Physical compatibility of Xuebijing injection with 53 intravenous drugs during simulated Y-site administration.

OBJECTIVE: Xuebijing injection (XBJ) is a commonly used herbal medicine injection in China. However, the physical compatibility of XBJ with other intravenous drugs remains unclear. The purpose of this research is to evaluate physical compatibility of Xuebijing injection (XBJ) with 53 intravenous drugs (including 31 Chinese medicine injections and 22 chemicals) during simulated Y-site administration. METHODS: Y-site administration was simulated in vitro by admixing 0.33 ml/ml XBJ with an equal volume of other diluted 53 intravenous drugs, respectively. Physical compatibility including visual inspection, Tyndall beam, particle limits, turbidity, pH, chromacity value, spectroscopic absorption of 550 nm and 420 nm (A550 nm and A420 nm) were observed and assessed at 0, 1, 2, and 4 h. Physical compatibility was defined as all solutions with no color changes, no gas evolution, particulate formation and no Tyndall beam within 4 hours, turbidity changes <0.5 nephelometric turbidity unit (NTU) compared to 0 h, particle limits allowed by the Chinese Pharmacopoeia (Ch.P) 2020 edition, pH changes <10% compared to 0, chromacity value changes <200 compared to 0 h, or photometrical changes of A420 nm <0.0400 or A550 nm <0.0100 compared to 0 h. RESULTS: XBJ was physically incompatible with 27 of the 53 intravenous drugs tested, 26 were compatible with XBJ for 4 h. CONCLUSIONS: XBJ should not be simultaneously co-administered with 27 of the 53 intravenous drugs during simulated Y-site. If coadministration was inevitable, flushing tube with NS or D5W before and after infusion of XBJ was needed. Assessment included visual inspection, Tyndall beam, turbidity measurement, particle counts, pH measurement, chromacity value measurement and absorption of A550 nm were proved to be valid and robust for the quality control of infusion and compatibility of Chinese herbal injection.

Impact of EDP-M on survival of patients with metastatic adrenocortical carcinoma: A population-based study.

INTRODUCTION: Historically, stage IV adrenocortical carcinoma (mACC) has a poor prognosis with a median overall survival (OS) of only 5 months. Based on the FIRM-ACT trial published in 2012, guidelines now advise first line systemic treatment with etoposide, cisplatin, doxorubicin and mitotane (EDP-M). The effect of EDP-M on patient survival in clinical practice in the Netherlands is unknown. METHODS: The data of all patients with mACC (2005-2020) were obtained from the Netherlands comprehensive cancer organization (IKNL). The effect of EDP-M on patient survival was assessed using Kaplan-Meier analysis and multivariate Cox regression analysis including clinical, therapy and tumor characteristics. RESULTS: In total 167 patients with mACC were included. For patients diagnosed from 2014 onwards, EDP-M (in 22 patients (22%)) lead to a numerically but not statistically significant improved OS compared to those not receiving EDP-M (11.8 vs 5.6 months, p = 0.525). For systemic treatments, patients treated with mitotane only had the best 5-year OS (11.4%, p = 0.006) regardless of year of diagnosis. In multivariate Cox regression analysis EPD-M was not associated with OS; palliative adrenalectomy (HR: 0.26, p = <.001) and local treatment of metastases (HR: 0.35, p = 0.001) were associated with a better OS and a primary tumor Ki-67 index > 20% (HR: 2.67, p = 0.003) with a worse OS from 2014 onwards. Patients diagnosed before 2014 had a significantly poorer OS compared to from 2014 onwards (5-yr: 4.5 vs 8.4%, OS: 6.8 vs 8.3 months, p = 0.032). CONCLUSION: OS for mACC in the Netherlands has improved in the last decade. Receiving EDP-M did not significantly improve OS for patients with mACC. The use of multimodality treatment including palliative adrenalectomy, mitotane and local treatment of (oligo-)metastases in appropriately selected patients has improved the OS for mACC patients since 2014.

Cytotoxic and Antitumor Effects of the Hydroalcoholic Extract of Tagetes erecta in Lung Cancer Cells.

