Homotherapy for heteropathy: therapeutic effect of Butein in NLRP3-driven diseases.

BACKGROUND: Aberrant inflammatory responses drive the initiation and progression of various diseases, and hyperactivation of NLRP3 inflammasome is a key pathogenetic mechanism. Pharmacological inhibitors of NLRP3 represent a potential therapy for treating these diseases but are not yet clinically available. The natural product butein has excellent anti-inflammatory activity, but its potential mechanisms remain to be investigated. In this study, we aimed to evaluate the ability of butein to block NLRP3 inflammasome activation and the ameliorative effects of butein on NLRP3-driven diseases. METHODS: Lipopolysaccharide (LPS)-primed bone-marrow-derived macrophages were pretreated with butein and various inflammasome stimuli. Intracellular potassium levels, ASC oligomerization and reactive oxygen species production were also detected to evaluate the regulatory mechanisms of butein. Moreover, mouse models of LPS-induced peritonitis, dextran sodium sulfate-induced colitis, and high-fat diet-induced non-alcoholic steatohepatitis were used to test whether butein has protective effects on these NLRP3-driven diseases. RESULTS: Butein blocks NLRP3 inflammasome activation in mouse macrophages by inhibiting ASC oligomerization, suppressing reactive oxygen species production, and upregulating the expression of the antioxidant pathway nuclear factor erythroid 2-related factor 2 (Nrf2). Importantly, in vivo experiments demonstrated that butein administration has a significant protective effect on the mouse models of LPS-induced peritonitis, dextran sodium sulfate-induced colitis, and high-fat diet-induced non-alcoholic steatohepatitis. CONCLUSION: Our study illustrates the connotation of homotherapy for heteropathy, i.e., the application of butein to broaden therapeutic approaches and treat multiple inflammatory diseases driven by NLRP3.

Design, Synthesis, and Anti-Leukemic Evaluation of a Series of Dianilinopyrimidines by Regulating the Ras/Raf/MEK/ERK and STAT3/c-Myc Pathways.

Although the long-term survival rate for leukemia has made significant progress over the years with the development of chemotherapeutics, patients still suffer from relapse, leading to an unsatisfactory outcome. To discover the new effective anti-leukemia compounds, we synthesized a series of dianilinopyrimidines and evaluated the anti-leukemia activities of those compounds by using leukemia cell lines (HEL, Jurkat, and K562). The results showed that the dianilinopyrimidine analog H-120 predominantly displayed the highest cytotoxic potential in HEL cells. It remarkably induced apoptosis of HEL cells by activating the apoptosis-related proteins (cleaved caspase-3, cleaved caspase-9 and cleaved poly ADP-ribose polymerase (PARP)), increasing apoptosis protein Bad expression, and decreasing the expression of anti-apoptotic proteins (Bcl-2 and Bcl-xL). Furthermore, it induced cell cycle arrest in G2/M; concomitantly, we observed the activation of p53 and a reduction in phosphorylated cell division cycle 25C (p-CDC25C) / Cyclin B1 levels in treated cells. Additionally, the mechanism study revealed that H-120 decreased these phosphorylated signal transducers and activators of transcription 3, rat sarcoma, phosphorylated cellular RAF proto-oncogene serine / threonine kinase, phosphorylated mitogen-activated protein kinase kinase, phosphorylated extracellular signal-regulated kinase, and cellular myelocytomatosis oncogene (p-STAT3, Ras, p-C-Raf, p-MEK, p-MRK, and c-Myc) protein levels in HEL cells. Using the cytoplasmic and nuclear proteins isolation assay, we found for the first time that H-120 can inhibit the activation of STAT3 and c-Myc and block STAT3 phosphorylation and dimerization. Moreover, H-120 treatment effectively inhibited the disease progression of erythroleukemia mice by promoting erythroid differentiation into the maturation of erythrocytes and activating the immune cells. Significantly, H-120 also improved liver function in erythroleukemia mice. Therefore, H-120 may be a potential chemotherapeutic drug for leukemia patients.

[Thoughts of treatment of tumor diseases based on toxic pathogen theory].

