PMID: 

Drug Des Devel Ther. 2019 ;13:1087-1098. Epub 2019 Apr 5. PMID: 31118562

Abstract Title: 

Lung cancer combination therapy: doxorubicin andβ-elemene co-loaded, pH-sensitive nanostructured lipid carriers.

Abstract: 

Co-delivery of drugs to achieve the synergistic anticancer effect is a promising strategy for lung cancer therapy. The purpose of this research is to develop a doxorubicin (DOX) andβ-elemene (ELE) co-loaded, pH-sensitive nanostructured lipid carriers (DOX/ELE Hyd NLCs).In this study, DOX/ELE Hyd NLCs were produced by a hot homogenization and ultrasonication method and used for lung cancer treatment. In vitro and in vivo efficiency as well as toxicity of the system was evaluated on lung cancer cell lines and lung tumor-bearing mice.DOX/ELE Hyd NLCs had a particle size of 190 nm, with a PDI lower than 0.2. DOX/ELE Hyd NLCs exhibited a significantly enhanced cytotoxicity (drug concentration causing 50% inhibition was 7.86μg/mL), synergy antitumor effect (combination index lower than 1), and profound tumor inhibition ability (tumor inhibition ratio of 82.9%) compared with the non pH-responsive NLCs and single-drug-loaded NLCs.Since the synergistic effect of the drugs was found in this system, it would have great potential to inhibit lung tumor cells and tumor growth.

read more

PMID: 

Int J Ophthalmol. 2019 ;12(11):1693-1698. Epub 2019 Nov 18. PMID: 31741856

Abstract Title: 

Inhibition ofβ-elemene on the expressions of HIF-lα, VEGF and iNOS in diabetic rats model.

Abstract: 

AIM: To evaluate the effect ofβ-elemene on the expressions of hypoxia-inducible factor (HIF)-lα, vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase (iNOS) in a streptozotocin (STZ) induced diabetic Sprague-Dawley (SD) rat model.METHODS: SD rats were administered an abdominal injection of STZ and induced to a diabetic model. After 6wk course of diabetes, the treatment groups were givenβ-elemene through periocular and intravitreous injection separately and the control groups were given blank emulsion injection. HE staining was used to observe the morphology of retina. The mRNA expressions of HIF-1α, VEGF and iNOS was assayed by real-time polymerase chain reaction (PCR) and the protein expression was measured by Western blot and immunocytochemistry methods.RESULTS: The results indicated that the protein and mRNA expressions of HIF-1α, VEGF and iNOS after treated by β-elemene periocularly and intravitreally injections were all found to be reduced compared with the levels in the diabetic rats group (

read more

PMID: 

Oncol Lett. 2020 Jan ;19(1):291-300. Epub 2019 Nov 14. PMID: 31897141

Abstract Title: 

β-elemene enhances cisplatin-induced apoptosis in bladder cancer cells through the ROS-AMPK signaling pathway.

Abstract: 

Cisplatin-based chemotherapy is the standard regimen for patients with bladder cancer, but its effectiveness is limited by high toxicity and the development of drug resistance.β-elemene (β-ELE), a compound extracted from, has antitumor activity in various malignancies and exhibits low toxicity. However, the effects and specific mechanism ofβ-ELE in bladder cancer remain unclear. The present study aimed to investigate the antitumor activity and possible mechanisms of β-ELE alone and in combination with cisplatin in bladder cancer cells. Cell viability was determined using Cell Counting Kit-8. Cell cycle and reactive oxygen species (ROS) analyses were performed by flow cytometry. Apoptosis was detected by Hoechst 33258 and Annexin-V/propidium iodide staining. Mitochondrial membrane potential was determined by staining with a JC-1 probe, flow cytometry and fluorescence microscopy. Protein expression was detected by western blotting. The results revealed that β-ELE significantly inhibited the proliferation of various bladder cancer cell lines and induced cell cycle arrest at G/G-phase in T24 and 5637 cells. Compared with cisplatin alone, co-treatment withβ-ELE increased cisplatin-mediated cytotoxicity against T24 cells, which resulted in the loss of mitochondrial membrane potential and release of cytochrome c into the cytoplasm. Co-treatment with β-ELE and cisplatin enhanced ROS accumulation and activation of 5'AMP-activated protein kinase (AMPK),which induced apoptosis. The results of the present study suggested that β-ELE inhibited the proliferation of bladder cancer cellsand enhanced cisplatin-induced mitochondria-dependent apoptosis via the ROS-AMPK signaling pathway. Combination therapy withβ-ELE requires further investigation as a potential treatment of bladder cancer.

read more

PMID: 

Biosci Rep. 2020 Feb 28 ;40(2). PMID: 32010942

Abstract Title: 

β-Elemene suppresses tumor growth of diffuse large B-cell lymphoma through regulating lncRNA HULC-mediated apoptotic pathway.

