Effects and Mechanisms of Curcumin for the Prevention and Management of Cancers: An Updated Review.

Cancer is the leading cause of death in the world. Curcumin is the main ingredient in turmeric (Curcuma longa L.), and is widely used in the food industry. It shows anticancer properties on different types of cancers, and the underlying mechanisms of action include inhibiting cell proliferation, suppressing invasion and migration, promoting cell apoptosis, inducing autophagy, decreasing cancer stemness, increasing reactive oxygen species production, reducing inflammation, triggering ferroptosis, regulating gut microbiota, and adjuvant therapy. In addition, the anticancer action of curcumin is demonstrated in clinical trials. Moreover, the poor water solubility and low bioavailability of curcumin can be improved by a variety of nanotechnologies, which will promote its clinical effects. Furthermore, although curcumin shows some adverse effects, such as diarrhea and nausea, it is generally safe and tolerable. This paper is an updated review of the prevention and management of cancers by curcumin with a special attention to its mechanisms of action.

Anticancer Effects and Mechanisms of Berberine from Medicinal Herbs: An Update Review.

Cancer has been a serious public health problem. Berberine is a famous natural compound from medicinal herbs and shows many bioactivities, such as antioxidant, anti-inflammatory, antidiabetic, anti-obesity, and antimicrobial activities. In addition, berberine shows anticancer effects on a variety of cancers, such as breast, lung, gastric, liver, colorectal, ovarian, cervical, and prostate cancers. The underlying mechanisms of action include inhibiting cancer cell proliferation, suppressing metastasis, inducing apoptosis, activating autophagy, regulating gut microbiota, and improving the effects of anticancer drugs. This paper summarizes effectiveness and mechanisms of berberine on different cancers and highlights the mechanisms of action. In addition, the nanotechnologies to improve bioavailability of berberine are included. Moreover, the side effects of berberine are also discussed. This paper is helpful for the prevention and treatment of cancers using berberine.

Effects and mechanisms of resveratrol for prevention and management of cancers: An updated review.

Cancer is a severe public health problem. Resveratrol is a famous natural compound that has various bioactivities, such as antioxidant, anti-inflammatory, antidiabetic and antiaging activities. Especially, resveratrol could prevent and treat various cancers, such as oral, thyroid, breast, lung, liver, pancreatic, gastric, colorectal, bladder, prostate and ovarian cancers. The underlying mechanisms have been widely studied, such as inhibiting cell proliferation, suppressing metastasis, inducing apoptosis, stimulating autophagy, modulating immune system, attenuating inflammation, regulating gut microbiota and enhancing effects of other anticancer drugs. In this review, we summarize effects and mechanisms of resveratrol on different cancers. This paper is helpful to develop resveratrol, crude extract containing resveratrol, or foods containing resveratrol into functional food, dietary supplements or auxiliary agents for prevention and management of cancers.

pH-Regulated Single and Double Charge Inversions on PEI-Coated Surfaces.

The pH-regulated charge inversions on polyethylenimine (PEI)-coated surfaces are indispensable to their applications in biomaterials and nanomaterials. Various PEI-coated surfaces, where single charge inversion happens, have been extensively investigated, while the surfaces where double charge inversion appears are less reported. Here, using a molecular theory, we systematically study the pH-regulated charge density of PEI-coated surfaces. The results suggest whether single or double charge inversion happens depends on PEI affinity to the surface and the bare surface charge density. The region of double charge inversion is much smaller than that of single charge inversion, revealing the reason why double charge inversion is less observed in experiments. Besides, the charge inversions are significantly influenced by the solution condition. The present work provides a useful guideline to the selection of the coated materials and the parameters of PEI solution in the design of PEI-coated surfaces aiming to promote their applications in multifunctional nanomaterials.

Prognosis assessment model based on low serum calcium in patients with acute pulmonary thromboembolism.

