A Self-Delivery Nanodrug Simultaneously Inhibits COX-2/PGE2 Mediated Inflammation and Downregulates PD-L1 to Boost Photoimmunotherapy.

Phototherapy promotes anti-tumor immunity by inducing immunogenic cell death (ICD), However, the accompanying inflammatory responses also trigger immunosuppression, attenuating the efficacy of photo-immunotherapy. Herein, they co-assembled a cell-membrane targeting chimeric peptide C16-Cypate-RRKK-PEG8-COOH (CCP) and anti-inflammatory diclofenac (DA) to develop a nanodrug (CCP@DA) that both enhances the immune effect of phototherapy and weakens the inflammation-mediated immunosuppression. CCP@DA achieves cell membrane-targeting photodynamic and photothermal synergistic therapies to damage programmed death ligand 1 (PD-L1) and induce a strong ICD to activate anti-tumor response. Simultaneously, the released DA inhibits the cycoperoxidase-2 (COX-2)/prostaglandin E2 (PGE2) pathway in tumor cells to inhibit pro-tumor inflammation and further down-regulate PD-L1 expression to relieve the immunosuppressive microenvironment. CCP@DA significantly inhibited tumor growth and inflammation both in vitro and in vivo, while maintaining a potent anti-tumor immune response. Additionally, it exhibits excellent anti-metastatic capabilities and prolongs mouse survival time with a single dose and low levels of near-infrared (NIR) light exposure. This work provides a valuable strategy to control the therapy-induced inflammation for high-efficiency photoimmunotherapy.

Self-Delivery Nanomedicines Reverse Thermal Resistance to Enhance Tumor Mild-Temperature Photothermal Therapy.

Tumoral thermal defense mechanisms considerably attenuate the therapeutic outcomes of mild-temperature photothermal therapy (PTT). Thus, developing a simple, efficient, and universal therapeutic strategy to sensitize mild-temperature PTT is desirable. Herein, we report self-delivery nanomedicines ACy NPs comprising a near-infrared (NIR) photothermal agent (Cypate), mitochondrial oxidative phosphorylation inhibitor (ATO), and distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG2000), which have a high drug-loading efficiency that can reverse tumoral thermal resistance, thereby increasing mild-temperature PTT efficacy. ACy NPs achieved targeted tumor accumulation and performed NIR fluorescence imaging capability in vivo to guide tumor PTT for optimized therapeutic outcomes. The released ATO reduced intracellular ATP levels to downregulate multiple heat shock proteins (including HSP70 and HSP90) before PTT, which reversed the thermal resistance of tumor cells, contributing to the excellent results of mild-temperature PTT in vitro and in vivo. Therefore, this study provides a simple, biosafe, advanced, and universal heat shock protein-blocking strategy for tumor PTT.

Nanodrugs mediate TAMs-related arginine metabolism interference to boost photodynamic immunotherapy.

As a potential treatment strategy for low immunogenic triple negative breast cancer (TNBC), photodynamic therapy (PDT) induced antitumor immunotherapy is greatly limited by the immunosuppressive tumor microenvironment (ITM), especially the M2 phenotype tumor-associated macrophages (TAMs). The balance of arginine metabolism plays an important role in TAMs polarization. Herein, a multifunctional nanoplatform (defined as HN-HFPA) was employed to burst the anti-tumor immunity of TNBC post PDT by reeducating TAMs through interfering the TAMs-associated arginine metabolism. The L-arginine (L-Arg) was loaded in the hollow cavity of HN-HFPA, which could not only generate nitric oxide (NO) for tumor therapy, but also serve as a substrate of arginine metabolism pathway. As an inhibitor of arginases-1 (Arg-1) of M2 TAMs, L-norvaline (L-Nor) was modified to the hyaluronic acid (HA), and coated in the surface of HFPA. After degradation of HA by hyaluronidase in tumor tissue and GSH-mediated disintegration, HN-HFPA depleted intracellular GSH, produced remarkable reactive oxygen species (ROS) under light irradiation and released L-Arg to generate NO, which induced tumor immunogenic cell death (ICD). Real-time ultrasound imaging of tumor was realized taking advantage of the gas feature of NO. The L-Nor suppressed the Arg-1 overexpressed in M2, which skewed the balance of arginine metabolism and reversed the ITM with increased ratios of M1 and CD8+ T cells, finally resulted in amplified antitumor immune response and apparent tumor metastasis inhibition. This study remodeled ITM to strengthen immune response post PDT, which provided a promising treatment strategy for TNBC.

