The function of Bazhen decoction in rescuing progeroid cell senescence via facilitating G-quadruplex resolving and telomere elongation.

ETHNOPHARMACOLOGICAL RELEVANCE: The Bazhen decoction is one of the most extensively used Traditional Chinese medicine (TCM) prescriptions for treatment of aging related diseases. However, due to the complexity of the components, the pharmacological mechanism of Bazhen decoction is still limited. AIM OF THE STUDY: In this study, with the aim of helping the clinical precision medicine of TCM, we try out a systematic analysis for dissecting the molecular mechanism of complicated TCM prescription: Bazhen decoction. We identify the pharmacological mechanism of Bazhen decoction in telomere elongation as revealed by systematic analysis. MATERIALS AND METHODS: By RNA sequencing and transcriptome analysis of Bazhen decoction treated wild type cells, we reveal the transcriptome profile induced by Bazhen decoction. We utilized the cells derived from Werner syndrome (WS) mice, which is known to be dysfunctional in telomere elongation due to the deficiency of DNA helicase Wrn. By Western blot, qPCR, Immunofluorescence, flow cytometry, telomere FISH, and SA-ß-Gal staining, we verify the transcriptome data and confirm the pharmacological function of Bazhen decoction and its drug containing serum in telomere elongation and reversing progeroid cell senescence. RESULTS: We reveal that Bazhen decoction may systematically regulate multiple anti-aging pathways, including stem cell regulation, protein homeostasis, cardiovascular function, neuronal function, anti-inflammation, anti-DNA damage induced stress, DNA helicase activity and telomere lengthening. We find that Bazhen decoction and its drug containing serum could up-regulate multiple DNA helicases and telomere regulating proteins. The increased DNA helicases promote the resolving of G-quadruplex (G4) structures, and facilitate DNA replication and telomere elongation. These improvements also endow the cellular resistance to DNA damages induced by replication stress, and rescue the WS caused cellular senescence. CONCLUSIONS: Together these data suggest that Bazhen decoction up-regulate the expression of DNA helicases, thus facilitate G4 resolving and telomere maintenance, which rescue the progeroid cellular senescence and contribute to its anti-aging properties. Our data reveal a new molecular mechanism of Bazhen decoction in anti-aging related diseases via elongating telomere, this may shed light in the application of Bazhen decoction in multiple degenerative diseases caused by telomere erosion.

Overexpression of PSR1 in Chlamydomonas reinhardtii induces luxury phosphorus uptake.

Remediation using micro-algae offers an attractive solution to environmental phosphate (PO4 3-) pollution. However, for maximum efficiency, pre-conditioning of algae to induce 'luxury phosphorus (P) uptake' is needed. To replicate this process, we targeted the global regulator PSR1 (Myb transcription factor: Phosphate Starvation Response 1) for over-expression in algae. Manipulating a single gene (PSR1) drove uptake of both PO4 3- and a Mg2+ counter-ion leading to increased PolyP granule size, raising P levels 4-fold to 8% dry cell weight, and accelerated removal of PO4 3- from the medium. Examination of the gene expression profile showed that the P-starvation response was mimicked under P-replete conditions, switching on luxury uptake. Hyper-accumulation of P depended on a feed-forward mechanism, where a small set of 'Class I' P-transporter genes were activated despite abundant external PO4 3- levels. The transporters drove a reduction in external PO4 3- levels, permitting more genes to be expressed (Class II), leading to more P-uptake. Our data pointed toward a PSR1-independent mechanism for detection of external PO4 3- which suppressed Class II genes. This model provided a plausible mechanism for P-overplus where prior P-starvation elevates PSR1 and on P-resupply causes luxury P-uptake. This is because the Class I genes, which include P-transporter genes, are not suppressed by the excess PO4 3-. Taken together, these discoveries facilitate a bio-circular approach of recycling nutrients from wastewater back to agriculture.

Dammarane-type saponins from Gynostemma pentaphyllum and their anti-aging activities via up-regulating mitochondria related proteins.

