Nutritional Therapy Strategies Targeting Tumor Energy Metabolism.

Cancer is the second leading cause of mortality worldwide. The heightened nutrient uptake, particularly glucose, and elevated glycolysis observed in rapidly proliferating tumor cells highlight the potential targeting of energy metabolism pathways for the treatment of cancer. Numerous studies and clinical trials have demonstrated the efficacy of nutritional therapy in mitigating the adverse effects of chemotherapy and radiotherapy, enhancing treatment outcomes, prolonging survival, and improving the overall quality of life of patients. This review article comprehensively examines nutritional therapy strategies that specifically address tumor energy metabolism. Moreover, it explores the intricate interplay between energy metabolism and the gut microbiota in the context of nutritional therapy. The findings aim to provide valuable insights for future clinical research endeavors in this field.

Design of a Sea Snake Antimicrobial Peptide Derivative with Therapeutic Potential against Drug-Resistant Bacterial Infection.

Infections caused by drug-resistant pathogens are a worldwide challenge for public health. Antimicrobial peptides (AMPs) are regarded as promising antibiotic alternatives for the treatment of drug-resistant infections. In the present study, a series of small peptides were designed based on our previously reported sea snake AMP Hc-CATH. From them, the lead peptide HC1-D2, a truncated peptide entirely substituted by d-amino acids, was selected. HC1-D2 exhibited significantly improved stability and antibiofilm and anti-inflammatory activities. Meanwhile, HC1-D2 retained potent, broad-spectrum, and rapid antimicrobial properties against bacteria and fungi, especially drug-resistant bacteria. Moreover, HC1-D2 showed low propensity to induce bacterial resistance and low cytotoxicity and hemolytic activity. Notably, HC1-D2 showed potent in vivo anti-infective ability in mouse peritonitis models infected by both standard and drug-resistant bacteria. It significantly decreased the bacterial counts in the abdominal cavity and spleen of mice and apparently increased the survival rates of the mice. Acting through the MAPKs inflammatory pathway, HC1-D2 selectively induced the production of chemokine and the subsequent immune cell recruitment to the infection site, while inhibiting the production of pro-inflammatory cytokines with undesirable toxicities. These much improved properties make HC1-D2 a promising candidate for the development of novel peptide anti-infective agents against drug-resistant infections.

Astaxanthin Inhibits PC-3 Xenograft Prostate Tumor Growth in Nude Mice.

Prostate cancer (PCa), the most common malignancy in men, is a major cause of cancer deaths. A better understanding of the mechanisms that drive tumor initiation and progression may identify actionable targets to improve treatment of this patient group. As a dietary carotenoid, astaxanthin has been demonstrated to exert beneficial effects against inflammation, cardiovascular disease, oxidative damage, or different cancer sites. This study used intragastric administration of astaxanthin to detect its role on tumor proliferation, apoptosis, microRNA (miRNA) overexpression, and microbacteria composition change by establishing androgen-independent PCa cell PC-3 xenograft nude mice. Nude mice were inoculated with androgen-independent prostate cancer PC-3 cells subcutaneously. The intervention was started when tumors reached 0.5-0.6 cm in diameter. Mice were intragastrically administered 100 mg/kg astaxanthin (HA), 25 mg/kg astaxanthin (LA), or olive oil (TC). The results showed that 100 mg/kg astaxanthin significantly inhibited tumor growth compared to the TC group, with an inhibitory rate of 41.7%. A decrease of Ki67 and proliferating cell nuclear antigen (PCNA) as well as an increase of cleaved caspase-3 were observed in HA-treated tumors, along with increasing apoptotic cells, obtained by TUNEL assay. The HA significantly elevated the levels of tumor suppressors miR-375 and miR-487b in tumor tissues and the amount of Lactobacillus sp. and Lachnospiraceae in mice stools, while there was no significant difference between LA and TC groups. These results provide a promising regimen to enhance the therapeutic effect in a dietary supplement manner.

Effects of astaxanthin on oxidative stress induced by Cu2+ in prostate cells.

Astaxanthin (AST), a carotenoid molecule extensively found in marine organisms and increasingly used as a dietary supplement, has been reported to have beneficial effects against oxidative stress. In the current paper, the effects of AST on viability of prostate cells were investigated by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay; cell apoptosis and intracellular reactive oxygen species (ROS) levels were determined by flow cytometry; the mitochondrial membrane potential (MMP) was measured by fluorospectrophotometer; and activities of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) were evaluated by a detection kit. The results show that copper ion (Cu2+) induced apoptosis, along with the accumulation of intracellular ROS and MDA, in both prostate cell lines (RWPE-1 and PC-3). AST treatments could decrease the MDA levels, increase MMP, and keep ROS stable in RWPE-1 cell line. An addition of AST decreased the SOD, GSH-Px, and CAT activities in PC-3 cell line treated with Cu2+, but had a contrary reaction in RWPE-1 cell lines. In conclusion, AST could contribute to protecting RWPE-1 cells against Cu2+-induced injuries but could cause damage to the antioxidant enzyme system in PC-3 cells.