Identifying essential genes in genome-scale metabolic models of consensus molecular subtypes of colorectal cancer.

Identifying essential targets in the genome-scale metabolic networks of cancer cells is a time-consuming process. The present study proposed a fuzzy hierarchical optimization framework for identifying essential genes, metabolites and reactions. On the basis of four objectives, the present study developed a framework for identifying essential targets that lead to cancer cell death and evaluating metabolic flux perturbations in normal cells that have been caused by cancer treatment. Through fuzzy set theory, a multiobjective optimization problem was converted into a trilevel maximizing decision-making (MDM) problem. We applied nested hybrid differential evolution to solve the trilevel MDM problem to identify essential targets in genome-scale metabolic models for five consensus molecular subtypes (CMSs) of colorectal cancer. We used various media to identify essential targets for each CMS and discovered that most targets affected all five CMSs and that some genes were CMS-specific. We obtained experimental data on the lethality of cancer cell lines from the DepMap database to validate the identified essential genes. The results reveal that most of the identified essential genes were compatible with the colorectal cancer cell lines obtained from DepMap and that these genes, with the exception of EBP, LSS, and SLC7A6, could generate a high level of cell death when knocked out. The identified essential genes were mostly involved in cholesterol biosynthesis, nucleotide metabolisms, and the glycerophospholipid biosynthetic pathway. The genes involved in the cholesterol biosynthetic pathway were also revealed to be determinable, if a cholesterol uptake reaction was not induced when the cells were in the culture medium. However, the genes involved in the cholesterol biosynthetic pathway became non-essential if such a reaction was induced. Furthermore, the essential gene CRLS1 was revealed as a medium-independent target for all CMSs.

Repurposing Astragalus Polysaccharide PG2 for Inhibiting ACE2 and SARS-CoV-2 Spike Syncytial Formation and Anti-Inflammatory Effects.

The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious threat to global public health. In an effort to develop novel anti-coronavirus therapeutics and achieve prophylactics, we used gene set enrichment analysis (GSEA) for drug screening and identified that Astragalus polysaccharide (PG2), a mixture of polysaccharides purified from Astragalus membranaceus, could effectively reverse COVID-19 signature genes. Further biological assays revealed that PG2 could prevent the fusion of BHK21-expressing wild-type (WT) viral spike (S) protein and Calu-3-expressing ACE2. Additionally, it specifically prevents the binding of recombinant viral S of WT, alpha, and beta strains to ACE2 receptor in our non-cell-based system. In addition, PG2 enhances let-7a, miR-146a, and miR-148b expression levels in the lung epithelial cells. These findings speculate that PG2 has the potential to reduce viral replication in lung and cytokine storm via these PG2-induced miRNAs. Furthermore, macrophage activation is one of the primary issues leading to the complicated condition of COVID-19 patients, and our results revealed that PG2 could regulate the activation of macrophages by promoting the polarization of THP-1-derived macrophages into an anti-inflammatory phenotype. In this study, PG2 stimulated M2 macrophage activation and increased the expression levels of anti-inflammatory cytokines IL-10 and IL-1RN. Additionally, PG2 was recently used to treat patients with severe COVID-19 symptoms by reducing the neutrophil-to-lymphocyte ratio (NLR). Therefore, our data suggest that PG2, a repurposed drug, possesses the potential to prevent WT SARS-CoV-2 S-mediated syncytia formation with the host cells; it also inhibits the binding of S proteins of WT, alpha, and beta strains to the recombinant ACE2 and halts severe COVID-19 development by regulating the polarization of macrophages to M2 cells.

BMX, a specific HDAC8 inhibitor, with TMZ for advanced CRC therapy: a novel synergic effect to elicit p53-, ß-catenin- and MGMT-dependent apoptotic cell death.