The importance of mitochondria in regulation of aging has been extensively recognized and confirmed. Gynostemma pentaphyllum (Thunb.) Makino, a homology of medicine and food, has been widely utilized as dietary supplement. In this study, the transcriptome of normal cells (wild type mouse embryo fibroblasts) regulated by the 30% aqueous EtOH extract of G. pentaphyllum was firstly evaluated by RNA sequencing and the results revealed that the G. pentaphyllum could up-regulate the genes involved in oxidative phosphorylation (OXPHOS) and sirtuin (SIRT) signaling pathways, indicating its effect in promoting cell viability might be attributed to the role of improving mitochondrial functions. To further discover the bioactive compounds, sixteen undescribed dammarane-type saponins along with twenty-eight known analogues were isolated from the active extract of G. pentaphyllum. Their structures were elucidated by means of comprehensive analysis of NMR and HRMS spectroscopic data. All isolates were evaluated for the regulatory effects on SIRT3 and translocase of the outer membrane 20 (TOM20), and thirteen of them exhibited satisfactory agonist activities on both SIRT3 and TOM20 at 5 µM. Furthermore, the preliminary structure-activity relationships analysis demonstrated the additional hydroxymethyl and carbonyl groups or less sugar residues in saponins could contribute positively to the up-regulatory effect on SIRT3 and TOM20. These findings encouraged the potential roles of G. pentaphyllum and its bioactive saponins in the development of natural drugs for the treatment of aging-related diseases.

An insertion and deletion mutant of adenovirus in Muscovy ducks.

Duck adenovirus 3 (DuAdV-3; strain HB) was isolated and sequenced. The genome of the Muscovy-duck-origin virus contains a 54-bp insertion in pVIII, a 3-bp deletion in the overlap region of 100K, 22K, and 33K, a 42-bp deletion at the junction of ORF64 and ORF67, and a 715-bp deletion in right noncoding region of the genome. Notably, HB has a strikingly shorter right inverted terminal repeat (ITR) of 50 bp, whereas all other DuAdV-3 isolates have a 721-bp ITR. These findings demonstrate that HB is an insertion and deletion mutant of DuAdV-3.

Risk Factors of Delayed Recovery of Gastrointestinal Function After Ileostomy Reversal for Rectal Cancer Patients.

PURPOSE: The aim of this study was to identify the risk factors associated with delayed recovery of gastrointestinal function after ileostomy reversal for rectal cancer patients. METHODS: In this retrospective study, the data of rectal cancer patients who underwent ileostomy reversal from January 2018 to December 2019 at the Sixth Affiliated Hospital of Sun Yat-sen University were assessed to investigate potential risk factors of delayed flatus after ileostomy reversal. RESULTS: A total of 282 patients were eligible for this study. Postoperative first flatus time ranged from 1 to 9 days, of which 58.8% patients presented with delayed flatus that was longer than 3 days. Univariate analysis showed that delayed postoperative flatus was significantly associated with the length of postoperative hospital stay (P<0.001) and postoperative complications (P=0.037). Multivariate analysis showed that intravenous fluid infusion at postoperative day 1 (POD1) (OR=1.001, 95% CI: 1.001-1.002, P=0.001) and duration of stoma ≥6 months (OR=2.005, 95% CI:1.155-3.657, P=0.014) were independent risk factors for delayed flatus. CONCLUSION: Increased intravenous fluid infusion at POD1 and duration of stoma ≥6 months were related to delayed recovery of gastrointestinal function after ileostomy reversal for rectal cancer patients.

Temporary impairment of renal function in patients with rectal cancer treated with diverting ileostomy.