Among all cancers, lung cancer is the one with the highest mortality rate, and it also has limited therapeutics. Antitumor agents based on medicinal plants have gained importance as a source of bioactive substances. Tagetes erecta is a plant of great cultural value, and recent reports have suggested its cytotoxic effects in tumor cells. Our objective was to evaluate the antitumor activity of Tagetes erecta extract in a lung carcinoma model. Hydroalcoholic extracts were obtained from fresh flowers and leaves of T. erecta; both extracts did not exert toxicity on Artemia salina. We observed cytotoxic effects induced by the floral extract in Lewis lung carcinoma (LLC) and breast tumor cell line (MCF7), but not by the leaf extract. In vivo, a xenograft lung carcinoma model was performed with LLC cells implanted on C57BL/6 mice, which showed that the floral extract reduced tumor growth and improved the effect of etoposide. Microscopic analysis of tumors showed a reduction in mitoses and an increase in necrotic areas with the extract and the etoposide. The main phytochemical compounds found are 2,3-dihydro-benzofuran, octadecanoic acid, benzenacetic acid, oleic acid, linoleic acid, and acetic acid. We conclude that the hydroalcoholic extract of T. erecta flowers has cytotoxic effects in lung carcinoma cells and enhances the effect of etoposide.

Enhancing the Effective Chemotherapy: The Combined Inhibition of Rhinacanthin-C, 5-Fluorouracil, and Etoposide on Oral Cancer Cells.

OBJECTIVE: To investigate the effects of rhinacanthin-C (Rh-C), 5-FU, and etoposide on growth inhibition, as well as the effects of a combination of these inhibitors on the oral cell lines SCC9 and HSC4. METHODS: Cancer cell growth inhibition and inhibition combination were determined using the SRB assay. Cell viability and early apoptosis were determined using flow cytometry on cells stained with Annexin 5 and PI. Western blotting was performed to study the molecular mechanism of these inhibitors on oral cancer cells. RESULTS: The results showed that etoposide, 5-FU, and Rh-C exhibited more potent anti-proliferative effects on HSC4 cells compared to SCC9 cells in a time- and concentration-dependent manner. The combination of Rh-C and 5-FU was more effective in inhibiting cell growth than the drugs used alone. The combination of 5-FU and Rh-C resulted in a decrease in live HSC4 cells, with the highest percentage of cell death observed at a ratio of 40:6 µM. Furthermore, the combination of 5-FU and Rh-C reduced P-Akt levels leading to a decrease in cell survival. CONCLUSIONS: HSC4 cells were found to be more sensitive to the inhibitory effect of these drugs compared to SCC9 cells. These findings suggest that the use of Rh-C as a complementary therapy with 5-FU may have the potential for the treatment of oral cancer. the underlying mechanisms responsible for this difference in sensitivity between the two cell lines need to be further investigated.

Anakinra versus etoposide-based therapy added to high-dose steroids for the treatment of secondary hemophagocytic lymphohistiocytosis.

OBJECTIVE: Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening, hyperinflammatory syndrome usually treated with high-dose steroids (HDS), often complemented with adjunct therapies, such as etoposide (HLH-94 protocol). Anakinra has been reported to effectively treat HLH; however, has not been comparatively examined with etoposide-based therapies. We sought to evaluate the effectiveness and durability of these treatment approaches. METHODS: We performed a retrospective analysis of all adult patients diagnosed with secondary HLH between January 2011 and November 2022 who received anakinra and HDS, the HLH-94 protocol, HDS alone, or supportive care. RESULTS: Thirty adult patients with secondary HLH were included. Cumulative incidence (CI) of response at 30 days was 83.3%, 60%, and 36.4% for patients treated with anakinra, the HLH-94 protocol, and HDS alone, respectively. CI of relapse at 1 year was 50%, 33.3%, and 0% with the HLH-94 protocol, HDS, and anakinra and HDS, respectively. Overall survival at 1 year was higher with anakinra and HDS compared to the HLH-94 protocol, yet was not statistically significant (77.8% vs. 33.3%; hazard ratio: 0.29; p = .25). CONCLUSION: Treatment with anakinra and HDS in adults with secondary HLH was associated with higher response rates with longer survival compared with alternative therapies and should be further investigated in this setting.

Determination of Selected Isoquinoline Alkaloids from Chelidonium majus, Mahonia aquifolium and Sanguinaria canadensis Extracts by Liquid Chromatography and Their In Vitro and In Vivo Cytotoxic Activity against Human Cancer Cells.