The toxic pathogen theory, an important part of the theories of traditional Chinese medicine(TCM), began in the Qin and Han dynasties, formed in the Jin, Sui, Tang, and Song dynasties, developed rapidly in the Ming and Qing dynasties, and conti-nued to develop in contemporary times based on the achievements of its predecessors. The continuous exploration, practice, and inheri-tance of many medical practitioners over the generations have facilitated the enrichment of its connotation. The toxic pathogen is violent, fierce, dangerous, prolonged, rapid in transmission, easy to hurt the internal organs, hidden, and latent, with many changes, and it is closely related to the development of tumor diseases. TCM has a history of thousands of years in the prevention and treatment of tumor diseases. It is gradually realized that the etiology of tumor is mainly attributed to the deficiency of healthy Qi and excess of to-xic pathogen, and the struggle between healthy Qi and toxic pathogen runs through the whole course of tumor, with the deficiency of healthy Qi as the prerequisite and the invasion of toxic pathogen as the root of the occurrence. The toxic pathogen has a strong carcinogenic effect and is involved in the whole process of tumor development, which is closely related to the malignant behaviors of tumors, including proliferation, invasion, and metastasis. This study discussed the historical origin and modern interpretation of the toxic pathogen theory in the prevention and treatment of tumors, with aims of sorting out the theoretical system based on the toxic pathogen theory in the treatment of tumor diseases, and illustrating the importance of the toxic pathogen theory in the treatment of tumors in the context of modern research on pharmacological mechanisms and the development and marketing of relevant anti-tumor Chinese medicinal preparations.

Effects of hormone replacement therapy on left ventricular diastolic function in postmenopausal women: a systematic review and meta-analysis.

BACKGROUND: Postmenopausal women tend to experience significant changes in left ventricular diastolic function (LVDF). However, there are conflicting reports about LVDF between postmenopausal women on hormone replacement therapy (HRT) and those not on HRT. This meta-analysis is to evaluate the effects of HRT on LVDF in postmenopausal women. METHODS: We conducted a systemic review of randomized controlled trials published up to December 31 2019 using Embase, Pubmed, and the Cochrane library database. RESULTS: Eight studies involving 668 postmenopausal women were identified. Our analysis indicated that the ratio of the peak velocity during early filing to late filling from atrial contraction improvement in HRT group was better than that in placebo group (MD 0.20, 95%CI 0.12 to 0.28). There was a significant reduction in deceleration time and left ventricular mass index in HRT group compared with placebo group (MD -21.01, 95%CI -40.11 to -1.91 vs MD -8.26, 95%CI -14.10 to -2.42). No significant difference was observed in left ventricular end systole diameter (MD 0.80, 95%CI -0.72 to 2.31), left ventricular end diastole diameter (MD -0.07, 95%CI -1.25 to 1.10), left atrial size (MD -0.33, 95%CI -1.34 to 0.68)and the isovolumic relaxation time (MD -12.08, 95%CI -27.65 to 3.5). CONCLUSIONS: Our meta-analysis illustrated that postmenopausal women seem to obtain more beneficial effects from HRT on LVDF, though future studies are required to elucidate the specific mechanisms for this phenomenon.

Assessment of preoperative hypercoagulability in patients with pancreatic ductal adenocarcinoma (PDAC) using rapid thromboelastography (r-TEG).

Patients with malignant tumors are usually accompanied with hypercoagulability state and high incidence risk of venous thromboembolism (VTE), especially in patients with pancreatic ductal adenocarcinoma (PDAC). However, conventional coagulation test is failed to identify this abnormity. We retrospectively reviewed clinical data of 78 PDAC patients and 79 age-matched controls with rapid thromboelastography (r-TEG) and conventional coagulation test. The main index of r-TEG include TEG-ACT (second), R (second), K (second), angleα (°) and MA (mm), and a short TEG-ACT, short R, a short K, a broad angleα and a prolonged MA can identify hypercoagulability. Compared with age-matched controls, the PADC patients were analyzed to have a shorter K value (72. + 24 ± 22.90 vs. 85.63 ± 32.81, P = 0.0014), increased angleα value (76.20 ± 3.68 vs. 74.415 ± 4.73, P = 0.009) and MA value (63.33 ± 7.19 vs. 60.89 ± 5.52, P = 0.18). Both TEG-ACT (101.72 ± 7.57 vs. 103.78 ± 7.33, P = 0.086) and R (32.95 ± 4.72 vs. 34.34 ± 4.61, P = 0.085) value showed no significant difference in two groups. The laboratory values for conventional coagulation test were within normal ranges: PT (11.65 ± 0.95 vs. 11.38 ± 0.79, P = 0.049), INR (1.01 ± 0.09 vs. 0.98 ± 0.08, P = 0.101), aPTT (28.75 ± 3.45 vs. 28.00 ± 2.98, P = 0.149) and TT (19.44 ± 1.12 vs. 19.69 ± 1.35, P = 0.212). Incidence rates of VTE were 3.8% (3 of 78 patients) and 1.3% (1 of 79 patients) respectively (Fisher's exact test: P = 0.367). Several r-TEG indexes can indicate coagulation disorders within PDAC patients, but the incidence rates of VTE for both PDAC patients and normal controls had no significant difference. Compare to the control group, the potential hypercoagulability of PDAC patients did not correlate to thrombotic complications.