BACKGROUND: Fluid and electrolyte disturbance, which impairs renal function, has been reported in patients with temporary ileostomy. However, the dynamic changes in serum electrolytes and renal function in rectal cancer patients with ileostomy have not been well described. In the present study, we aimed to evaluate alterations in serum electrolytes and renal function in rectal cancer patients undergoing ileostomy creation and closure. METHODS: The levels of serum potassium, serum sodium, serum blood urea nitrogen, serum creatinine and estimated glomerular filtration rate (eGFR) were analyzed in 320 patients with rectal cancer including 156 patients with an ileostomy (the ileostomy group) and 164 patients without an ileostomy (the control group). RESULTS: After index surgery, the levels of serum potassium and serum creatinine in the ileostomy group were significantly higher than those in the control group (P<0.05). In contrast, the levels of serum sodium and the eGFR showed decreases in the ileostomy group compared to the control group after index surgery (P<0.05). At 3 months after ileostomy creation, the ileostomy group had a significantly increased rate of eGFR <60 mL/min/1.73 m2 compared to the control group (5.8% vs. 1.2%, P=0.032). In line with the results of univariate analysis, multivariable analysis identified ileostomy and diabetes as independent risk factors for a decreased eGFR (P=0.005 and P=0.022, respectively). Furthermore, a significantly rebound of eGFR was observed in patients after ileostomy closure (P=0.013). CONCLUSIONS: Ileostomy can cause temporary electrolyte disturbance and renal function impairment in patients with rectal cancer. Diabetes is an independent risk factor for renal function damage in patients with rectal cancer who receive a temporary ileostomy.

UV-curable hyperbranched polyester sealant with tunable mechanical properties.

Different types of wounds have different requirements of a wound sealant. One of the requirements of concern is the adaptability of the mechanical properties of biomaterials to native tissues. However, the mechanical properties of current sealant are untunable or adjustable in a small range normally. Therefore, the scope of application of these sealant is limited. In this study, we developed hyperbranched polyester (HBP)-based UV-curable sealant with tunable mechanical properties. This sealant was cured under UV-light for 2 minutes and exhibited strong adhesion with tissues. The shear adhesive strength of it to the porcine skin ranged between 20-30 kPa, which was higher than the fibrin glue (∼10 kPa). Moreover, the elastic modulus of the sealant in a tensile test ranged between 27-54 MPa, depending on the degree of acrylation of the HBPs. Additionally, we assessed the biocompatibility of the sealant by co-culturing it with mouse mesenchymal stem cells (mMSCs) for 7 days and discovered that the cell viability was unaffected. This sealant with a tunable elastic modulus might be a promising candidate for treating wounds with different elastic moduli.

Nomogram for Predicting Anastomotic Leakage after Rectal Cancer Surgery in Elderly Patients with Dysfunctional Stomata.

PURPOSE: Anastomotic leakage after rectal cancer surgery in elderly patients is a critical challenge. Many risk factors have been found and many interventions tried, but anastomotic leakage in elderly patients remains difficult to deal with. This study aimed to create a nomogram for predicting anastomotic leakage after rectal surgery in elderly rectal cancer patients with dysfunctional stomata. METHODS: We collected data from 326 consecutive elderly patients with dysfunctional stomata after rectal cancer surgery at the Sixth Affiliated Hospital, Sun Yat-Sen University from January 2014 to December 2019. Risk factors of anastomotic leakage were identified with multivariate logistic regression and used to create a nomogram. Predictive performance was evaluated by the area under the receiver-operating characteristic (ROC) curve. RESULTS: American Society of Anesthesiologists score ≥3, male sex, and neoadjuvant radiotherapy were identified as significantly associated factors that could be combined for accurate prediction of anastomotic leakage on multivariate logistic regression and development of a nomogram.The area under the ROC curve for this model was 0.645. The C-index value for this model was 0.645, indicating moderate predictive ability of the risk of anastomotic leakage. CONCLUSION: The nomogram showed good ability to predict anastomotic leakage in elderly patients with rectal cancer after surgery, and might be helpful in providing a reference point for selection of surgical procedures and perioperative treatment.

Fixing the Broken Phosphorus Cycle: Wastewater Remediation by Microalgal Polyphosphates.