The search for new substances with cytotoxic activity against various cancer cells, especially cells that are very resistant to currently used chemotherapeutic agents, such as melanoma cells, is a very important scientific aspect. We investigated the cytotoxic effect of Chelidonium majus, Mahonia aquifolium and Sanguinaria canadensis extracts obtained from different parts of these plants collected at various vegetation stages on FaDu, SCC-25, MCF-7, and MDA-MB-231 cancer cells. Almost all the tested extracts showed higher cytotoxicity against these cancer cells than the anticancer drug etoposide. The highest cytotoxicity against the FaDu, SCC-25, MCF-7 and MDA-MB-231 cancer cell lines was obtained for the Sanguinaria candensis extract collected before flowering. The cytotoxicity of extracts obtained from different parts of Chelidonium majus collected at various vegetation stages was also evaluated on melanoma cells (A375, G361 and SK-MEL-3). The highest cytotoxic activity against melanoma A375 cells was observed for the Chelidonium majus root extract, with an IC50 of 12.65 µg/mL. The same extract was the most cytotoxic against SK-MEL-3 cells (IC50 = 1.93 µg/mL), while the highest cytotoxic activity against G361 cells was observed after exposure to the extract obtained from the herb of the plant. The cytotoxic activity of Chelidonium majus extracts against melanoma cells was compared with the cytotoxicity of the following anticancer drugs: etoposide, cisplatin and hydroxyurea. In most cases, the IC50 values obtained for the anticancer drugs were higher than those obtained for the Chelidonium majus extracts. The most cytotoxic extract obtained from the root of Chelidonium majus was selected for in vivo cytotoxic activity investigations using a Danio rerio larvae xenograft model. The model was applied for the first time in the in vivo investigations of the extract's anticancer potential. The application of Danio rerio larvae xenografts in cancer research is advantageous because of the transparency and ease of compound administration, the small size and the short duration and low cost of the experiments. The results obtained in the xenograft model confirmed the great effect of the investigated extract on the number of cancer cells in a living organism. Our investigations show that the investigated plant extracts exhibit very high cytotoxic activity and can be recommended for further experiments in order to additionally confirm their potential use in the treatment of various human cancers.

Pathological complete response to neoadjuvant tislelizumab plus chemotherapy in stage IIIB small cell lung cancer: A case report and literature review.

Immunotherapy plus chemotherapy has been approved for the first-line treatment of extensive-stage small cell lung cancer (ES-SCLC, stage IV). Recently, the 2023 version of the National Comprehensive Cancer Network Guidelines recommended immunotherapy plus chemotherapy as the neoadjuvant regimen in patients with resectable non-small cell lung cancer (NSCLC). However, it is still unclear whether the combination regimen of immunotherapy plus chemotherapy is also beneficial for SCLC in the neoadjuvant context. Here, we report the case of a patient with stage IIIB SCLC who showed long-term survival and good tolerance to the neoadjuvant chemoimmunotherapy consisting of tislelizumab (an anti-PD-1 monoclonal antibody) plus etoposide-carboplatin. The patient achieved pathological complete response after receiving two cycles of neoadjuvant tislelizumab and chemotherapy followed by surgery. Two courses of post-operative tislelizumab and etoposide-carboplatin treatment were performed. The patient has survived for more than 23 months with no recurrence or metastases after neoadjuvant therapy. Multiplexed immunofluorescence and immunohistochemistry staining showed that the post-treatment specimens had remarkable immune cells infiltration, including CD3+ T cells, CD4+ T cells, and CD8+ T cells, which contrasted with very low levels of these cells in the pre-treatment samples. This study is, to the best of our knowledge, the first attempt to present the neoadjuvant chemoimmunotherapy of tislelizumab in combination with etoposide-carboplatin in SCLC. Our study suggested that neoadjuvant tislelizumab plus chemotherapy may facilitate radical resection and benefit patients with locally advanced (stage IIB-IIIC) SCLC.

Real-world efficacy of DA-EPOCH-R/HD-MTX regimen in CD5-positive diffuse large B cell lymphoma: a single-institute analysis.

CD5-positive diffuse large B cell lymphoma (CD5+ DLBCL) is a high-risk lymphoma type. Recently, the PEARL5 (a Phase II trial of DA-EPOCH and Rituximab with HD-MTX therapy for newly diagnosed DLBCL with CD5 expression) study demonstrated the efficacy of the DA-EPOCH-R (cyclophosphamide, etoposide, doxorubicin, vincristine, prednisone, and rituximab)/HD-MTX (high-dose methotrexate) regimen for CD5+ DLBCL. In this report, we revealed the impact of the DA-EPOCH-R/HD-MTX regimen on the clinical course of CD5+ DLBCL in the real-world. We retrospectively compared CD5+ and CD5- DLBCL patients diagnosed from January 2017 to December 2020 and analyzed their clinicopathological characteristics, treatment, and prognosis. There was no difference in age, sex, clinical stage, and cell of origin; however, the CD5-positive group had higher lactate dehydrogenase levels and a worse performance status than the CD5-negative group (p=0.00121 and p=0.0378, respectively). International prognostic index (IPI) was worse in the CD5-positive group than in the CD5-negative group (p=0.0498), but NCCN-IPI (National Comprehensive Cancer Network-IPI) was no different between the two groups. The CD5-positive group was more frequently treated with the DA-EPOCH-R/HD-MTX regimen than the CD5-negative group (p =0.001857). Complete remission rate and 1-year overall survival did not differ between the CD5-positive and -negative groups (90.0% vs 81.4%, p=0.853; 81.8% vs 76.9%, p=0.433). We conclude that the DA-EPOCH-R/HD-MTX regimen is effective for CD5+ DLBCL in this single institute analysis.