BACKGROUND AND OBJECTIVE: The pulmonary embolism severity index (PESI) and simplified PESI (sPESI) are recommended to recognize patients with acute pulmonary thromboembolism (PTE) with low prognosis risk, which is of great significance for treatment. This study aims to verify the influence of hypocalcaemia on the prognosis of patients with PTE and to establish a new prognosis assessment model. METHODS: This is an observational, multicentre study enrolling patients with PTE from February 2010 to June 2020 across 12 Chinese hospitals. Variables in PESI, serum calcium levels and patient survival status as of 5 July 2020 were collected. The area under the curve of the receiver operating characteristic curve, sensitivity, specificity and Youden index were used to evaluate model performance. RESULTS: In the cohort of 4196 patients with PTE, independent associations existed between hypocalcaemia and mid- and long-term mortalities (p <0.05). By including hypocalcaemia, the new 30-day death risk prediction rule, Peking Union Medical College Hospital rule (PUMCH rule), showed significantly higher specificity (0.622 [0.582, 0.661]; p <0.001) than the PESI (0.514 [0.473, 0.554]) and sPESI (0.484 [0.444, 0.525]) and similar sensitivity (0.963 [0.810, 0.999]; p = 0.161) with PESI (0.889 [0.708, 0.976]) and sPESI (0.963 [0.810, 0.999]) in the internal validation cohort. Well-performing predictive validity was also verified on a constructed external validation cohort. CONCLUSION: Hypocalcaemia is independently associated with mid- and long-term PTE mortalities. The PUMCH rule showed significantly higher specificity than the PESI and sPESI and similar sensitivity, which may be used as a prognostic assessment tool for patients with acute PTE.

The investigation of genetic and clinical features in patients with hereditary spastic paraplegia in central-Southern China.

OBJECTIVE: Hereditary spastic paraplegias (HSP) is a clinically and genetically heterogeneous group of neurodegenerative disorders. We describe the genetic and clinical features of a cohort of five HSP families from central-southern China. METHODS: Using targeted exome-sequencing technology, we investigated the genetic and clinical features in five HSP families. We reviewed the clinical histories of these patients as well as the molecular and functional characterization of the associated gene variants. We also performed functional analysis of an intron variant of SPAST in vitro. RESULTS: We identified a known SPAST mutation (p.Pro435Leu) in a family with autosomal dominant HSP (AD-HSP) and four novel variants in two HSP families and a sporadic case. These identified four novel variants included a variant in SPG11 (p.Val1979Ter), two variants in B4GALNT1 (p.Ser475Phe and c.1002 + 2 T > G), and a splicing site variant in SPAST (c.1245+5G>A). Minigene analysis of the splicing variant in SPAST (c.1245+5G>A) revealed that the mutation resulted in mRNAs with a loss of exon 9. The SPG4 family carrying c.1245+5G>A variant in SPAST exhibited genetic anticipation, with a decreased age at onset and increased severity in successive generations. The proband with p.Val1979Ter variant in SPG11 showed characteristic clinical features of early-onset, severe spasticity, and corpus callosum atrophy which were highly suggestive of the diagnosis of SPG11-associated HSP. CONCLUSIONS: Our findings strongly support variable phenotype of B4GALNT1-related SPG26 and also expand the clinical and mutation spectrum of HSP caused by mutations in SPAST, SPG11, and B4GALNT1. These results will help to improve the efficiency of early diagnosis in patients clinically suspected of HSP.

Overexpression of kinesin superfamily members as prognostic biomarkers of breast cancer.

BACKGROUND: Kinesin superfamily (KIFs) has a long-reported significant influence on the initiation, development, and progress of breast cancer. However, the prognostic value of whole family members was poorly done. Our study intends to demonstrate the value of kinesin superfamily members as prognostic biomarkers as well as a therapeutic target of breast cancer. METHODS: Comprehensive bioinformatics analyses were done using data from TCGA, GEO, METABRIC, and GTEx. LASSO regression was done to select tumor-related members. Nomogram was constructed to predict the overall survival (OS) of breast cancer patients. Expression profiles were testified by quantitative RT-PCR and immunohistochemistry. Transcription factor, GO and KEGG enrichments were done to explore regulatory mechanism and functions. RESULTS: A total of 20 differentially expressed KIFs were identified between breast cancer and normal tissue with 4 (KIF17, KIF26A, KIF7, KIFC3) downregulated and 16 (KIF10, KIF11, KIF14, KIF15, KIF18A, KIF18B, KIF20A, KIF20B, KIF22, KIF23, KIF24, KIF26B, KIF2C, KIF3B, KIF4A, KIFC1) overexpressed. Among which, 11 overexpressed KIFs (KIF10, KIF11, KIF14, KIF15, KIF18A, KIF18B, KIF20A, KIF23, KIF2C, KIF4A, KIFC1) significantly correlated with worse OS, relapse-free survival (RFS) and distant metastasis-free survival (DMFS) of breast cancer. A 6-KIFs-based risk score (KIF10, KIF15, KIF18A, KIF18B, KIF20A, KIF4A) was generated by LASSO regression with a nomogram validated an accurate predictive efficacy. Both mRNA and protein expression of KIFs are experimentally demonstrated upregulated in breast cancer patients. Msh Homeobox 1 (MSX1) was identified as transcription factors of KIFs in breast cancer. GO and KEGG enrichments revealed functions and pathways affected in breast cancer. CONCLUSION: Overexpression of tumor-related KIFs correlate with worse outcomes of breast cancer patients and can work as potential prognostic biomarkers.