Nr2f1b control venous specification and angiogenic patterning during zebrafish vascular development.

BACKGROUND: The specification of vein and the patterning of intersegmental vessels (ISV) controlled by transcription factor is not fully characterized. The orphan nuclear receptor Chicken ovalbumin upstream promoter transcription factor II (CoupTFII, a.k.a NR2F2) positively regulates vein identity in mice. In this study, we show that nr2f1b is important for vein and tip cell identity during zebrafish development. RESULTS: Nr2f1b mRNA is expressed in ventral lateral mesoderm at 15S stage and in vessels at 24 hpf consistent with a role in early vascular specification. Morpholino knockdown of nr2f1b results in a decrease in both vein cell number and expression of the vein specific marker flt4 and mrc1, suggested its role in venous specification. We also show loss of nr2f1b reduced ISV cell number and impairs ISV growth, which is likely due to the impairment of angiogenic cells migration and/or proliferation by time-lapse imaging. Consequently, nr2f1b morphants showed pericardial edema and circulation defects. Overexpression of nr2f1b under the fli promoter increases the number of venous cells and ISV endothelial cells indicated the function of nr2f1b is required and necessary for vascular development. We further showed that nr2f1b likely interact with Notch signalling. nr2f1b expression is increased in rbpsuh morphants and DAPT-treatment embryos suggested nr2f1b is negatively regulated by Notch activity. CONCLUSIONS: We show nr2f1b control venous specification and angiogenic patterning during zebrafish vascular development, which is mediated by Notch signalings.

Anti-inflammatory and uric acid lowering effects of Euodiae fructus on hyperuricemia and gout mice.

The metabolic disease hyperuricemia (HUA) is caused by presence of excessive serum uric acid (UA), which leads to an increased risk of chronic kidney disease and gout. As a widely used traditional Chinese medicine, Euodiae fructus (ER) has strong anti-inflammatory and analgesic effects, however, its therapeutic effects on HUA and gout have not been investigated. To investigate the potential effects and underlying mechanisms, the effect of ER on proinflammatory cytokines and NLRP3 inflammasome activation was studied in mouse bone marrow macrophages. Moreover, a mouse model of HUA and gouty arthritis was established by coadministration of potassium oxonate (PO) and monosodium urate crystals to mice fed a high-fat diet (HFD) for 37 consecutive days. Oral administration of ER aqueous extract was given 1 hour later after the injection of PO for 10 days. Our study showed that ER is a powerful NLRP3 inhibitor in mouse macrophages. Most importantly, ER (0.75 g/kg) treatment substantially decreased the ankle joint thickness ratio, serum UA, creatinine and blood urea nitrogen levels (p < 0.05). Additionally, ER (0.75 g/kg) dramatically reversed the increases in renal urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) as well as the decreases in organic anion transporter 1 (OAT1) and ATP binding cassette subfamily G member 2 (ABCG2) levels (p < 0.05). Moreover, ER (0.75 g/kg) markedly ameliorated the production of the serum inflammatory cytokines IL-1ß and TNF-α (p < 0.01), and improved the activation of NLRP3 inflammasome signaling in the kidneys. Taken together, these data indicate that ER, a powerful and specific NLRP3 inhibitor, has multiple anti-HUA, anti-gout and anti-inflammatory effects. Our investigation is designed to experimentally support the conventional use of ER-containing classical herbal formulas in the treatment of HUA-related disorders and may add a new dimension to the clinical application of ER.

Glycyrrhizin and the Related Preparations: An Inspiring Resource for the Treatment of Liver Diseases.