Phosphorus (P), in the form of phosphate derived from either inorganic (Pi) or organic (Po) forms is an essential macronutrient for all life. P undergoes a biogeochemical cycle within the environment, but anthropogenic redistribution through inefficient agricultural practice and inadequate nutrient recovery at wastewater treatment works have resulted in a sustained transfer of P from rock deposits to land and aquatic environments. Our present and near future supply of P is primarily mined from rock P reserves in a limited number of geographical regions. To help ensure that this resource is adequate for humanity's food security, an energy-efficient means of recovering P from waste and recycling it for agriculture is required. This will also help to address excess discharge to water bodies and the resulting eutrophication. Microalgae possess the advantage of polymeric inorganic polyphosphate (PolyP) storage which can potentially operate simultaneously with remediation of waste nitrogen and phosphorus streams and flue gases (CO2, SOx, and NOx). Having high productivity in photoautotrophic, mixotrophic or heterotrophic growth modes, they can be harnessed in wastewater remediation strategies for biofuel production either directly (biodiesel) or in conjunction with anaerobic digestion (biogas) or dark fermentation (biohydrogen). Regulation of algal P uptake, storage, and mobilization is intertwined with the cellular status of other macronutrients (e.g., nitrogen and sulphur) in addition to the manufacture of other storage products (e.g., carbohydrate and lipids) or macromolecules (e.g., cell wall). A greater understanding of controlling factors in this complex interaction is required to facilitate and improve P control, recovery, and reuse from waste streams. The best understood algal genetic model is Chlamydomonas reinhardtii in terms of utility and shared resources. It also displays mixotrophic growth and advantageously, species of this genus are often found growing in wastewater treatment plants. In this review, we focus primarily on the molecular and genetic aspects of PolyP production or turnover and place this knowledge in the context of wastewater remediation and highlight developments and challenges in this field.

A highly divergent hepacivirus-like flavivirus in domestic ducks.

Using random amplification and reverse transcription-PCR, a novel RNA virus was detected in sera of domestic ducks. The full genome of the virus was determined for three strains, identifying the first hepacivirus-like flavivirus in birds. The virus, that we tentatively named duck hepacivirus-like virus (DuHV), possesses several unique molecular features, such as possession of the largest hepacivirus-like polyprotein gene and a Pegivirus A-like internal ribosome entry site. Sequence comparisons and phylogenetic and sliding-window analyses indicated that DuHV is most closely related to, but highly divergent from, the known hepaciviruses. DuHV was detected in 69.7 % of 185 serum samples from four duck species and in 31 of 33 flocks from five provinces of China, reflecting a high prevalence in duck populations and a wide geographical distribution. The detection of DuHV in the same flock in November 2018 and April 2019 suggested that persistent infection can be established in the infected ducks.

Analysis of peripheral blood T-cell subsets and regulatory T-cells in multiple myeloma patients.

To study the peripheral blood T-cell subsets and regulatory T-cells of multiple myeloma (MM) patients. 48 MM patients and 24 healthy controls were enrolled. Changes in peripheral blood T-cell subsets in the MM patients i.e. CD4+CD25+T cells and CD4+CD25+CD127lowT regulatory cells (CD4+CD25+CD127lowTregs) and in healthy controls were measured using flow cytometry and immunohischemistry. The total T-cells (CD3+) in peripheral blood lymphocyte and auxiliary/induced T-cells (CD3+CD4+ T cell) of the 48 MM patients showed no statistical significance when compared with those of the control group. Suppressor/cytotoxicity T-cells (CD3+CD8+ T cell) increased (p < 0.05). CD4+CD25+T cells and CD4+CD25+CD127low Tregs were significantly higher than corresponding values in the healthy group (p < 0.05). The CD4+/CD8+ T cell ratio of Stage III MM patients was significantly lower than that of the control group (p < 0.05). The CD4+CD25+T cells and CD4+CD25+CD127low Tregs of MM patients in the stable and the progressive stages  were significantly higher than those of MM patients in the control group (p < 0.05). The abnormality of the peripheral blood T-cell subset, increased expression of CD4+CD25+CD127low Tregs, and low cellular immunity of MM patients are related to clinical staging and progression of the disease. The quantity of CD4+CD25+CD127lowTregs of peripheral blood cells of MM patients could be significantly increased through the inhibition of CD4+ and CD8+T cell activities. CD4+CD25+CD127low Tregs promotes tumor growth through the inhibition of immunologic cell proliferation. Immunological dysfunction based on Tregs cells plays an important role in the pathogenic course.