Mixed Primary Hepatocellular Carcinoma and Hepatic Neuroendocrine Carcinoma: Case Report and Literature Review.

Mixed hepatocellular carcinoma with neuroendocrine carcinoma (HCC-NEC) is extremely rare, comprising about 0.46% of primary hepatic tumors. A 63-year-old man who was a chronic alcoholic presented with a nine-centimeter-sized hepatic mass. His serum alpha-fetoprotein and protein induced by vitamin K antagonist-II levels were 22,815 ng/mL and 183 mAU/mL, respectively. The patient underwent a right hemihepatectomy, including the middle hepatic vein. The tumor consisted of poorly differentiated HCC (20%) and large- and small-cell-type NEC (80%) components as per the pathological examination. Immunohistochemically chromogranin and synaptophysin were positive in the areas of NEC and negative in the areas of HCC. Adjuvant chemotherapy with a combination of cisplatin and etoposide was administered after surgery. At postoperative 5 months, the patient complained of right flank pain, and CT showed a new mass measuring 7.3 cm in the right adrenal gland. Postoperatively, after 6.5 months, more recurred masses were noted on the posterior aspect of the right kidney and both lungs. Although the regimen was changed from etoposide to irinotecan, additional recurred masses were developed in the liver, lung, and brain. He passed away 12 months after the surgery. After reviewing and analyzing previous literature, the 1 and 2 year overall survival rates are 57.3 and 43.6%, respectively, and the 1 and 2 year disease-free survival rates are 36.2 and 29.0%, respectively. Mixed HCC-NEC is a very rare tumor, and the surgical outcome is poor.

Long-Term Complete Remission of a Patient With Double-Hit Diffuse Large B-Cell Lymphoma Treated by Chemoimmunotherapy and Chinese Herbal Medicine.

Double-hit diffuse large B-cell lymphoma (DHL) is an uncommon subtype of lymphoma which poorly responds to current drug therapies and has low rates of long-term survival in the patients. Herein, we report a case of a 73-year-old Caucasian male who was diagnosed with DHL with double-hit mutations of rearrangement of both c-MYC and BCL2 in November 2013. He commenced the standard R-CHOP-14 chemotherapy (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone) but changed to dose-adjusted DA-EPOCH-R protocol (etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone, and rituximab) in the second and third cycles due to double-hit mutation. Because of intolerance to the intensive therapy, the patient decided to switch to Chinese medicine intervention. From March 2014 to December 2019, he was prescribed with a classical Chinese herbal formula-Sijunzi Decoction plus Prunella vulgaris based prescriptions. After 2 months of the Chinese herbal medicine intervention, the patient felt his right groin mass disappeared. Imaging follow-up showed no residual masses, and no lymphadenopathy was seen. During the period of Chinese herbal medicine treatment, his adherence and tolerability were well maintained with no adverse events. Imaging surveillances afterward found no evidence of lymphoma recurrence. His regular blood tests indicated that the patient's blood counts were normal and stable; no hematologic toxicity, hepatoxicity, or nephrotoxicity associated with Chinese herbal medicine were found. Follow-up visits until 2020 found that he had been living and enjoying a good quality of life for over 8 years post-diagnosis. This case study illustrates the potential values of Chinese herbal medicine in DHL treatment, alongside chemo-immunotherapy, and in maintaining long-term survival and satisfactory quality of life for DHL patients. The case report provides clinicians with preliminary evidence of the use of Chinese herbal medicine as a therapeutic strategy in the management of DHL.

Rosemary (Rosmarinus officinalis L.) essential oil alleviates testis failure induced by Etoposide in male rats.