Liver diseases and their related complications endanger the health of millions of people worldwide. The prevention and treatment of liver diseases are still serious challenges both in China and globally. With the improvement of living standards, the prevalence of metabolic liver diseases, including non-alcoholic fatty liver disease and alcoholic liver disease, has increased at an alarming rate, resulting in more cases of end-stage liver disease. Therefore, the discovery of novel therapeutic drugs for the treatment of liver diseases is urgently needed. Glycyrrhizin (GL), a triterpene glycoside from the roots of licorice plants, possesses a wide range of pharmacological and biological activities. Currently, GL preparations (GLPs) have certain advantages in the treatment of liver diseases, with good clinical effects and fewer adverse reactions, and have shown broad application prospects through multitargeting therapeutic mechanisms, including antisteatotic, anti-oxidative stress, anti-inflammatory, immunoregulatory, antifibrotic, anticancer, and drug interaction activities. This review summarizes the currently known biological activities of GLPs and their medical applications in the treatment of liver diseases, and highlights the potential of these preparations as promising therapeutic options and their alluring prospects for the treatment of liver diseases.

Inhibitory effects of recombinant IL-4 and recombinant IL-13 on UHMWPE-induced bone destruction in the murine air pouch model.

PURPOSE: We administered recombinant interleukin (IL)-4 and recombinant IL-13 locally into the air pouch of mice to improve bone resorption induced by ultra-high-molecular-weight polyethylene (UHMWPE) particles. METHODS: Air pouches were established on the back of BALB/c mice, followed by the surgical introduction of a section of calvaria from a syngeneic mouse donor. We stimulated the bone-implanted pouches with the UHMWPE suspension. We divided UHMWPE-containing mice into four study groups to receive injections of phosphate-buffered saline (control), IL-4 alone, IL-13 alone, or IL-4 and IL-13 into the pouches. We harvested the tissues at 14 d after treatment for molecular and histological analyses. RESULTS: The inhibitory effect of IL-4 was stronger than that of IL-13 toward osteoclast differentiation and osteoblast for the induction of osteoprotegerin production and down-regulation of receptor for activation of nuclear factor-κB ligand production. Furthermore, the combined treatment with both IL-4 and 1L-13 had a more important role in inhibiting bone resorption in these pouches with UHMWPE stimulation, compared with IL-4 or IL-13 treatment alone. CONCLUSIONS: Local administration of recombinant IL-4 and IL-13 may be a feasible and effective therapeutic candidate to treat or prevent wear debris-associated osteolysis.

Long Term Outcomes of No-Touch Isolation Principles Applied in Pancreaticoduodenectomy for Treatment of Pancreatic Adenocarcinoma: A Multicenter Retrospective Study with Propensity Score Matching.

Background: The recurrence and liver metastasis rates are still high in pancreatic head cancer with curative surgical resection. A no-touch isolation principle in pancreaticoduodenectomy (PD) may improve this situation, however, the exact advantages and efficacy of these principles have not been confirmed. Materials and methods: Among 370 patients who underwent PD, three centers were selected and classified into two groups: the no-touch PD group (n = 70) and the conventional PD group (n = 300). Propensity score matching was used to control for selection bias at a ratio of 1:1. The confounding variables were age, sex, body mass index, adjuvant chemotherapy, carbohydrate antigen 19-9, tumor size and tumor differentiation. Results: Patients in the no-touch PD group had better overall survival (OS) and disease-free survival (DFS) than those in the conventional PD group (OS: 17 vs. 13 months, p = 0.0035, DFS: 15 vs. 12 months, p = 0.087), with lower 1- and 2-year disease-related mortality rates (1-year: 32.9% vs. 47%, p = 0.032; 2-year: 42.5% vs. 82% p = 0.000) and recurrence and liver metastasis rates (1-year: 30.0% vs. 43.3%, p = 0.041; 2-year: 34.3% vs. 48.7%, p = 0.030). Compared with the matched conventional PD group, the no-touch PD group also had a better OS (17 vs. 12 months, p = 0.032). Conclusions: Our study showed the no-touch isolation principle may be a better choice to improve long-term survival for pancreatic cancer patients.

Cystathionine ß-Synthase Suppresses NLRP3 Inflammasome Activation via Redox Regulation in Microglia.