BACKGROUND: Despite advances in treatment, patients with refractory colorectal cancer (CRC) still have poor long-term survival, so there is a need for more effective therapeutic options. METHODS: To evaluate the HDAC8 inhibition efficacy as a CRC treatment, we examined the effects of various HDAC8 inhibitors (HDAC8i), including BMX (NBM-T-L-BMX-OS01) in combination with temozolomide (TMZ) or other standard CRC drugs on p53 mutated HT29 cells, as well as wild-type p53 HCT116 and RKO cells. RESULTS: We showed that HDAC8i with TMZ cotreatment resulted in HT29 arrest in the S and G2/M phase, whereas HCT116 and RKO arrest in the G0/G1 phase was accompanied by high sub-G1. Subsequently, this combination approach upregulated p53-mediated MGMT inhibition, leading to apoptosis. Furthermore, we observed the cotreatment also enabled triggering of cell senescence and decreased expression of stem cell biomarkers. Mechanistically, we found down-expression levels of ß-catenin, cyclin D1 and c-Myc via GSK3ß/ß-catenin signaling. Intriguingly, autophagy also contributes to cell death under the opposite status of ß-catenin/p62 axis, suggesting that there exists a negative feedback regulation between Wnt/ß-catenin and autophagy. Consistently, the Gene Set Enrichment Analysis (GSEA) indicated both apoptotic and autophagy biomarkers in HT29 and RKO were upregulated after treating with BMX. CONCLUSIONS: BMX may act as a HDAC8 eraser and in combination with reframed-TMZ generates a remarkable synergic effect, providing a novel therapeutic target for various CRCs. Video Abstract.

Effect and Mechanism of Flavored Tongxie Yaofang Decoction for Diarrheal Irritable Bowel Syndrome under Intestinal Microecology.

This research was to analyze the effect of flavored Tongxie Yaofang on diarrheal irritable bowel syndrome (IBS) by the situation of intestinal microecology. The treatment mechanism was analyzed, so as to provide a more effective treatment method for patients clinically. 60 IBS patients were selected as the research objects and were divided according to the different treatment methods. For the control group (n = 20 cases), oral pinaverium bromide tablets were given. For the treatment group (n = 40 cases), the flavored Tongxie Yaofang decoction was given in addition to conventional treatment. The curative effects on the two groups of patients were evaluated in combination with the changes in intestinal microecology. With the syndrome score, the total effective rate of the treatment group (92.5%) was obviously superior to the control group (80%) (P < 0.05). The clinical symptoms such as abdominal pain, abdominal distension, and diarrhea in the treatment group were significantly relieved after treatment in contrast to the control group (P < 0.05). Intestinal Bifidobacterium, Escherichia coli, and Bifidobacterium/Escherichia coli (B/E) ratio were all greatly higher than those in the control group (P < 0.05). In summary, flavored Tongxie Yaofang had a good effect in improving the symptoms of patients with diarrheal IBS and improved the microflora of Bifidobacterium and Escherichia coli in the intestinal tract of patients.

Virofree, an Herbal Medicine-Based Formula, Interrupts the Viral Infection of Delta and Omicron Variants of SARS-CoV-2.

Coronavirus disease 2019 (COVID-19) remains a threat with the emergence of new variants, especially Delta and Omicron, without specific effective therapeutic drugs. The infection causes dysregulation of the immune system with a cytokine storm that eventually leads to fatal acute respiratory distress syndrome (ARDS) and further irreversible pulmonary fibrosis. Therefore, the promising way to inhibit infection is to disrupt the binding and fusion between the viral spike and the host ACE2 receptor. A transcriptome-based drug screening platform has been developed for COVID-19 to explore the possibility and potential of the long-established drugs or herbal medicines to reverse the unique genetic signature of COVID-19. In silico analysis showed that Virofree, an herbal medicine, reversed the genetic signature of COVID-19 and ARDS. Biochemical validations showed that Virofree could disrupt the binding of wild-type and Delta-variant spike proteins to ACE2 and its syncytial formation via cell-based pseudo-typed viral assays, as well as suppress binding between several variant recombinant spikes to ACE2, especially Delta and Omicron. Additionally, Virofree elevated miR-148b-5p levels, inhibited the main protease of SARS-CoV-2 (Mpro), and reduced LPS-induced TNF-α release. Virofree also prevented cellular iron accumulation leading to ferroptosis which occurs in SARS-CoV-2 patients. Furthermore, Virofree was able to reduce pulmonary fibrosis-related protein expression levels in vitro. In conclusion, Virofree was repurposed as a potential herbal medicine to combat COVID-19. This study highlights the inhibitory effect of Virofree on the entry of Delta and Omicron variants of SARS-CoV-2, which have not had any effective treatments during the emergence of the new variants spreading.