Knockdown of heme oxygenase-1 promotes apoptosis and autophagy and enhances the cytotoxicity of doxorubicin in breast cancer cells.

Heme oxygenase-1 (HMOX-1) is a microsomal enzyme that exerts anti-apoptotic and cytoprotective effects. In the present study, HMOX-1 was demonstrated to be overexpressed and able to be induced by doxorubicin in breast cancer cell lines. Knockdown of HMOX-1 using short interfering (si)RNA enhanced the cytotoxicity of doxorubicin in MDA-MB-231 and BT549 cells. Knockdown of HMOX-1 downregulated B cell lymphoma (Bcl)-2 and Bcl-extra large expression, and significantly enhanced doxorubicin-induced apoptosis in MDA-MB-231 and BT549 cells. Additionally, knockdown of HMOX-1 upregulated light chain 3B expression and markedly increased the accumulation of autophagic vacuoles in MDA-MB-231 and BT549 cells treated with doxorubicin. These results indicated that HMOX-1 may be involved in conferring the chemoresistance of breast cancer cells, by preventing apoptosis and autophagy. Therefore, HMOX-1 may represent a potential therapeutic target for enhancing the cytotoxicity and efficacy of doxorubicin during the treatment of breast cancer.

[Protective effects of rosiglitazone intervention on monocrotaline-induced pulmonary arterial hypertension in rats and related inflammatory mechanisms].

OBJECTIVE: To investigate the protective effects of rosiglitazone intervention on monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) in rats and the possible mechanisms. METHODS: Thirty-two Sprague-Dawley rats were randomly divided into 4 groups: control group with a subcutaneous injection of normal saline. PAH group, high-dose and low-dose rosiglitazone intervention groups all with a subcutaneous injection of MCT and then gastric infusion of normal saline (1.5 ml/d), rosiglitazone (5, 2.5 mg·kg(-1)×d(-1)). At Day 21, the mean pulmonary arterial pressure (mPAP) was detected by right heart catheter. Then rats were sacrificed and their lungs extracted. Perivascular inflammation was scored with the subjective scale of 0 to 4. The tunica media thickness percentage of small pulmonary arteries (WT%) of rats was calculated. Interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α) and monocyte chemotactic protein 1 (MCP-1) of lung tissue were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared with the PAH group ((37 ± 5) mm Hg (1 mm Hg = 0.133 kPa), 45.5% ± 5.5%), the mPAP and WT% of the high-dose ((27 ± 4) mm Hg, 13.1% ± 3.9%) and low-dose ((28 ± 4) mm Hg, 16.7% ± 1.7%) rosiglitazone intervention group were significantly lower (P < 0.01), but were still higher than those of the control group ((17 ± 3) mm Hg, 8.9% ± 2.3%) (P < 0.05 or P < 0.01). The perivascular inflammation score and levels of IL-6, TNF-α, MCP-1 of high-dose and low-dose rosiglitazone intervention groups were significantly lower than those of the PAH group (P < 0.01). Compared with the low-dose rosiglitazone intervention group, all the above indices of the high-dose rosiglitazone intervention group appeared much lower (P > 0.05). CONCLUSION: The protective effects of rosiglitazone against MCT-induced PH are correlated with drug dose and may be due to the inhibition of inflammation.