Aims: Cystathionine ß-synthase (CBS) is essential for homocysteine (Hcy) transsulfuration, yielding cysteine as a common precursor of hydrogen sulfide (H2S), glutathione (GSH), and other sulfur molecules, which produce neuroprotective effects in neurological conditions. We previously reported a disruption of microglial CBS/H2S signaling in a Parkinson's disease (PD) mouse model. Yet, it remains unclear whether CBS affects nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome activity and other pathologies in PD. Results: Microglial CBS expression decreased after lipopolysaccharide (LPS) stimulation. Elevated GSSG (the oxidized GSH) content and decreased H2S generation were found in the brains of microglial cbs conditional-knockout (cbscKO) mice, whereas serum and brain Hcy levels remained unaltered. Moreover, microglial cbscKO mice were susceptible to NLRP3 inflammasome activation and dopaminergic neuron losses caused by LPS injection into the substantia nigra, whereas cbs overexpression or activation produced opposite effects. In vitro studies showed that cbs overexpression or activation suppressed microglial NLRP3 inflammasome activation and interleukin (IL)-1ß secretion by reducing mitochondrial reactive oxygen species (mitoROS) level. Conversely, ablation of cbs enhanced NLRP3 expression and mitoROS generation and augmented microglial NLRP3 inflammasome activity in response to adenosine triphosphate challenge, which was blocked by the mitoROS scavenger. Innovation and Conclusion: The study demonstrated an elevated GSSG level and reduced H2S generation, which correlated with a susceptible status of microglia in the brain of cbscKO mice. Our findings reveal a critical role of CBS in restraining the microglial NLRP3 inflammasome by controlling redox homeostasis and highlight that activation or upregulation of CBS may become a potential strategy for PD treatment.

Environmental pollutants induce NLRP3 inflammasome activation and pyroptosis: Roles and mechanisms in various diseases.

Environmental pollution is changing with economic development. Most environmental pollutants are characterized by stable chemical properties, strong migration, potential toxicity, and multiple exposure routes. Harmful substances are discharged excessively, and large quantities of unknown new compounds are emerging, being transmitted and amplifying in the food chain. The increasingly severe problems of environmental pollution have forced people to re-examine the relationship between environmental pollution and health. Pyroptosis and activation of the NLRP3 inflammasome are critical in maintaining the immune balance and regulating the inflammatory process. Numerous diseases caused by environmental pollutants are closely related to NLRP3 inflammasome activation and pyroptosis. We intend to systematically explain the steps and important events that are common in life but easily overlooked by which environmental pollutants activate the NLRP3 inflammasome and pyroptosis pathways. This comprehensive review also discusses the interaction network between environmental pollutants, the NLRP3 inflammasome, pyroptosis, and diseases. Thus, research progress on the impact of decreasing oxidative stress levels to inhibit the NLRP3 inflammasome and pyroptosis, thereby repairing homeostasis and reshaping health, is systematically examined. This review aims to deepen the understanding of the impact of environmental pollutants on life and health and provide a theoretical basis and potential programs for the development of corresponding treatment strategies.

Gallic acid alleviates gastric precancerous lesions through inhibition of epithelial mesenchymal transition via Wnt/ß-catenin signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Gallic acid (GA) is a natural polyphenolic compound derived from Rhus chinensis Mill. with a variety of biological activities such as astringent sweat, cough, dysentery, hemostasis, and detoxification, and is widely used in China as a treatment for cough, bleeding, and gastrointestinal disorders. In recent years, the anticancer activity of GA has been demonstrated in a variety of cancers, affecting multiple cellular pathways associated with cancer onset, development and progression. AIM OF THE STUDY: To investigate the role and potential mechanism of GA on gastric precancerous lesions (GPL), the key turning point of gastritis to gastric cancer, with the aim of delaying, blocking or reversing the dynamic overall process of "inflammation-cancer transformation" and thus blocking GPL to prevent the development of gastric cancer. MATERIALS AND METHODS: In this study, we established N-Nitroso-N-methylurea (MNU)-induced GPL mice model and induced precancerous lesions of gastric cancer cells (MC), i.e. epithelial mesenchymal transition (EMT), in human gastric mucosal epithelial cells (GES-1) with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). We used conventional pathology, immunohistochemistry, RNA sequencing, Western blot and other techniques to study the therapeutic effect of GA on GPL and its possiblemechanism in vitro and in vivo. RESULTS: The results showed that compared with normal GES-1 cells, MC cells had the characteristics of malignant cells such as abnormal proliferation, invasion and metastasis, accompanied by decreased expression of EMT-related protein E-cadherin and increased expression of N-cadherin and Vimentin. GA can inhibit the malignant behavior of MC cell proliferation and induce its G0/G1 phase arrest, which is achieved by downregulating the Wnt/ß-catenin signaling pathway and thereby inhibiting the EMT process. However, when we incubated with the Wnt pathway activator (Wnt agonist 1), the effect of GA was reversed. Furthermore, analysis of human gastric specimens showed that activation of the Wnt/ß-catenin pathway was significantly associated with GPL pathological changes. Meanwhile, GA reversed MNU-induced intestinal metaplasia and partial dysplasia in GPL mice. CONCLUSION: Taken together, these results indicate that GA prevents the occurrence and development of GPL by inhibiting the Wnt/ß-catenin signaling pathway and then inhibiting the EMT process, which may become potential candidates for the treatment of GPL.