Assessing the potential of four cathelicidins for the management of mouse candidiasis and Candida albicans biofilms.

As the most common fungal pathogen of humans, severe drug resistance has emerged in the clinically isolated Candida albicans, which lead to the urgency to develop novel antifungal agents. Here, four our previously characterized cathelicidins (cathelicidin-BF, Pc-CATH1, Cc-CATH2, Cc-CATH3) were selected and their antifungal activities against C. albicans were evaluated in vitro and in vivo using amphotericin B and LL-37 as control. Results showed that all four cathelicidins could eradicate standard and clinically isolated C. albicans strains with most MIC values ranging from 1 to 16 µg/ml, in less than 0.5 h revealed by time-kill kinetic assay. Four peptides only exhibited slight hemolytic activity with most HC50 > 200 µg/ml, and retained potent anti-C. albicans activity at salt concentrations below and beyond physiological level. In animal experiment, 50 mg/kg administration of the four cathelicidins could significantly reduce the fungal counts in a murine oral candidiasis model induced by clinically isolated C. albicans. The antibiofilm activity of cathelicidin-BF, the most potent among the five peptides was evaluated, and result showed that cathelicidin-BF strongly inhibited C. albicans biofilm formation at 20 µg/ml. Furthermore, cathelicidin-BF also exhibited potent anti-C. albicans activity in established biofilms as measured by metabolic and fluorescent viability assays. Structure-function analyses suggest that they mainly adopt an α-helical conformations, which enable them to act as a membrane-active molecule. Altogether, the four cathelicidins display great potential for antifungal agent development against candidiasis.

Growth inhibitory effect of polyunsaturated fatty acids (PUFAs) on colon cancer cells via their growth inhibitory metabolites and fatty acid composition changes.

BACKGROUND: Colorectal cancer is common. Polyunsaturated fatty acids (PUFAs) exert growth-inhibitory and pro-apoptotic effects on colon cancer cells. Metabolites of PUFAs such as prostaglandins (PGs), leukotrienes (LTs) and lipoxins (LXs) play a significant role in colon cancer. METHODS: Human colon cancer LoVo and RKO cells were cultured with different concentration of PUFAs and 5-fluorouracil (5-FU) in vitro. Cell morphological changes, fatty acid composition, formation of PGE2, LTB4 and LXA4 and expression of COX-2, ALOX5, PGD synthase (PGDS), microsomal prostaglandin E synthase (mPGES) were assessed in LoVo and RKO cells when supplemented with PUFAs and 5-FU. RESULTS: PUFAs and 5-FU inhibited growth of LoVo and RKO cells to the same extent at the doses used and produced significant alterations in their shape. As expected, higher concentrations of supplemented PUFAs were noted in the cells compared to control. LA, GLA, AA, ALA and EPA supplementation to LoVo cells suppressed production of PGE2, LTB4,and ALOX5, mPGES expression, but enhanced that of LXA4; whereas DHA enhanced PGE2 and LXA4 synthesis but decreased LTB4 formation and COX-2, ALOX5, mPGES expression. In contrast, 5-FU enhanced formation of PGE2, LTB4 and mPGES expression, but suppressed LXA4 synthesis and COX-2 expression. PGE2, LTB4 synthesis and ALOX5 expression was suppressed by LA, GLA, ALA and DHA; whereas AA, EPA and 5-FU enhanced PGE2 but paradoxically AA decreased and EPA and 5-FU enhanced LTB4 synthesis in RKO cells. All the PUFAs tested enhanced, while 5-FU decreased LXA4 formation in RKO cells; whereas GLA, AA, and 5-FU augmented while LA, ALA, EPA and DHA enhanced COX-2 expression in RKO cells. CONCLUSIONS: Tumoricidal action of PUFAs on colorectal LoVo and RKO cancer cells in vitro was associated with increased formation of LXA4, decreased synthesis of PGE2 and LTB4 and suppressed expression of COX-2, ALOX5, mPGES, whereas 5-FU produced contrasting actions on these indices.

Effects of fish oil with a high content of n-3 polyunsaturated fatty acids on mouse gut microbiota.