The effect of poor compliance on the pharmacokinetics of carbamazepine and its epoxide metabolite using Monte Carlo simulation.

AIM: To study the effects of delayed and missed doses (poor compliance) on the pharmacokinetics of carbamazepine (CBZ) and its main active metabolite carbamazepine-10,11-epoxide (CBZE) in Chinese epilepsy patients using Monte Carlo simulation. METHODS: CBZ and CBZE time-concentration profiles in various scenarios were generated based on a population pharmacokinetic study in Chinese epilepsy patients using Monte Carlo simulation. The scenarios included patients given multiple doses of CBZ that ranged from 100 to 300 mg three times daily or from 200 to 300 mg every 12 h. The therapeutic range of CBZ and CBZE for each scenario was estimated to assess the effect of delayed or missed doses and to design corresponding rescue regimens. Moreover, the impact of body weight, absorption rate and co-therapy with other antiepileptic drugs (phenytoin, phenobarbital and valproic acid) on the dosage recommendation was investigated in the event of poor compliance. RESULTS: The risk for a sub-therapeutic range of CBZ and CBZE was increased in a dose-dependent manner in both two and three times daily regimens when delayed or missed doses occurred. The effects of poor compliance was less prominent on the lower daily doses compared with those on the higher daily doses. The dose recommendations, in the event of poor compliance, were time related and dose dependent. Patient body weight, absorption rate and co-therapy with phenytoin, phenobarbital and valproic acid had no significant impact on the dose recommendation. CONCLUSION: Patients with epilepsy should take the delayed doses as soon as they remember, and partial missed doses may need to be taken near or at the next scheduled time.

Risk assessment of breast cancer in Guangdong, China: a community-based survey.

OBJECTIVES: Compared with Western countries, the incidence rates for breast cancer in China are still low. However, breast cancer appears to be hitting Chinese women at a much younger age, with a peak between 40 and 50 years. Furthermore, breast tumors of Asian women have molecular and genetic characteristics that are different from those of Caucasian women. METHODS: A community-based study was designed to evaluate the relationship between lifestyles and breast cancer risk in Chinese women residing in Guangzhou. 16,314 subjects completed the questionnaire. Potential confounding factors included sociodemographic characteristics. RESULTS: 33 individuals reported a history of breast cancer, yielding a prevalence rate of 202.3/100000. Associations between subjects'demographic and breast cancer risk factors were assessed. Breast cancer is associated with family history of breast cancer, X-rays received, benign breast disease and hyperlipoidemia or hypercholesteremia with elevated odds ratios. CONCLUSIONS: Family history of breast cancer, X-ray received benign breast disease and hyperlipoidemia or hypercholesteremia were significantly associated with risk of breast cancer and may have potential for breast cancer risk assessment.

Additive effect of tadalafil and simvastatin on monocrotaline-induced pulmonary hypertension rats.

OBJECTIVES: Tadalafil, an oral phosphodiesterase type-5 inhibitor, induces pulmonary vasorelaxation by inhibiting the breakdown of cyclic guanosine monophosphate whereas simvastatin, an oral 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor, has been shown to reverse pulmonary hypertension (PH) and attenuate vascular remodeling in animal models of pulmonary hypertension. We investigated whether the combination of tadalafil and simvastatin, which has different mechanisms of action, is superior to either drug alone in a rat model of monocrotaline-induced PH. METHODS: Male Sprague-Dawley rats were randomized to gavage with a vehicle, tadalafil (10 mg/kg/day), simvastatin (2 mg/kg/day), or tadalafi + simvastatin 21 days after the monocrotaline (60 mg/kg) injections. The hemodynamic and histological changes in the pulmonary arterioles, right heart hypertrophy, interleukin 6 (IL-6) levels and perivascular inflammation in the lungs were measured 35 days after monocrotaline exposure. RESULTS: The combination of tadalafil and simvastatin showed significantly more improvement in the mean pulmonary hypertension pressure (mPAP) and right ventricular hypertrophy compared with each monotherapy (p < 0.05). Combination therapy had additive effects on the increases in lung IL-6 levels and the perivascular inflammation score. CONCLUSIONS: These results suggest that the combination of tadalafil and simvastatin bears promise as an approach to treat PH, especially PH associated with inflammation.