Copper deprivation enhances the chemosensitivity of pancreatic cancer to rapamycin by mTORC1/2 inhibition.

Cuproplasia, or copper-dependent cell proliferation, has been observed in varieties of solid tumors along with aberrant copper homeostasis. Several studies reported good response of patients to copper chelator assisted neoadjuvant chemotherapy, however, the internal target molecules are still undetermined. Unravel copper-associated tumor signaling would be valuable to forge new links to translate biology of copper into clinical cancer therapies. We evaluated the significance of high-affinity copper transporter-1 (CTR1) by bioinformatic analysis, and in 19 pairs of clinical specimens. Then, with the help of gene interference and chelating agent, enriched signaling pathways were identified by KEGG analysis and immunoblotting. Accompanying biological capability of pancreatic carcinoma-associated proliferation, cell cycle, apoptosis, and angiogenesis were investigated. Furthermore, a combination of mTOR inhibitor and CTR1 suppressor has been assessed in xenografted tumor mouse models. Hyperactive CTR1 was investigated in pancreatic cancer tissues and proven to as the key point of cancer copper homeostasis. Intracellular copper deprivation induced by CTR1 gene knock-down or systematic copper chelation by tetrathiomolybdate suppressed proliferation and angiogenesis of pancreatic cancer cell. PI3K/AKT/mTOR signaling pathway was suppressed by inhibiting the activation of p70(S6)K and p-AKT, and finally inhibited mTORC1 and mTORC2 after copper deprivation. Additionally, CTR1 gene silencing successfully improved the anti-cancer effect of mTOR inhibitor rapamycin. Our study reveals that CTR1 contributes to pancreatic tumorigenesis and progression, by up-regulating the phosphorylation of AKT/mTOR signaling molecules. Recovering copper balance by copper deprivation addresses as promising strategy for improved cancer chemotherapy.

Inhibitory effect of adenovirus-mediated siRNA-targeting BMPR-IB on UHMWPE-induced bone destruction in the murine air pouch model.

OBJECTIVE: Adenovirus expressing small interfering RNA (siRNA)-targeting BMPR-IB was locally administered into the air pouch of mice to improve bone resorption induced by ultra-high molecular weight polyethylene (UHMWPE) particles. METHOD: Air pouches were established on the back of BALB/c mice, followed by the surgical introduction of a section of calvaria from a syngeneic mouse donor. The bone-implanted pouches were stimulated with the UHMWPE suspension. UHMWPE-containing mice were divided into three study groups to receive injections of adenovirus expressing BMPR-IB siRNA (BMPR-IB group), adenovirus expressing missense siRNA, and virus-free culture medium (control group) into the pouches, respectively. The tissues were harvested at 14 days after the treatment for molecular and histological analyses. RESULTS: Adenovirus-mediated BMPR-IB siRNA treatment significantly improved UHMWPE particle-induced bone resorption, reduced TRAP and RANK gene and protein expression levels, and diminished the number of TRAP-positive cells. Furthermore, the BMPR-IB siRNA inhibited osteoclast differentiation by targeting osteoblast for the induction of osteoprotegerin formation and downregulation of receptor for activation of nuclear factor-κB ligand production. CONCLUSIONS: This study suggested that loss of bone morphogenetic protein signaling by BMPR-IB siRNA directs osteoblasts to decrease bone destruction in part by downregulating osteoclastogenesis through the receptor for activation of nuclear factor-κB ligand-osteoprotegerin pathway. Local administration of adenovirus expressing siRNA-targeting BMPR-IB may be a feasible and effective therapeutic candidate to treat or prevent wear debris-associated osteolysis.