Abstract: 

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is considered the most common aggressive subtype of lymphoma. A number of DLBCL patients fail to achieve a response to currently available therapies or develop resistance.β-Elemene is derived from herb Curcuma wenyujin, and exhibits anti-tumor activity in both solid and non-solid tumors through modulating several molecular signaling pathways. We aimed to explore the role of β-elemene in DLBCL treatment and elucidate the involved mechanism.MATERIALS AND METHODS: Cell viability, apoptosis and expressions of related proteins were assessed and in vivo study were performed to determine the tumor suppressive effect ofβ-elemene and explore the molecular mechanisms.RESULTS: β-Elemene significantly suppressed the viability of DLBCL cells, and β-elemene down-regulated the lncRNA HULC expression and regulated key pro-apoptotic and anti-apoptotic proteins to induce significant apoptosis of DLBCL cells. HULC overexpression could decrease the β-elemene induced apoptosis,while HULC knockdown increased the apoptosis in DLBCL cells. In vivo study further confirmed that β-elemene could suppress the growth of DLBCL xenograft and regulate the HULC expression and the critical proteins of the apoptotic pathway.CONCLUSION: β-Elemene performs as a tumor suppressor and modulator of HULC-mediated apoptotic pathway in DLBCL and will be an alternative candidate for clinical application.

read more

PMID: 

Biochem Biophys Res Commun. 2020 Jan 29. Epub 2020 Jan 29. PMID: 32007276

Abstract Title: 

Artemisinin sensitizes tumor cells to NK cell-mediated cytolysis.

Abstract: 

The antimalarial drug Artemisinin has been reported to possess direct anti-tumor effects on various types of tumor cells. However, its anti-tumor potential has not been fully revealed, and its effects on tumor susceptibility to immune surveillance by the host are still unknown. Natural killer (NK) cells are the first line in tumor surveillance by the host, and have been recognized as a promising target for tumor immunotherapy. Here, we reported that Artemisinin sensitized tumor cells to NK cell cytolysis. Both human K562 and Raji tumor cells, and mouse YAC-1 tumor cells were more susceptible to human or mouse NK cell cytolysis in vitro after Artemisinin pretreatment. Conjugation formation between tumor cells and NK cells was increased after pretreatment with Artemisinin. Such effects on tumor cells by Artemisinin might not be the results of tumor recognition by NK cells, since major ligands of NK cell surface receptors were not affected. Mechanistically, although Artemisinin didn't induce tumor cell apoptosis, Artemisinin enriched apoptosis-related gene sets in these tumor cells, which might predispose tumor cells to apoptosis upon NK cell cytolysis. Moreover, NK cell numbers, percentages, maturation and functions were preserved in the presence of Artemisinin in vitro, suggesting that Artemisinin displays detrimental effects only on tumor cells but not on immune cells. These data reveal a novel anti-tumor mechanism of Artemisinin and demonstrate that Artemisinin could be a promising drug candidate for cancer treatment.

read more

PMID: 

Life Sci. 2020 Feb 1 ;242:117228. Epub 2019 Dec 24. PMID: 31881227

Abstract Title: 

MDM2 inhibition-mediated autophagy contributes to the pro-apoptotic effect of berberine in p53-null leukemic cells.

Abstract: 