Restorative resection of radiation rectovaginal fistula can better relieve anorectal symptoms than colostomy only.

BACKGROUND: Radiation-induced rectovaginal fistula (RVF) is a severe and difficult complication after pelvic malignancy radiation. This study was to retrospectively compare the outcomes of restorative resection and colostomy only in remission of anorectal symptoms. METHODS: We enrolled a cohort of 26 consecutive cases who developed RVF after pelvic radiation. Two main procedures for these patients in our institution were used: one was restorative resection and pull-through coloanal anastomosis with a prophylactic colostomy, and another was a simple colostomy without resection. Thus, we divided these patients into these two groups. Anorectal symptoms including rectal pain, bleeding, tenesmus, and perineal mucous discharge were recorded and scored prior to surgery and at postoperative multiple time points. RESULTS: The baseline was similar among the two groups. All patients acquired good efficacy with improved symptoms at postoperative 6, 12, and 24 months, when compared to baseline. In addition, the resection group showed a better remission of tenesmus (6 months 33.3 vs 0%; 12 months 66.7 vs 16.7%) and perineal mucous discharge (6 months 88.9 vs 6.7%; 12 months 77.8 vs 15.4%; 24 months 85.7 vs 25.0%). Furthermore, three (30%) patients in the resection group successfully reversed stomas while no stoma was closed in the simple colostomy group. CONCLUSIONS: Both restorative resection procedure and colostomy only can improve anorectal symptoms of radiation-induced RVF, but restorative resection can completely relieve anorectal symptoms in selected cases.

Shuttling of (deoxy-) purine nucleotides between compartments of the diatom Phaeodactylum tricornutum.

Diatom plastids show several peculiarities when compared with primary plastids of higher plants or algae. They are surrounded by four membranes and depend on nucleotide uptake because, unlike in plants, nucleotide de novo synthesis exclusively occurs in the cytosol. Previous analyses suggest that two specifically adapted nucleotide transporters (NTTs) facilitate the required passage of nucleotides across the innermost plastid membrane. However, nucleotide transport across the additional plastid membranes remains to be clarified. Phylogenetic studies, transport assays with the recombinant protein as well as GFP-based targeting analyses allowed detailed characterization of a novel isoform (PtNTT5) of the six NTTs of Phaeodactylum tricornutum. PtNTT5 exhibits low amino acid similarities and is only distantly related to all previously characterized NTTs. However, in a heterologous expression system, it acts as a nucleotide antiporter and prefers various (deoxy-) purine nucleotides as substrates. Interestingly, PtNTT5 is probably located in the endoplasmic reticulum, which in diatoms also represents the outermost plastid membrane. PtNTT5, with its unusual transport properties, phylogeny and localization, can be taken as further evidence for the establishment of a sophisticated and specifically adapted nucleotide transport system in diatom plastids.

Rapid induction of GFP expression by the nitrate reductase promoter in the diatom Phaeodactylum tricornutum.