Rosemary (Rosmarinus officinalis L.) is a shrub used to treat hepatic, intestinal, renal, respiratory, and reproductive failures. Etoposide a plant-based compound derived from Podophyllum pelltatum, has been used for human malignancies treatment. However, it induces testis, and hepatic failures. In the present study, impact of rosemary essential oil against testis failure, lipid parameters, and hepatic enzymes in male rats has been studied. Forty male Wistar albino rats were grouped in a completely randomized design with Etoposide injection (ETO), rosemary supplementation (ROS), with Etoposide injection and rosemary supplement (ETO+ROS), and control rats with no Etoposide injection and no rosemary (CON). The experiment lasted for seven consecutive weeks including one week as acclimatization time. At the end of the experiment, rats were sacrificed by cervical dislocation, and blood samples were analyzed for serum alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), low-density lipoprotein-Cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), total cholesterol (TC), total Protein (TP), glucose (GLU) and testosterone. The left testis was harvested for histological examination. Results showed that rats with Etoposide injection had higher ALT, AST, and ALP the control rats. No significant difference was found among treatments in terms of glucose concentration in blood. Rosemary supplemntaion decreased cholesterol and TG concentration and increased HDL concentration in male rats. Furthermore, administration of rosemary essential oil increased blood testosterone but decreased ALT and AST. The epithelial height of seminiferous tubules was decreased significantly in ET as compared with CON. Rosemary essential oil lessened the adverse effect of Etopside on epithelial height in rat testis as it is shown in ET+ROS. In conclusion, dietary supplementation of rosemary essential oil alleviated liver toxicity and functional testis damage induced by Etopside.

Lycopene modulates hepatic toxicity and testicular injury induced by etoposide in male rats.

OBJECTIVE: Lycopene (C40H56), a carotenoid found in red colour fruits, is known as a powerful antioxidant that protects cells from damage caused by reactive oxygen species (ROS). Etoposide inhibits topoisomerase II activity and restricts the development of cancer cells, though it establishes oxidative stress. To study the effect of lycopene (Ly) against hepatotoxicity and testis injury induced by etoposide in male rats. ANIMALS: Forty male Wister albino rats. SETTINGS: The experiment lasted for seven consecutive weeks including one week as acclimatization time. DESIGN: The experiment was in a completely randomized design with a 2×2 factorial arrangement. INTERVENTION(S): The animals were grouped as follow: No etoposide injection and no lycopene (control), lycopene supplementation (LY), etoposide injection (ET), and rats with etoposide injection and lycopene supplement (ET+LY). MAIN OUTCOME MEASURE(S): At the end of the experiment, rats were sacrificed by cervical dislocation. Blood samples were harvested and analyzed for serum alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), low-density lipoprotein-Cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), total cholesterol (TC), Total Protein (TP), glucose (GLU) and testosterone. The left testis was manipulated for histological examination. RESULT(S): The result of experiment showed that rats with etoposide injection had higher ALT, AST, and ALP than the control rats. In contrast co-treated rats (ET+LY) significantly modulated the levels of the hepatic parameters. Administration of lycopene increased testosterone concentration and germinal epithelium of seminiferous tubules in testes rats. CONCLUSION(S): Lycopene might be a promising agent with hepatoprotective effect in restoring testis injury induced by etoposide in rats.

Phytochemical Analysis, Total Phenolic, Flavonoid Contents, and Anticancer Evaluations of Solvent Extracts and Saponins of H. digitata.

Cancer is one of the most challenging diseases in the modern era for the researchers and investigators. Extensive research worldwide is underway to find novel therapeutics for prevention and treatment of diseases. The extracted natural sources have shown to be one of the best and effective treatments for cell proliferation and angiogenesis. Different approaches including disc potato model, brine shrimp, and chorioallantoic membrane (CAM) assay were adopted to analyze the anticancer effects. Habenaria digitata was also evaluated for MTT activity against NIH/3T3 cell line. The dexamethasone, etoposide, and vincristine sulfate were used as a positive control in these assays. All of the extracts including crude extracts (Hd.Cr), saponin (Hd.Sp), n-hexane (Hd.Hx), chloroform (Hd.Chf), ethyl acetate (Hd.EA), and aqueous fraction (Hd.Aq) were shown excellent results by using various assays. For example, saponin and chloroform have displayed decent antitumor and angiogenic activity by using potato tumor assay. The saponin fraction and chloroform were shown to be the most efficient in potato tumor experiment, demonstrating 87.5 and 93.7% tumor suppression at concentration of 1000 µg/ml, respectively, with IC50 values of 25.5 and 18.3 µg/ml. Additionally, the two samples, chloroform and saponins, outperformed the rest of the test samples in terms of antiangiogenic activity, with IC50 28.63 µg/ml and 16.20 µg/ml, respectively. In characterizing all solvent fractions, the chloroform (Hd.Chf) and saponin (Hd.Sp) appeared to display good effectiveness against tumor and angiogenesis but very minimal activity against A. tumefaciens. The Hd.Chf and Hd.Sp have been prospective candidates in the isolation of natural products with antineoplastic properties.