Correction of the Estimated Hearing Level of NB Chirp ABR in Normal Hearing Population.

INTRODUCTION: The narrowband chirp (NB Chirp), a frequency-specific sound stimulus signal obtained by limiting the frequency bandwidth based on chirp, is applied to the frequency specified auditory brainstem response (fsABR) increasingly. Although some studies demonstrated that NB Chirp-evoked auditory brainstem response (NB Chirp ABR) causes a better neural response than tone burst-evoked auditory brainstem response and is preferred for fsABR, there is little known about how to better estimate an individual's hearing level through the threshold of NB Chirp ABR. The present study intended to compare the accuracy and deviation of NB Chirp ABR corrected by different approaches in estimating the hearing level of people with normal hearing. METHODS: A total of 66 volunteers with normal hearing were randomly divided into a model group (n = 26), test group 1 (n = 20), and test group 2 (n = 20). The model group was used to calculate the threshold difference between NB Chirp ABR and pure-tone audiometry at 500 Hz, 1,000 Hz, 2,000 Hz, and 4,000 Hz, as well as the regression equation, providing a reference for the correction of estimated hearing level of NB Chirp ABR. Test group 1 was used to observe the accuracy and deviation of the "noncorrection (N)," "threshold difference (A1)," and "regression equation (A2)" methods in correcting the estimated hearing level of NB Chirp ABR. Test group 2 was used to replicate the analysis of test group 1 to verify the repeatability of the experimental results. All data were analyzed using SPSS 24.0. RESULTS: Test group 1 and test group 2 had similar results. First, the accuracy of the estimated hearing level of N was significantly higher than that of A1 or A2. Second, compared with "0," the deviation of the estimated hearing level of N was bigger than that of A1 or A2 at 500 Hz and 1,000 Hz, while similar at 2,000 Hz and 4,000 Hz. Finally, there was no significant difference in the deviation of the estimated hearing level between A1 and A2 at 500 Hz and 1,000 Hz. CONCLUSION: Among people with normal hearing, it was necessary to correct NB Chirp ABR at 500 Hz and 1,000 Hz for lower deviation of the estimated hearing level. Both correction approaches based on threshold difference and regression equation can be used.

Autophagy-inhibiting biomimetic nanodrugs enhance photothermal therapy and boost antitumor immunity.

The instinctive protective stress responses of tumor cells hamper low-temperature photothermal therapy (LTPTT), resulting in tumor recurrence and metastasis. The rapid blood clearance and low-efficiency tumor enrichment of nanomedicines also decrease the efficacy of LTPTT. In this study, we fabricated coassembled photothermal agents (indocyanine green, ICG) and autophagy inhibitors (chloroquine, CQ) and red blood cell and cancer cell hybrid membrane (RCm)-camouflaged ICGCQ@RCm nanoparticles (ICGCQ@RCm NPs) to enhance tumor LTPTT. The ICGCQ@RCm NPs exhibited prolonged blood drug circulation and markedly enhanced drug accumulation in tumor tissues. The ICGCQ@RCm NPs reduced the thermal tolerance of tumor cells to sensitize ICG-mediated LTPTT by inhibiting protective autophagy. The ICGCQ@RCm NPs exerted strong immunogenic cell death (ICD) after efficient LTPTT to activate antitumor immunity. In addition, ICGCQ@RCms optimized the therapeutic efficacy by imaging-guided LTPTT, taking advantage of the near-infrared (NIR) fluorescence of ICG. Consequently, the ICGCQ@RCm NPs effectively inhibited tumors under mild LTPTT, significantly suppressed tumor metastasis and prolonged the survival time of tumor-bearing mice. Furthermore, the ICGCQ@RCm NPs showed high biosafety in vitro and in vivo. The ICGCQ@RCm NPs demonstrated tumor-targeting and imaging-guided autophagy inhibition-sensitized LTPTT using two Food and Drug Administration (FDA)-approved drugs, which have great potential for clinical application.