Optimization of succinic acid fermentation with Actinobacillus succinogenes by response surface methodology (RSM).

Succinic acid is considered as an important platform chemical. Succinic acid fermentation with Actinobacillus succinogenes strain BE-1 was optimized by central composite design (CCD) using a response surface methodology (RSM). The optimized production of succinic acid was predicted and the interactive effects between glucose, yeast extract, and magnesium carbonate were investigated. As a result, a model for predicting the concentration of succinic acid production was developed. The accuracy of the model was confirmed by the analysis of variance (ANOVA), and the validity was further proved by verification experiments showing that percentage errors between actual and predicted values varied from 3.02% to 6.38%. In addition, it was observed that the interactive effect between yeast extract and magnesium carbonate was statistically significant. In conclusion, RSM is an effective and useful method for optimizing the medium components and investigating the interactive effects, and can provide valuable information for succinic acid scale-up fermentation using A. succinogenes strain BE-1.

Simvastatin protects against the development of monocrotaline-induced pulmonary hypertension in rats via a heme oxygenase-1-dependent pathway.

Heme oxygease-1 (HO-1) is the rate-limiting enzyme in heme catabolism. Induction of HO-1 has been shown to have vasodilatory, anti-inflammatory, and proapoptotic effects. More recently, experimental studies suggested the potential of simvastatin as a novel therapy for pulmonary hypertension (PH); however, the underlying mechanism remains to be investigated. The aim of this study was to evaluate whether HO-1 is required for the pulmonary vascular protective effects of simvastatin. Simvastatin (2 mg/kg/day) was administered once daily to rats for 4 weeks after monocrotaline (MCT) injection. Zn-protoporphyrin (Znpp), a potent inhibitor of HO, was used to confirm the role of HO-1. The hemodynamic changes, right heart hypertrophy, interleukin-6 (IL-6) level, and HO-1 protein expression in lungs were measured at day 28. Simvastatin significantly ameliorated mean pulmonary arterial hypertension (20.6 mm Hg). In addition, perivascular infiltration of inflammatory cells and the level of IL-6 were decreased in simvastatin treatment group. Simvastatin also increased significantly lung HO-1 protein expression. Inhibiting HO-1 using Znpp resulted in a loss of the effect of simvastatin in MCT rats. These results suggest that HO-1 expression is critical for the vascular protective effects of simvastatin in MCT-induced PH rats.

[Effects of sodium valproate on neutrophils' oxidative metabolism and oxidant status in children with idiopathic epilepsy].

OBJECTIVE: To evaluate the influence of VPA treatment on neutrophils' oxidative metabolism and oxidant status in epileptic children. METHOD: Twenty-six newly diagnosed epileptic children with idiopathic epilepsy and 30 healthy children were included in the study. The activation rates of neutrophils and stimulation indexes were detected in patients before and 6 months and 12 months after VPA treatment respectively and in all the healthy children by flow cytometry with dihydrorhodamine as fluorochrome. The activities of myeloperoxidase from neutrophils were also detected. Malondialdehyde as an indicator of lipid peroxidation and antioxidant enzymes including superoxide dismutase, catalase, and glutathione peroxidase were measured in plasma respectively. RESULT: The activation rates of neutrophils in patients treated with VPA after 6 and 12 months were (11.50 ± 6.52)% and (14.31 ± 5.76)% respectively, which were significantly higher than the data of control group (5.90 ± 3.77)% and pretreatment level (7.42 ± 3.15)%. The stimulation indexes 6 and 12 months after VPA therapy were (474.88 ± 118.98) and (416.31 ± 110.00) respectively, which were lower than the data of control group (544.83 ± 140.83) and pretreatment level (535.23 ± 111.55). The plasma MPO activities and levels of malondialdehyde in VPA treated patients were also higher while the activities of SOD and CAT were significantly lower than the control and untreated groups. GSH-Px levels did not differ between the groups. Multiple linear regression analysis showed that the time of treatment and the activation rates of neutrophils were indicators which had positive correlation with the levels of plasma MDA and that SOD activities were inversely correlated with MDA levels. CONCLUSION: VPA which is frequently used in childhood epilepsy may activate the neutrophils of patients and cause oxidative stress and prolonged treatment may aggravate it.

