. The protein expression level of the JAK2/STAT3 pathway was also significantly decreased by JB. CONCLUSION: JB had a novel inhibitory effect on inflammation and bone destruction in CIA rats, and the mechanism might be related to the JAK2/STAT3 signaling pathway.