Computer-Aided Design for Identifying Anticancer Targets in Genome-Scale Metabolic Models of Colon Cancer.

The efficient discovery of anticancer targets with minimal side effects is a major challenge in drug discovery and development. Early prediction of side effects is key for reducing development costs, increasing drug efficacy, and increasing drug safety. This study developed a fuzzy optimization framework for Identifying AntiCancer Targets (IACT) using constraint-based models. Four objectives were established to evaluate the mortality of treated cancer cells and to minimize side effects causing toxicity-induced tumorigenesis on normal cells and smaller metabolic perturbations. Fuzzy set theory was applied to evaluate potential side effects and investigate the magnitude of metabolic deviations in perturbed cells compared with their normal counterparts. The framework was applied to identify not only gene regulator targets but also metabolite- and reaction-centric targets. A nested hybrid differential evolution algorithm with a hierarchical fitness function was applied to solve multilevel IACT problems. The results show that the combination of a carbon metabolism target and any one-target gene that participates in the sphingolipid, glycerophospholipid, nucleotide, cholesterol biosynthesis, or pentose phosphate pathways is more effective for treatment than one-target inhibition is. A clinical antimetabolite drug 5-fluorouracil (5-FU) has been used to inhibit synthesis of deoxythymidine-5'-triphosphate for treatment of colorectal cancer. The computational results reveal that a two-target combination of 5-FU and a folate supplement can improve cell viability, reduce metabolic deviation, and reduce side effects of normal cells.

Synthesis, biological evaluation, and structure-activity relationships of new tubulin polymerization inhibitors based on 5-amino-1,2,4-triazole scaffold.

Based on our previous research, thirty new 5-amino-1H-1,2,4-triazoles possessing 3,4,5-trimethoxyphenyl moiety were synthesized, and evaluated for antiproliferative activities. Among them, compounds IIa, IIIh, and IIIm demonstrated significant antiproliferative activities against a panel of tumor cell lines, and the promising compound IIIm dose-dependently caused G2/M phase arrest in HeLa cells. Furthermore, analogue IIa exhibited the most potent tubulinpolymerization inhibitory activity with an IC50 value of 9.4 µM, and molecular modeling studies revealed that IIa formed stable interactions in the colchicine-binding site of tubulin, suggesting that 5-amino-1H-1,2,4-triazole scaffold has potential for further investigation to develop novel tubulin polymerization inhibitors with anticancer activity.

Oncogene inference optimization using constraint-based modelling incorporated with protein expression in normal and tumour tissues.

Cancer cells are known to exhibit unusual metabolic activity, and yet few metabolic cancer driver genes are known. Genetic alterations and epigenetic modifications of cancer cells result in the abnormal regulation of cellular metabolic pathways that are different when compared with normal cells. Such a metabolic reprogramming can be simulated using constraint-based modelling approaches towards predicting oncogenes. We introduced the tri-level optimization problem to use the metabolic reprogramming towards inferring oncogenes. The algorithm incorporated Recon 2.2 network with the Human Protein Atlas to reconstruct genome-scale metabolic network models of the tissue-specific cells at normal and cancer states, respectively. Such reconstructed models were applied to build the templates of the metabolic reprogramming between normal and cancer cell metabolism. The inference optimization problem was formulated to use the templates as a measure towards predicting oncogenes. The nested hybrid differential evolution algorithm was applied to solve the problem to overcome solving difficulty for transferring the inner optimization problem into the single one. Head and neck squamous cells were applied as a case study to evaluate the algorithm. We detected 13 of the top-ranked one-hit dysregulations and 17 of the top-ranked two-hit oncogenes with high similarity ratios to the templates. According to the literature survey, most inferred oncogenes are consistent with the observation in various tissues. Furthermore, the inferred oncogenes were highly connected with the TP53/AKT/IGF/MTOR signalling pathway through PTEN, which is one of the most frequently detected tumour suppressor genes in human cancer.