AIMS: Berberine (BBR) is reported to induce apoptosis and inhibit migration of leukemic cells, but the underlying pharmacological mechanisms have not been fully revealed. This study aims to investigate the possible mechanisms from the perspective of autophagy.MAIN METHODS: P-53-null leukemic cell lines Jurkat and U937 were used for the in vitro study. MDC staining was used for observation of autophagy in leukemic cells, and Western blot analysis was for determination of the expression levels of autophagy-associated proteins. Apoptosis of the leukemic cells was detected by flow cytometry. Cellular location of MDM2 was observed with immunofluorescence staining. Ubiquitination of MDM2 was assessed by immunoprecipitation. Male 6-8-week-old NOD/SCID mice were used for evaluating the effect of BBR on chemotherapy sensitivity in vivo.KEY FINDINGS: BBR induced autophagy in p53-null leukemic cells, which was inhibited by autophagy inhibitors 3-methyladenine. 3-methyladenine also inhibited BBR-induced apoptosis in leukemic cells. In addition, BBR not only decreased MDM2 mRNA expression, but also enhanced MDM2 self-ubiquitination in leukemic cells. Forced overexpression of MDM2 reversed the effect of BBR on autophagy and apoptosis. Furthermore, BBR promoted doxorubicin-induced autophagy and cell death in the leukemic cells and overexpression of MDM2 suppressed these effects. In vivo, BBR combined with doxorubicin achieved better therapeutic effect than doxorubicin alone.SIGNIFICANCE: MDM2 inhibits autophagy and apoptosis in leukemic cells in a p53-independent manner. BBR induces autophagy in p53-null leukemic cells through downregulating MDM2 expression at both transcriptional and post-transcriptional levels, which may contribute to the anti-cancer effect of BBR in leukemia.

read more

PMID: 

J Integr Med. 2020 Jan 16. Epub 2020 Jan 16. PMID: 32005442

Abstract Title: 

Berberine for prevention of dementia associated with diabetes and its comorbidities: A systematic review.

Abstract: 

BACKGROUND: A growing number of epidemiological studies indicate that metabolic syndrome (MetS) and its associated features play a key role in the development of certain degenerative brain disorders, including Alzheimer's disease and vascular dementia. Produced by several different medicinal plants, berberine is a bioactive alkaloid with a wide range of pharmacological effects, including antidiabetic effects. However, it is not clear whether berberine could prevent the development of dementia in association with diabetes.OBJECTIVE: To give an overview of the therapeutic potential of berberine as a treatment for dementia associated with diabetes.SEARCH STRATEGY: Database searches A and B were conducted using PubMed and ScienceDirect. In search A, studies on berberine's antidementia activities were identified using"berberine"and"dementia"as search terms. In search B, recent studies on berberine's effects on diabetes were surveyed using"berberine"and"diabetes"as search terms.INCLUSION CRITERIA: Clinical and preclinical studies that investigated berberine's effects associated with MetS and cognitive dysfunction were included.DATA EXTRACTION AND ANALYSIS: Data from studies were extracted by one author, and checked by a second; quality assessments were performed independently by two authors.RESULTS: In search A, 61 articles were identified, and 22 original research articles were selected. In search B, 458 articles were identified, of which 101 were deemed relevant and selected. Three duplicates were removed, and a total of 120 articles were reviewed for this study. The results demonstrate that berberine exerts beneficial effects directly in the brain: enhancing cholinergic neurotransmission, improving cerebral blood flow, protecting neurons from inflammation, limiting hyperphosphorylation of tau and facilitatingβ-amyloid peptide clearance. In addition, evidence is growing that berberine is effective against diabetes and associated disorders, such as atherosclerosis, cardiomyopathy, hypertension, hepatic steatosis, diabetic nephropathy, gut dysbiosis, retinopathy and neuropathy, suggesting indirect benefits for the prevention of dementia.CONCLUSION: Berberine could impede the development of dementia via multiple mechanisms: preventing brain damages and enhancing cognition directly in the brain, and indirectly through alleviating risk factors such as metabolic dysfunction, and cardiovascular, kidney and liver diseases. This study provided evidence to support the value of berberine in the prevention of dementia associated with MetS.

read more

PMID: 

Andrology. 2020 Feb 3. Epub 2020 Feb 3. PMID: 32012485

Abstract Title: 

Protective effect of Berberine on reproductive function and spermatogenesis in diabetic rats via inhibition of ROS/JAK2/NFκB pathway.

Abstract: 