[Prognostic factors for patients with pulmonary thromboembolism after orthopaedic surgery].

OBJECTIVE: To investigate the changes of serum enzymes and their prognostic value in patients with pulmonary thromboembolism after orthopaedic surgery. METHODS: Clinical data of 134 cases of confirmed pulmonary thromboembolism after orthopaedic surgery from 1997 to 2010 were reviewed.The 134 cases were divided into dead group (n=28) and survival group (n=106). The clinical presentation, electrocardiogram, arterial oxygen pressure (PaO2), chest X-ray, echocardiography,and serum enzymes including alanine transaminase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (γ-GT), lactate dehydrogenase (LDH), creatine kinase (CK) and creatine kinase isoenzyme (CK-MB) were analyzed. And multivariable Logistic regression was conducted to identify the risk factors of in-hospital death. RESULTS: The average age of dead patients was higher than that of survival patients (P=0.043), while the P(O2) of dead patients was much lower than that of survival patients (P=0.035). The percentage of syncope, hypotension, right bundle-branch block and SIQIIITIII, pulmonary hypertension and right ventricular dysfunction in dead patients were higher than those in survival patients (P=0.009, P=0.041, P=0.018, P=0.030, P=0.042 and P=0.038), respectively. There were significant differences of elevated serum ALT, LDH and CK-MB levels between dead patients and survival patients (P=0.042, P=0.035 and P=0.017). Logistic regression indicated that the risk factors for death of patients with PTE after orthopaedic surgery were age (OR, 1.182; 95% CI, 1.010-1.383; P=0.036), hypoxemia (OR, 1.128; 95% CI, 1.018-1.249; P=0.022), hypotension (OR, 3.346; 95% CI, 1.116-10.031; P=0.031), right ventricular dysfunction (OR, 4.083; 95% CI, 1.040- 16.035; P=0.044) and elevated serum CK-MB levels (OR, 3.466; 95% CI, 1.054-11.400; P=0.041). CONCLUSION: The incidence rate of elevated serum ALT, LDH and CK-MB levels in patients who died of pulmonary thromboembolism after orthopaedic surgery was higher than that of survival patients; Age, hypoxemia, hypotension and right ventricular dysfunction were independent risk factors of in-hospital death; The CK-MB might be a useful biomarker for risk stratification of acute PTE.

The mixture of procyanidins extracted from the lotus seed pod and bilobalide ameliorates scopolamine-induced memory impairment in mice.

OBJECTIVE: To study the co-effect of procyanidins extracted from the lotus seed pod (LSPC) and bilobalide (BIL) on ameliorating scopolamine-induced learning and memory impairment in young mice. METHODS: Fifty male Kunming mice with similar learning and memory capabilities were selected by Morris water maze test and were randomized into 5 groups (n=10 in each group): control group, scopolamine group, L-(LSPC+BIL) group (50 mg/kg LSPC+10 mg/kg BIL), M-(LSPC+BIL) group (100 mg/kg LSPC+20 mg/kg BIL), H-(LSPC+BIL) group (150 mg/kg LSPC+30 mg/kg BIL). Scopolamine model with impaired learning and memory was established by scopolamine treatment (1 mg/kg), and after 10 min mice were tested. In L-, M-, and H-(LSPC+BIL) groups, mice were treated with LSPC and BIL ig. for 30 days, while mice in the other 2 groups were treated with normal saline ig. instead. After the 30-day's treatment, the co-effect of LSPC and BIL on learning and memory was tested by Morris water maze and the step-down avoidance tests. RESULTS: The memory impairment caused by scopolamine in young mice could be ameliorated by co-treatment of LSPC and BIL, as indicated by significantly shorter escape latency and swimming distance in the Morris water maze test, when compared with those in the scopolamine group. In the step-down avoidance test, mice in all the 3 dose groups showed significantly smaller number of errors and longer latency than mice in the scopolamine group did. CONCLUSION: Co-treatment of LSPE and BIL can ameliorate scopolamine-induced learning and memory impairment in young mice.