Biogenic volatile organic compound emissions from Pinus massoniana and Schima superba seedlings: Their responses to foliar and soil application of nitrogen.

Increasing nitrogen (N) deposition is one of the main drivers of global change, while the emission of biogenic volatile organic compounds (BVOCs) from plant in response to elevated N deposition is poorly understood, especially with respect to the response to foliar application of N. In this study, BVOC emissions from two tree species (Pinus massoniana Lamb. and Schima superba Gardn. et Champ.) were determined by dynamic chamber coupled with a proton transfer reaction-time of flight-mass spectrometer. Two N application methods, namely soil application of N (SAN) and foliar application of N (FAN), and three N levels (5.6, 15.6 and 20.6 g N m-2 yr-1) were employed by applying NH4NO3 every week for 1.5 years. The results showed that: (1) oxygenated volatile organic compounds (OVOCs, mainly acetaldehyde, methyl alcohol, ethenone and acetone) and non-methane hydrocarbons (NMHCs, mainly monoterpenes, propyne, 1,3-butadiene and propylene) were the dominant BVOCs for all the treatments, accounting for 32.40-65.72% and 19.21-47.39% of total 100 determined BVOC compounds, respectively; (2) for S. superba seedlings, both SAN and FAN treatments significantly decreased total BVOC emissions (11.83% to 66.23%). However, total BVOCs from P. massoniana significantly increased with N addition for SAN treatment, while no difference were found in the FAN treatment; (3) BVOC emission rates for FAN treatment were significantly lower than those for SAN treatment, indicating that previous studies which simulated N deposition by adding N directly to soil might have imprecisely estimated their effects on plant BVOC emissions. Considering the inconsistent responses of BVOC emissions to different N application methods for different plant species, close attention should be paid on the effects of N deposition or even global change on plant BVOC emissions in the future.

Clinical, pathophysiologic, and genomic analysis of the outcomes of primary head and neck malignancy after pulmonary metastasectomy.

The median overall survival (OS) of some head and neck malignancies, such as head and neck squamous cell carcinoma (HNSCC), with metastatic lesions was only 12 months. Whether aggressive pulmonary metastasectomy (PM) improves survival is controversial. Patients with primary head and neck malignancy undergoing PM were enrolled. Clinical outcomes were compared among different histological types. Whole-exome sequencing was used for matched pulmonary metastatic samples. The genes where genetic variants have been identified were sent for analysis by DAVID, IPA, and STRING. Forty-nine patients with primary head and neck malignancies were enrolled. Two-year postmetastasectomy survival (PMS) rates of adenoid cystic carcinoma, thyroid carcinoma, nasopharyngeal carcinoma, and HNSCC were 100%, 88.2%, 71.4%, and 59.2%, respectively (P = 0.024). In HNSCC, the time to distant metastasis was an independent predictive factor of the efficacy of PM. Several pathways, such as branched-chain amino acid (BCAA) consumption, were significantly associated with the progression of HNSCC [P < 0.001, fold enrichment (FE) = 5.45]. Moreover, metabolism-associated signaling pathways also seemed to be involved in cancer metastasis. Histological types and time to distant metastasis were important factors influencing the clinical outcomes of PM. For HNSCC, metabolic-associated signaling pathways were significantly associated with tumor progression and distant metastasis. Future validations are warranted.

Identification of Withaferin A as a Potential Candidate for Anti-Cancer Therapy in Non-Small Cell Lung Cancer.