New alkaloids and their in vitro antitumor activity of Corydalis balansae.

The chemical investigation on Corydalis balansae resulted in the isolation of three previous undescribed compounds (1, 10, and 11) and 17 known compounds. Compound 1 and 2 were obtained as two lignanamide dimers, and compound 11 had a spiro [benzofuranone-benzazepine] skeleton, which was found in Corydalis for the first time. The structures of new compound were determined by the detailed analysis of 1D/2D NMR, UV, and IR data. Absolute configurations of compounds 10 and 11 were defined by their crystal X-ray diffraction data and calculations of electronic circular dichroism (ECD). The CCK-8 method was used to assay the inhibition effect of all the compounds on the growth of Hela, MGC-803, A549, and HepG2 cancer cells. Compound 2, 13, and 14 showed moderate inhibitory activity against the tested cell lines. Compound 2 exhibited potential antitumor activity against MGC-803 cells with an IC50 value of 20.8 µM, while the positive control etoposide was 17.3 µM. Furthermore, results from the cellular-mechanism investigation indicated that compound 2 could induce S-phase cell-cycle arrest and MGC-803 cells apoptosis, which was triggered by the up-regulation of PARP1, caspase-3 and -9, Bax, and down-regulation of Bcl-2. The 2-induced strong apoptosis indicated that compound 2 had good potential as an antitumor lead compound.

A single-beam of light priming the immune responses and boosting cancer photoimmunotherapy.

Mirroring the rapid clinical performance, immune checkpoint blockade (ICB) leads a remarkable clinical advance in combating cancer, but suffers poor response in most cancers. The low presence of tumor-infiltration lymphocytes and the poor immunogenicity in tumor microenvironment (TME) are the main factors hindering the effectiveness of ICB in the treatment of immunological "cold" tumors. Aiming at boosting immune response via TME modulation, we report a near-infrared laser-guided photoimmuno-strategy in which synergistic phototherapy, immune adjuvant, and ICB are integrated into one versatile nanoporphyrin platform. The prepared nanoporphyrins are self-assembled from purpurin18-lipids and have photodynamic/photothermal and immunomodulatory effects that can be tuned under a single laser irradiation, concomitant with fluorescence or MSOT imaging. In this work, the contributions of each component in the nanoporphyrin platform were specified. In particular, phototherapy-driven in situ tumor cell death provided abundant tumor-associated antigens to initiate immune responses. With the assist of spatiotemporally delivered immune adjuvant, phototherapy potentiated tumor immunogenicity, reprogrammed "cold" tumors into "hot" ones, and sensitized tumors to ICB therapy. Further combined with PD-L1 blockade, the photoimmune-strategy substantially stimulated tumor-specific immune-responses and long-term immunological memory against primary tumor, abscopal tumor as well as metastatic foci. Such single light-primed photoimmunotherapy offers a promising solution to overcome common hurdles in ICB treatment and can potentially be integrated into existing clinical practice.

The effects of green tea in the diet of broilers challenged with coccidiosis on their performance, carcass characteristics, intestinal mucosal morphology, blood constituents and ceca microflora.

BACKGROUND: Coccidiosis is an endemic protozoal disease of chickens normally controlled by ionophores. However, coccidiostats are also antibiotics, and evidence of resistance in both coccidia and bacteria may develop and reduce antibacterial activity in humans. This has led to a search for natural coccidiostats, such as green tea. OBJECTIVES: To study the effects of supplementing broilers with various levels and types of green tea, in comparison to use of a conventional coccidiostat or a control, unsupplemented diet. METHODS: A total of 360 male, day-old Ross 308 broilers (days 1-42) were used to evaluate the gut morphology and performance when challenged with coccidiosis and fed varying dietary levels of green tea powder or extract. Treatments were Negative control (NC, unsupplemented control diet); positive control (PC, control diet + commercial coccidiostat); control diets with 0.2, 0.3 or 0.4 g/kg green tea extract (GTE 0.2, 0.3 and 0.4); and control diets with 1, 2 or 3 g/kg green tea powder (GTP 1, 2 and 3). RESULTS: Compared with NC, PC and all green tea treatments, but particularly GTE0.4, increased feed intake and growth rate, with the best feed conversion ratio at GTE0.4. As a proportion of carcase weight, higher inclusion rates increased intestine weight and decreased abdominal fat. The duodenum, jejunum and ileum of birds fed green tea, and particularly GTE0.4, had longer, wider villi, and shallower crypts. Epithelium thickness was reduced by green tea and PC, compared to NC. Clostridium perfringens and coliform populations decreased in proportion to green tea inclusion rate and decreased in PC. Lactobacilli increased with green tea and were more for NC than PC. Green tea at the highest concentrations reduced blood glucose and LDL and VLDL cholesterol. CONCLUSIONS: Green tea offers a possible replacement for conventional ionophores to control coccidiosis in broiler chickens. The best inclusion rate was 0.4 g/kg.