The Role of Primary Tumor Resection in Patients With Pancreatic Neuroendocrine Tumors With Liver Metastases.

Background: Liver metastases (LMs) are common in advanced pancreatic neuroendocrine tumor (PNET) patients. Currently, the benefit of primary tumor resection (PTR) in the setting of PNET patients with liver metastases is still controversial in several guidelines. Methods: Data were extracted from the Surveillance, Epidemiology and End Results (SEER) database to evaluate this issue. The main index of interest in our study was overall survival time. Results: Information on 536 PNET patients with liver metastases from the SEER database was identified. A total of 214 patients (PTR group) received primary tumor resection, and more than half of them (132 patients) had synchronous LM resection. The other 322 PNET patients (non-PTR group) with liver metastases did not receive primary tumor resection. A significant survival benefit was gained from PTR when compared with non-PTR patients, both in OS (72.93 ± 2.7 vs. 36.80 ± 2.22 months) and 3- or 5-year survival rates (75.1% vs. 28.9% and 67.9% vs. 22.3%, respectively). No difference was found between PTR alone and PTR with synchronous LM resection. From univariate and multivariate analyses, younger age (<65 years) and good or moderate tumor differentiation may be more important when considering primary tumor resection. However, we found that all grades of tumor differentiation could result in a better overall survival time after primary tumor resection. Conclusion: Our study suggested that primary tumor resection in pancreatic neuroendocrine patients with liver metastases could result in a longer survival time. Primary tumor resection with synchronous liver metastasis resection was not related to a better survival benefit. This treatment strategy may routinely be taken into consideration in these patients.

Natural Products-Based Nanoformulations: A New Approach Targeting CSCs to Cancer Therapy.

Cancer stem cells (CSCs) lead to the occurrence and progression of cancer due to their strong tumorigenic, self-renewal, and multidirectional differentiation abilities. Existing cancer treatment methods cannot effectively kill or inhibit CSCs but instead enrich them and produce stronger proliferation, invasion, and metastasis capabilities, resulting in cancer recurrence and treatment resistance, which has become a difficult problem in clinical treatment. Therefore, targeting CSCs may be the most promising approach for comprehensive cancer therapy in the future. A variety of natural products (NP) have significant antitumor effects and have been identified to target and inhibit CSCs. However, pharmacokinetic defects and off-target effects have greatly hindered their clinical translation. NP-based nanoformulations (NPNs) have tremendous potential to overcome the disadvantages of NP against CSCs through site-specific delivery and by improving their pharmacokinetic parameters. In this review, we summarize the recent progress of NPNs targeting CSCs in cancer therapy, looking forward to transforming preclinical research results into clinical applications and bringing new prospects for cancer treatment.

[Differences of drought tolerance of the main tree species in Dongling Mountain, Beijing, China as indicated by tree rings]. / æ ‘æœ¨å¹´è½®æ­ç¤ºçš„ä¸œçµå±±ä¸»è¦æ ‘ç§é—´å¹²æ—±è€å—æ€§å·®å¼‚.

Forests in Beijing exhibit vulnerability to increasing stress of extreme drought in recent years. To investigate the drought tolerance of different tree species, we chose three tree species (Larix principis-rupprechtii, Pinus tabuliformis, and Quercus wutaishanica) from the forest of Dongling Mountain in Beijing and used dendroecological method to analyze the relationship between radial growth and climate, as well as their resistance and resilience to extreme drought events. Our results showed that the radial growth of L. principis-rupprechtii and P. tabuliformis was significantly negatively correlated with monthly mean temperature from May to June, but that of Q. wutaishanica was significantly negatively correlated with monthly mean temperature only in May. The radial growth of L. principis-rupprechtii was significantly positively correlated with monthly mean precipitation in June, monthly mean relative humidity from May to June and August to September. The radial growth of P. tabuliformis was significantly positively correlated with monthly mean precipitation and monthly mean relative humidity from June to August. The radial growth of Q. wutaishanica was significantly positively correlated with monthly mean precipitation in February and May, and monthly mean relative humidity in May. The radial growth of all the three species was significantly positively correlated with monthly mean SPEI (standardized precipitation evapotranspiration index) from May to July. L. principis-rupprechtii was least drought tolerant, as indicated by the greatest growth reduction (46.6%-69.6%), lowest resistance (0.534, 0.304, 0.530) and resilience (0.686, 0.570, 0.753) during the three extreme drought events occurred in the 1994, 2001-2002, and 2007. In contrast, tree growth of Q. wutaishanica showed the highest drought resistance in 2007, whereas no significant differences were observed between other two species. Extreme drought events caused by continuous high temperature and reduced precipitation during the growing season accounted for the reduction in tree radial growth. The various physiological and ecological strategies of tree species were the possible reasons for the difference in drought tolerance. Our results could provide a basis for the selection of suitable afforestation tree species and the formulation of forest protection mea-sures to maintain forest ecosystem functions and services under the background of undergoing climate change.