Low response rate and recurrence are common issues in lung cancer; thus, identifying a potential compound for these patients is essential. Utilizing an in silico screening method, we identified withaferin A (WA), a cell-permeable steroidal lactone initially extracted from Withania somnifera, as a potential anti-lung cancer and anti-lung cancer stem-like cell (CSC) agent. First, we demonstrated that WA exhibited potent cytotoxicity in several lung cancer cells, as evidenced by low IC50 values. WA concurrently induced autophagy and apoptosis and the activation of reactive oxygen species (ROS), which plays an upstream role in mediating WA-elicited effects. The increase in p62 indicated that WA may modulate the autophagy flux followed by apoptosis. In vivo research also demonstrated the anti-tumor effect of WA treatment. We subsequently demonstrated that WA could inhibit the growth of lung CSCs, decrease side population cells, and inhibit lung cancer spheroid-forming capacity, at least through downregulation of mTOR/STAT3 signaling. Furthermore, the combination of WA and chemotherapeutic drugs, including cisplatin and pemetrexed, exerted synergistic effects on the inhibition of epidermal growth factor receptor (EGFR) wild-type lung cancer cell viability. In addition, WA can further enhance the cytotoxic effect of cisplatin in lung CSCs. Therefore, WA alone or in combination with standard chemotherapy is a potential treatment option for EGFR wild-type lung cancer and may decrease the occurrence of cisplatin resistance by inhibiting lung CSCs.

Modified Sijunzi decoction can alleviate cisplatin-induced toxicity and prolong the survival time of cachectic mice by recovering muscle atrophy.

ETHNOPHARMACOLOGICAL RELEVANCE: Sijunzi decoction is a well-known traditional Chinese medicine (TCM) commonly used for invigorating vital energy and for the enhancement of immunity. Modified Sijunzi decoctions have been extensively used to treat cachexia and improve the quality of life of cancer patients undergoing chemotherapy. AIM OF THE STUDY: This study was aimed to provide comprehensive evidence for the anti-cachectic effect of a modified Sijunzi decoction (Zhen-Qi; ZQ-SJZ) and characterize its anti-cachectic mechanism, especially in cisplatin-induced muscle atrophy. MATERIALS AND METHODS: We employed a Lewis lung carcinoma (LLC)-induced cancer cachectic mouse model to demonstrate the anti-cachectic effect of ZQ-SJZ. Moreover, we provided an in vitro C2C12 myotube formation model to investigate the effect of ZQ-SJZ in hampering cisplatin-induced muscle atrophy. RESULTS: The administration of ZQ-SJZ can recover tumor- and/or cisplatin-induced body weight loss, intestinal mucosal damage, as well as forelimb grip strength and myofiber size. The administration of ZQ-SJZ also significantly prolonged the survival of LLC-induced cachectic mice under cisplatin treatment. Mechanistically, ZQ-SJZ increased the levels of myogenic proteins, such as myosin heavy chain (MyHC) and myogenin, and decreased the atrophy-related protein, atrogin-1, in cisplatin-treated C2C12 myotubes in vitro. In addition, cisplatin-induced mitochondria dysfunction could be hampered by the co-administration of ZQ-SJZ, by which it recovered the cisplatin-mediated decrease in PGC-1α and PKM1 levels. CONCLUSIONS: The administration of ZQ-SJZ can recover tumor- and/or cisplatin-induced cachectic conditions and significantly prolong the survival of LLC-induced cachectic mice under cisplatin treatment. The profound effect of ZQ-SJZ in hampering tumor- and/or cisplatin-induced cachexia may be due to its modulation of the mitochondrial function and subsequent myogenesis. Taken together, these results demonstrated the anti-cachectic mechanism of ZQ-SJZ and its potential use as a palliative strategy to improve the efficacy of chemotherapy.

Antcin-H Isolated from Antrodia cinnamomea Inhibits Renal Cancer Cell Invasion Partly through Inactivation of FAK-ERK-C/EBP-ß/c-Fos-MMP-7 Pathways.