BACKGROUND: Diabetes mellitus (DM) induces impairment of male reproductive system and is considered as a key factor that could partially provide an explanation for male infertility. Thus, understanding the mechanism underlying DM-induced infertility will aid in the identification of novel therapeutic stratagems.OBJECTIVES: To delineate the role of ROS/JAK2/NFκB pathway in DM-induced low reproductive function and impaired spermatogenesis. Additionally, to investigate the protective effect of monomeric Berberine (BB), that inhibits ROS/JAK2/NFκB pathway, in the pathogenesis of DM-induced infertility.METHODS: 12-week-old male Sprague-Dawley rats were divided into four groups: control group, DM group, control plus BB group, and DM plus BB group. Streptozotocin was used to induce DM. After treating the rats with BB for 4 weeks, fertility tests were conducted to investigate the reproductive function, and testis weight along with sperm motility were assessed through microscope. Oxidative stress was evaluated by DHE staining. TUNEL staining was utilized to detect the state of apoptosis. Cell experiments were carried out to define the role of BB in vitro. Immunohistochemistry, immunofluorescence and western blotting were employed to measure the protein expression.RESULTS: Our results indicate that the reproductive function of DM rats was low, accompanied by decreased testis weight and sperm motility in addition to the impairment of the seminiferous tubules. However, there was a significant improvement in the reproductive function parameters in the BB-treated DM rats. Subsequently, our data revealed that DM rats produce an increased level of ROS in the testis, which activates JAK2 further activating the NFκB pathway, leading to increased apoptosis and impaired cells in the testicles. However, BB could attenuate the ROS production and abrogate activation of JAK2/NFκB pathway, thus inhibiting the apoptosis in the testicular cells of DM rats.CONCLUSION: ROS/JAK2/NFκB pathway is involved in the DM-induced low reproductive function and impaired spermatogenesis. BB can play a protective role in preserving the reproductive function and spermatogenesis in DM by inhibiting ROS/JAK2/NFκB pathway.

read more

PMID: 

Nat Prod Res. 2020 Feb 3:1-6. Epub 2020 Feb 3. PMID: 32011175

Abstract Title: 

Potential application of berberine in the treatment ofsepsis.

Abstract: 

Gram-negative sepsis ranks as the leading cause of death in intensive care units. Despite the development of new antibiotics, mortality from gram-negative sepsis remains high. The present study aims to investigate theeffects of berberine (BBR) administration on septic death induced by intraperitonealinjection. The results showed that (i) single 5 mg/kg dose of BBR increases the survival of septic mice, (ii) BBR administration improves the antimicrobial efficacy of antibiotic drug, (iii) BBR pre-treatment prevents improvements of BBR therapy without affecting the pro-survival effects of antibiotic drug. The effects of BBR administration were associated with immunological alterations represented by changes in CD4+ and CD8+ lymphocytes population and IL-6 and TNF-α production. This study highlighted the benefits of berberine administration as antibiotic adjuvant insepsis. Furthermore, information about berberine-induced immunological perturbations and their influence on host response to infection and therapy has been shown.

read more

PMID: 

Drug Des Devel Ther. 2020 ;14:87-101. Epub 2020 Jan 9. PMID: 32021094

Abstract Title: 

In vitro Antifungal Effects of Berberine Againstspp. In Planktonic and Biofilm Conditions.

Abstract: 

Purpose: Antifungal resistance associated with the extensive use of antifungals and biofilm formation presents major clinical challenges. Thus, new therapeutic strategies for fungal infections are urgently required. This study aimed to evaluate the in vitro antifungal effects of the natural bioactive alkaloid berberine againstspp. in planktonic and biofilm conditions.Methods: Using the CLSI M27-A3 reference method for broth dilution antifungal susceptibility testing of yeasts, the MICs for five standard strains comprised of(ATCC 10231, ATCC 90028),(ATCC 6258),(ATCC 90030),(MYA 646), and six clinical isolates (CLC1-CLC6) were tested. The 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction assay was used to evaluate the inhibitory effects of berberine againstbiofilms. The optical density value at 490 nm was measured and illustrated using concentration-absorbance curves. Finally, the effects were quantified by confocal laser scanning microscopy (CLSM), and 3-dimensional reconstruction was performed. The viability inhibition rates, biofilm formation, and thickness decrease rates were tested and analyzed using independent-samples-test. The differences among the fivestrains were analyzed using one way ANOVA.Results: The MICs for the five standard strains described above were 80, 160, 10, 20, and 40μg/mL, respectively, which was similar to that of the clinical isolates, suggesting the stable, broad-spectrum antifungal activity of berberine. Berberine exerted concentration-dependent inhibitory effects againstbiofilms, which were enhanced with the maturation ofbiofilms. Berberine decreased the viability ofbiofilms, with inhibition rates by CLSM ranging from 19.89± 0.57% to 96.93 ± 1.37%. Following 3-dimensional reconstruction, the biofilms of the berberine-treated group displayed a poorly developed architecture, and the biofilm thickness decrease rates ranged from 15.49 ± 8.45% to 30.30 ± 15.48%.Conclusion: Berberine exhibited significant antifungal activity inspp. The results provide a useful reference for multipleinfections and biofilm infections associated with antifungal resistance. Therefore, berberine might have novel therapeutic potential as an antifungal agent or a major active component of antifungal drugs.

read more