Memantine protects blood-brain barrier integrity and attenuates neurological deficits through inhibiting nitric oxide synthase ser1412 phosphorylation in intracerebral hemorrhage rats: involvement of peroxynitrite-related matrix metalloproteinase-9/NLRP3 inflammasome activation.

Memantine has demonstrated beneficial effects on several types of brain insults via therapeutic mechanisms mainly related to its activity as a receptor antagonist of N-methyl-d-aspartate. However, the influences of memantine on intracerebral hemorrhage (ICH) remain obscure. This research probed into the neurovascular protective mechanisms of memantine after ICH and its impacts on neuronal nitric oxide synthase (nNOS) ser1412 phosphorylation. ICH model was established by employing intrastriatal collagenase injection in rats. After modeling, rats were then allocated randomly into sham-operated (sham), vehicle-treated (ICH+V), and memantine-administrated (ICH+M) groups. Memantine (20 mg/kg/day) was intraperitoneally administered 30 min after ICH and thenceforth once daily. Rats were dedicated at 0.25, 6, 12, 24 h, 3 and 7 d post-ICH for measurement of corresponding indexes. Behavioral changes, brain edema, levels of nNOS ser1412 phosphorylation, peroxynitrite, matrix metalloproteinase (MMP)-9, NLRP3, IL-1ß and numbers of dying neurons, as well as the cellular localization of gelatinolytic activity, were detected among the groups. Memantine improved the neurologic deficits and mitigated brain water content, levels of MMP-9, NLRP3, IL-1ß and dying neurons. Additionally, treatment with memantine also reduced nNOS ser1412 phosphorylation and peroxynitrite formation compared with the ICH+V group at 24 h after ICH. In situ zymography simultaneously revealed that gelatinase activity was primarily colocalized with vessel walls and neurons. We concluded that memantine ameliorated blood-brain barrier disruption and neurologic dysfunction in an ICH rat model. The underlying mechanism might involve repression of nNOS ser1412 phosphorylation, as well as peroxynitrite-related MMP-9 and NLRP3 inflammasome activation.

Which Surgeries Are the Best Choice for Chronic Pancreatitis: A Network Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Surgery is an effective choice for the treatment of chronic pancreatitis (CP). However, there is no clear consensus regarding the best choice among the surgical procedures. The aim of this study is to conduct a network meta-analysis of randomized controlled trials comparing treatment outcomes to provide high-quality evidences regarding which is the best surgery for CP. METHODS: A systematic search of the PubMed (MEDLINE), SCIE, EMBASE, CENTRAL, and CDSR databases were performed to identify studies comparing surgeries for CP from the beginning of the databases to May 2020. Pain relief and mortality were the primary outcomes of interest. RESULTS: Ten studies including a total of 680 patients were identified for inclusion. PPPD had a better postoperative short-term pain relief and quality of life (QOL), but a worse pancreatic exocrine function deficiency and high morbidity. Berne had a significant postoperative long-term pain relief and mortality with a lower risk of pancreatic exocrine function deficiency. CONCLUSION: The main surgical procedures including the PPPD, Beger procedure, Frey modification and Berne modification can efficaciously treat CP. The Berne modification may be first choice with better efficacy and less complications in pancreatic function, but the impact of postoperative QOL cannot be ignored. Furthermore, when the CP patients have a mass in the pancreatic head which cannot be distinguished from pancreatic cancer, the only legitimate choice should be PPPD or classical pancreaticoduodenectomy.