Transcriptional Reactivation of Lignin Biosynthesis for the Heterologous Production of Etoposide Aglycone in Nicotiana benthamiana.

Nicotiana benthamiana is a valuable plant chassis for heterologous production of medicinal plant natural products. This host is well suited for the processing of organelle-localized plant enzymes, and the conservation of the primary metabolism across the plant kingdom often provides required plant-specific precursor molecules that feed a given pathway. Despite this commonality in metabolism, limited precursor supply and/or competing host pathways can interfere with yields of heterologous products. Here, we use transient transcriptional reprogramming of endogenous N. benthamiana metabolism to drastically improve flux through the etoposide pathway derived from the medicinal plant Podophyllum spp. Specifically, coexpression of a single lignin-associated transcription factor, MYB85, with pathway genes results in unprecedented levels of heterologous product accumulation in N. benthamiana leaves: 1 mg/g dry weight (DW) of the etoposide aglycone, 35 mg/g DW (-)-deoxypodophyllotoxin, and 3.5 mg/g DW (-)-epipodophyllotoxin─up to two orders of magnitude above previously reported biosynthetic yields for the etoposide aglycone and eight times higher than what is observed for (-)-deoxypodophyllotoxin in the native medicinal plant. Unexpectedly, transient activation of lignin metabolism by transcription factor overexpression also reduces the production of undesired side products that likely result from competing N. benthamiana metabolism. Our work demonstrates that synthetic activation of lignin biosynthesis in leaf tissue is an effective strategy for optimizing the production of medicinal compounds derived from phenylpropanoid precursors in the plant chassis N. benthamiana. Furthermore, our results highlight the engineering value of MYB85, an early switch in lignin biosynthesis, for on-demand modulation of monolignol flux and support the role of MYB46 as a master regulator of lignin polymer deposition.

Ameliorative potential role of Rosmarinus officinalis extract on toxicity induced by etoposide in male albino rats.

The present work was showed to assess the effect of administration of rosemary extract on etoposide-induced toxicity, injury and proliferation in male rats were investigated. Forty male albino rats were arranged into four equal groups. 1st group, control; 2nd group, etoposide; 3rd group, co-treated rosemary & etoposide; 4th group, rosemary alone. In comparison to the control group, etoposide administration resulted in a significant increase in serum ALT, AST, ALP, total bilirubin, total protein, and gamma GT. In contrast; a significant decrease in albumin level in etoposide group as compared to G1. G3 revealed a significant decrease in AST, ALT, ALP, total protein and total bilirubin levels and a significant rise in albumin level when compared with G2. Serum levels of urea, creatinine, potassium ions, and chloride ions significantly increased; while sodium ions were significantly decreased in G2 when compared with G1. Also, there was an increase of MDA level for etoposide treated group with corresponding control rats. However, there was a remarkable significant decrease in SOD, GPX and CAT levels in G2 as compared to G1. There was a significant increase in serum hydrogen peroxide (H2O2) and Nitric oxide (NO) levels in group treated with etoposide when compared to control group. It was noticeable that administrated by rosemary alone either with etoposide had not any effect on the levels of H2O2 and Nitric oxide. Serum level of T3 and T4 was significantly increased in etoposide-administered rats in comparison with G1. The administration of rosemary, either alone or with etoposide, increased the serum levels of T3 and T4 significantly when compared to control rats. The gene expression analysis showed significant downregulation of hepatic SOD and GPx in (G2) when compared with (G1). The treatment with rosemary extract produced significant upregulation of the antioxidant enzymes mRNA SOD and GPx. MDA gene was increased in (G2) when contrasted with (G1). Treatment of the etoposide- induced rats with rosemary extract delivered significant decrease in MDA gene expression when compared with etoposide group. Rats treated with etoposide showed significant decline in hepatic Nrf2 protein expression, when compared with G1. While, supplementation of Etoposide- administered rats with the rosemary produced a significant elevation in hepatic Nrf2 protein levels. Additionally, the liver histological structure displayed noticeable degeneration and cellular infiltration in liver cells. It is possible to infer that rosemary has a potential role and that it should be researched as a natural component for etoposide-induced toxicity protection.