An essential prerequisite for a controlled transgene expression is the choice of a suitable promoter. In the model diatom Phaeodactylum tricornutum, the most commonly used promoters for trans-gene expression are the light dependent lhcf1 promoters (derived from two endogenous genes encoding fucoxanthin chlorophyll a/c binding proteins) and the nitrate dependent nr promoter (derived from the endogenous nitrate reductase gene). In this study, we investigated the time dependent expression of the green fluorescent protein (GFP) reporter under control of the nitrate reductase promoter in independently genetically transformed P. tricornutum cell lines following induction of expression by change of the nitrogen source in the medium via flow cytometry, microscopy and western blotting. In all investigated cell lines, GFP fluorescence started to increase 1 h after change of the medium, the fastest increase rates were observed between 2 and 3 h. Fluorescence continued to increase slightly for up to 7 h even after transfer of the cells to ammonium medium. The subsequent decrease of GFP fluorescence was much slower than the increase, probably due to the stability of GFP. The investigation of several cell lines transformed with nr based constructs revealed that, also in the absence of nitrate, the promoter may show residual activity. Furthermore, we observed a strong variation of gene expression between independent cell lines, emphasising the importance of a thorough characterisation of genetically modified cell lines and their individual expression patterns.

Mycobacterial Interspersed Repetitive Unit Can Predict Drug Resistance of Mycobacterium tuberculosis in China.

BACKGROUND: Recently, Mycobacterial Interspersed Repetitive Unit (MIRU) was supposed to be associated with drug resistance in Mycobacterium tuberculosis (M. tuberculosis), but whether the association exists actually in local strains in China was still unknown. This research was conducted to explore that association and the predictability of MIRU to drug resistance of Tuberculosis (TB). METHODS: The clinical isolates were collected and the susceptibility test were conducted with Lowenstein-Jensen (LJ) medium for five anti-TB drug. Based on PCR of MIRU-VNTR (Variable Number of Tandem Repeat) genotyping, we tested the number of the repeat unite of MIRU. Then, we used logistic regression to evaluate the association between 15 MIRU and drug resistance. In addition, we explored the most suitable MIRU locus of identified MIRU loci for drug resistance by multivariate logistic regression. RESULTS: Of the 102 strains, one isolate was resistant to rifampicin and one isolate was resistant to streptomycin. Among these fifteen MIRU, there was a association between MIRU loci polymorphism and anti-tuberculosis drug resistance, ETRB (P = 0.03, OR = 0.19, 95% CI 0.05-0.81) and ETRC (P = 0.01, OR = 0.14, 95% CI 0.03-0.64) were negatively related to isoniazid resistance; MIRU20 (P = 0.05, OR = 2.87, 95% CI 1.01-8.12) was positively associated with ethambutol resistance; and QUB11a (P = 0.02, OR = 0.79, 95% CI 0.65-0.96) was a negative association factor of p-aminosalicylic acid resistance. CONCLUSION: Our research showed that MIRU loci may predict drug resistance of tuberculosis in China. However, the mechanism still needs further exploration.

Novel and Effective Almagate Enema for Hemorrhagic Chronic Radiation Proctitis and Risk Factors for Fistula Development.

Radiation proctitis is a common complication after radiotherapy for pelvic malignant tumors. This study was conducted to assess the efficacy of novel almagate enemas in hemorrhagic chronic radiation proctitis (CRP) and evaluate risk factors related to rectal deep ulcer or fistula secondary to CRP. All patients underwent a colonoscopy to confirm the diagnosis of CRP and symptoms were graded. Typical endoscopic and pathological images, risk factors, and quality of life were also recorded. A total of 59 patients were enrolled. Gynecological cancers composed 93.1% of the primary malignancies. Complete or obvious reduction of bleeding was observed in 90% (53/59) patients after almagate enema. The mean score of bleeding improved from 2.17 to 0.83 (P<0.001) after the enemas. The mean response time was 12 days. No adverse effects were found. Moreover, long-term successful rate in controlling bleeding was 69% and the quality of life was dramatically improved (P=0.001). The efficacy was equivalent to rectal sucralfate, but the almagate with its antacid properties acted more rapidly than sucralfate. Furthermore, we firstly found that moderate to severe anemia was the risk factor of CRP patients who developed rectal deep ulcer or fistulas (P= 0.015). We also found abnormal hyaline-like thick wall vessels, which revealed endarteritis obliterans and the fibrosis underlying this disease. These findings indicate that almagate enema is a novel effective, rapid and well-tolerated method for hemorrhagic CRP. Moderate to severe anemia is a risk factor for deep ulceration or fistula.