Antcin-H, a natural triterpene, is purified from a famous anticancer medicinal mushroom, Antrodia cinnamomea, in Taiwan. This study showed that antcin-H inhibited the growth of human renal carcinoma 786-0 cells; the IC50 value (for 48 h) was 170 µM. Besides, the migration and invasion of 786-0 cells were suppressed by antcin-H under noncytotoxic concentrations (<100 µM); these events were accompanied by inhibition of FAK and Src kinase activities, decrease of paxillin phosphorylation, impairment of lamellipodium formation, and upregulation of TIMPs and downregulation of MMPs, especially MMP-7 expression. Luciferase reporter assay showed that antcin-H repressed the MMP-7 promoter activity, in parallel to inhibiting c-Fos/AP-1 and C/EBP-ß transactivation abilities. Moreover, antcin-H suppressed the activity of ERK1/2 and decreased the binding ability of C/EBP-ß and c-Fos on the upstream/enhancer region of MMP-7 promoter. Overall, this study demonstrated that the anti-invasive effect of antcin-H in human renal carcinoma 786-0 cells might be at least in part by abrogating focal adhesion complex and lamellipodium formation through inhibiting the Src/FAK-paxillin signaling pathways and decreasing MMP-7 expression through suppressing the ERK1/2-AP-1/c-Fos and C/EBP-ß signaling axis. Our findings provide the evidence that antcin-H may be an active component existing in A. cinnamomea with anticancer effect.

Flux balance analysis predicts Warburg-like effects of mouse hepatocyte deficient in miR-122a.

The liver is a vital organ involving in various major metabolic functions in human body. MicroRNA-122 (miR-122) plays an important role in the regulation of liver metabolism, but its intrinsic physiological functions require further clarification. This study integrated the genome-scale metabolic model of hepatocytes and mouse experimental data with germline deletion of Mir122a (Mir122a-/-) to infer Warburg-like effects. Elevated expression of MiR-122a target genes in Mir122a-/-mice, especially those encoding for metabolic enzymes, was applied to analyze the flux distributions of the genome-scale metabolic model in normal and deficient states. By definition of the similarity ratio, we compared the flux fold change of the genome-scale metabolic model computational results and metabolomic profiling data measured through a liquid-chromatography with mass spectrometer, respectively, for hepatocytes of 2-month-old mice in normal and deficient states. The Ddc gene demonstrated the highest similarity ratio of 95% to the biological hypothesis of the Warburg effect, and similarity of 75% to the experimental observation. We also used 2, 6, and 11 months of mir-122 knockout mice liver cell to examined the expression pattern of DDC in the knockout mice livers to show upregulated profiles of DDC from the data. Furthermore, through a bioinformatics (LINCS program) prediction, BTK inhibitors and withaferin A could downregulate DDC expression, suggesting that such drugs could potentially alter the early events of metabolomics of liver cancer cells.

Evaluation of the medicinal herb Graptopetalum paraguayense as a treatment for liver cancer.

BACKGROUND: Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third most common cause of cancer-related death worldwide. Sorafenib is the only drug for patients with advanced-stage hepatocellular carcinoma (HCC) that has been shown to confer a survival benefit to patients with HCC; however, it has many side effects. Thus, alternate therapeutic strategies with improved safety and therapeutic efficacy for the management of HCC should be developed. METHODS AND FINDINGS: We demonstrate that an extract of Graptopetalum paraguayense (GP) down-regulated the expression levels of several onco-proteins, including AURKA, AURKB, and FLJ10540, in HCC cells. To isolate the active components in the GP extracts, we prepared extracts fractions and assessed their effects on the expression of onco-proteins in HCC cells. The fraction designated HH-F3 was enriched in active ingredients, exhibited cytotoxic effects, and suppressed the expression of the onco-proteins in HCC cells. The structure of the main active compound in HH-F3 was found to be similar to that of the proanthocyanidin compounds derived from Rhodiola rosea. In addition, a distinct new compound rich in 3, 4, 5-trihydroxy benzylic moieties was identified in the HH-F3 preparations. Mechanistic studies indicated that HH-F3 induced apoptosis in HCC cells by promoting the loss of mitochondrial membrane potential and the production of reactive oxygen species. HH-F3 also enhanced PTEN expression and decreased AKT phosphorylation at Ser473 in a concentration-dependent manner in HCC cells. Moreover combination of GP or HH-F3 and sorafenib synergistically inhibits the proliferation of Huh7 cells. The treatment of a rat model with diethylnitrosamine (DEN)-induced liver cancer with extracts of GP and HH-F3 decreased hepatic collagen contents and inhibited tumor growth. CONCLUSIONS: These results indicate that GP extracts and HH-F3 can protect the liver by suppressing tumor growth; consequently, these compounds could be considered for the treatment of HCC.