Comparative study of the ameliorative effects of omega-3 versus selenium on etoposide-induced changes in Sertoli cells and ectoplasmic specialization of adult rat testes: immunohistochemical and electron microscopic study.

Etoposide (Eto) is an anti-cancer drug that is associated with serious adverse effects on male reproductive function. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) and selenium (Se) are known as anti-inflammatory, anti-apoptotic and anti-oxidant agents. This work was designed to investigate changes in the biochemical parameters as well as alterations in Sertoli cell vimentin expression, ultrastructure and ectoplasmic specializations (ESs) following Eto treatment and to assess the ameliorative effect of ω-3 versus Se on these alterations. Eighty four adult male albino rats were used and classified into four groups: group I (control group), group II (Eto group) received Eto in a single intra-peritoneal (IP) dose (60 mg/kg B.W.), group III (Eto & ω-3 group) received the single IP dose of Eto as well as ω-3 (300 mg/kg B.W./day by intra-gastric intubation) starting 5 days before Eto injection till the time of sacrifice & group IV (Eto & Se group) received the single IP dose of Eto as well as Se (0.5 mg/kg B.W./day IP) starting 5 days before Eto injection till the time of sacrifice. The rats were subdivided into 2 subgroups (a) and (b) that were sacrificed 3 and 7 days after Eto injection respectively. Eto administration in group II induced increase in malondialdehyde (MDA), decrease in superoxide dismutase (SOD), collapse of Sertoli cell vimentin filaments and ultrastructural degenerative changes in both Sertoli cells and ESs. Se (group IV) reversed Eto toxic effects potently, while ω-3 (group III) had some limited protective effects.

Effect of Kaempferol and Its Glycoside Derivatives on Antioxidant Status of HL-60 Cells Treated with Etoposide.

Kaempferol is a well-known antioxidant found in many plants and plant-based foods. In plants, kaempferol is present mainly in the form of glycoside derivatives. In this work, we focused on determining the effect of kaempferol and its glycoside derivatives on the expression level of genes related to the reduction of oxidative stress-NFE2L2, NQO1, SOD1, SOD2, and HO-1; the enzymatic activity of superoxide dismutases; and the level of glutathione. We used HL-60 acute promyelocytic leukemia cells, which were incubated with the anticancer drug etoposide and kaempferol or one of its three glycoside derivatives isolated from the aerial parts of Lens culinaris Medik.-kaempferol 3-O-[(6-O-E-caffeoyl)-ß-d-glucopyranosyl-(1→2)]-ß-d-galactopyranoside-7-O-ß-d-glucuropyranoside (P2), kaempferol 3-O-[(6-O-E-p-coumaroyl)-ß-d-glucopyranosyl-(1→2)]-ß-d-galactopyranoside-7-O-ß-d-glucuropyranoside (P5), and kaempferol 3-O-[(6-O-E-feruloyl)-ß-d-glucopyranosyl-(1→2)]-ß-d-galactopyranoside-7-O-ß-d-glucuropyranoside (P7). We showed that none of the tested compounds affected NFE2L2 gene expression. Co-incubation with etoposide (1 µM) and kaempferol (10 and 50 µg/mL) leads to an increase in the expression of the HO-1 (9.49 and 9.33-fold at 10 µg/mL and 50 µg/mL, respectively), SOD1 (1.68-fold at 10 µg/mL), SOD2 (1.72-fold at 10-50 µg/mL), and NQO1 (1.84-fold at 50 µg/mL) genes in comparison to cells treated only with etoposide. The effect of kaempferol derivatives on gene expression differs depending on the derivative. All tested polyphenols increased the SOD activity in cells co-incubated with etoposide. We observed that the co-incubation of HL-60 cells with etoposide and kaempferol or derivative P7 increases the level of total glutathione in these cells. Taken together, our observations suggest that the antioxidant activity of kaempferol is related to the activation of antioxidant genes and proteins. Moreover, we observed that glycoside derivatives can have a different effect on the antioxidant cellular systems than kaempferol.