[Meta-analysis of diagnostic accuracy of magnetic resonance in restaging of rectal cancer after preoperative chemoradiotherapy].

OBJECTIVE: To estimate the diagnostic accuracy of magnetic resonance(MR) in restaging of rectal cancer after preoperative chemoradiotherapy(CRT). METHODS: Comprehensive search of literature concerning the diagnosis of MR for rectal cancer after preoperative CRT was performed from databases of PubMed, EMbase, OVID and WOK. Sensitivity and specificity of MR on restaging of rectal cancer after preoperative CRT were investigated by SAS and MetaDiSc software. RESULTS: Thirteen articles including 749 patients were enrolled in this meta-analysis. For T3-T4 stage, sensitivity of MR was 82.1%(95%CI:67.9%-90.9%), specificity was 53.5%(95%CI:39.3%-67.3%), and diagnostic odds ratio(DOR) was 5.34(2.73, 6.59). For lymph node involvement, sensitivity of MR was 61.8%(95%CI:50.7%-71.8%), specificity was 72.0%(95%CI:61.3%-80.7%), and DOR was 4.33(95%CI:2.84-6.59). For circumferential resection margin(CRM) by MR, pooled sensitivity was 85.4%(95%CI:60.5%-95.7%), specificity was 80.0%(95%CI:57.4%-92.3%), and DOR was 27.62(95%CI:13.03-58.55). CONCLUSIONS: Restaging accuracy of T3-T4 and lymph nodes involvement of rectal cancer after preoperative CRT by MR is not high. MR may be a good method to make reassessment of CRM. To avoid overtreatment for T0-T2, negative lymph node and circumferential resection of rectal cancer, restaging by MR after preoperative CRT is important.

The inhibitory effects of a new cobalt-based polyoxometalate on the growth of human cancer cells.

A new cobalt-based polyoxometalate, (Himi)2[Bi(2)W2(0)O(66)(OH)(4)Co2(H2O)(6)Na(4) (H2O)14] · 17H2O (imi = iminazole) (BWCN) has been synthesized and structurally characterized. The inhibitory activities against selected human cancer lines were also determined in this study. The cell viability and chemoresistance of BWCN on human colon carcinoma HT-29 cells were assessed by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazoliumbromide), cell morphology changes, a comet assay and western blot analysis. The typical morphologic changes of apoptosis and DNA damage indicated that BWCN could have a distinct proliferation inhibitory effect on cancer cells. BWCN as a chemotherapeutic agent also induced apoptosis on HT-29 cells and showed a significant expression of cleaved-caspase-3. These results suggested that the active site of BWCN is the polymeric anion based on the basic tectonic block {BiW(9)}, and the possible mechanism is related to the interference of DNA synthesis in cancer cells.

Novel nitrogen-enriched oridonin analogues with thiazole-fused A-ring: protecting group-free synthesis, enhanced anticancer profile, and improved aqueous solubility.

Oridonin (1), a complex ent-kaurane diterpenoid isolated from the traditional Chinese herb Isodon rubescens , has demonstrated great potential in the treatment of various human cancers due to its unique and safe anticancer pharmacological profile. Nevertheless, the clinical development of oridonin for cancer therapy has been hampered by its relatively moderate potency, limited aqueous solubility, and poor bioavailability. Herein, we report the concise synthesis of a series of novel nitrogen-enriched oridonin derivatives with thiazole-fused A-ring through an efficient protecting group-free synthetic strategy. Most of them, including compounds 7-11, 13, and 14, exhibited potent antiproliferative effects against breast, pancreatic, and prostate cancer cells with low micromolar to submicromolar IC50 values as well as markedly enhanced aqueous solubility. These new analogues obtained by rationally modifying the natural product have been demonstrated not only to significantly induce the apoptosis and suppress growth of triple-negative MDA-MB-231 breast cancer both in vitro and in vivo but also effective against drug-resistant ER-positive MCF-7 clones.