BACKGROUND AND AIMS: Many studies show that fish oil with high content of n-3 polyunsaturated fatty acids (PUFAs) plays an important role in human health and disease. But the effects of fish oil with high content of PUFAs on gut microbiota, which are also known play a significant role in several human diseases, is not clear. In the present study we evaluated the effects of fish oil with high content of n-3 PUFAs on gut microbiota. METHODS: Changes in gut microbiota in ICR mice after supplementation of fish oil (containing eicosapentaenoic acid and docosahexaenoic acid: ∼40 and 27% respectively) for 15 days was characterized using the hypervariable V3 region of the 16 rRNA gene-based polymerase chain reaction (PCR)-denaturing gradient gel electrophoresis (DGGE) profiling, DNA sequencing, and phylogenetic analysis techniques. RESULTS: Fish oil treatment resulted in a decrease in Helicobacter, Uncultured bacterium clone WD2_aaf07d12 (GenBank: EU511712.1), Clostridiales bacterium, Sphingomonadales bacterium and Pseudomonas species Firmicutes, and several uncultured bacteria. CONCLUSIONS: Fish oil with a high content of n-3 PUFAs are capable of producing significant changes in the gut microbiota that may, at least in part, explain the health benefits or injury induced by fish oil use.

Cathelicidin-BF, a snake cathelicidin-derived antimicrobial peptide, could be an excellent therapeutic agent for acne vulgaris.

Cathelicidins are a family of antimicrobial peptides acting as multifunctional effector molecules in innate immunity. Cathelicidin-BF has been purified from the snake venoms of Bungarus fasciatus and it is the first identified cathelicidin antimicrobial peptide in reptiles. In this study, cathelicidin-BF was found exerting strong antibacterial activities against Propionibacterium acnes. Its minimal inhibitory concentration against two strains of P. acnes was 4.7 µg/ml. Cathelicidin-BF also effectively killed other microorganisms including Staphylococcus epidermidis, which was possible pathogen for acne vulgaris. Cathelicidin-BF significantly inhibited pro-inflammatory factors secretion in human monocytic cells and P. acnes-induced O2.- production of human HaCaT keratinocyte cells. Observed by scanning electron microscopy, the surfaces of the treated pathogens underwent obvious morphological changes compared with the untreated controls, suggesting that this antimicrobial peptide exerts its action by disrupting membranes of microorganisms. The efficacy of cathelicidin-BF gel topical administering was evaluated in experimental mice skin colonization model. In vivo anti-inflammatory effects of cathelicidin-BF were confirmed by relieving P. acnes-induced mice ear swelling and granulomatous inflammation. The anti-inflammatory effects combined with potent antimicrobial activities and O2.- production inhibition activities of cathelicidin-BF indicate its potential as a novel therapeutic option for acne vulgaris.

A bi-functional anti-thrombosis protein containing both direct-acting fibrin(ogen)olytic and plasminogen-activating activities.

UNLABELLED: Direct-acting fibrin(ogen)olytic agents such as plasmin have been proved to contain effective and safety thrombolytic potential. Unfortunately, plasmin is ineffective when administered by the intravenous route because it was neutralized by plasma antiplasmin. Direct-acting fibrin(ogen)olytic agents with resistance against antiplasmin will brighten the prospect of anti-thrombosis. As reported in 'Compendium of Materia Medica', the insect of Eupolyphaga sinensis Walker has been used as traditional anti-thrombosis medicine without bleeding risk for several hundreds years. Currently, we have identified a fibrin(ogen)olytic protein (Eupolytin1) containing both fibrin(ogen)olytic and plasminogen-activating (PA) activities from the beetle, E. sinensis. OBJECTIVES: To investigate the role of native and recombinant eupolytin1 in fibrin(ogen)olytic and plasminogen-activating processes. METHODS AND RESULTS: Using thrombus animal model, eupolytin1 was proved to contain strong and rapid thrombolytic ability and safety in vivo, which are better than that of urokinase. Most importantly, no bleeding complications were appeared even the intravenous dose up to 0.12 µmol/kg body weight (3 times of tested dose which could completely lyse experimental thrombi) in rabbits. It is the first report of thrombolytic agents containing both direct-acting fibrin(ogen)olytic and plasminogen-activating activities. CONCLUSIONS: The study identified novel thrombolytic agent with prospecting clinical potential because of its bi-functional merits containing both plasmin- and PA-like activities and unique pharmacological kinetics in vivo.

Colorectal cancer cell growth inhibition by linoleic acid is related to fatty acid composition changes.

Polyunsaturated fatty acids (PUFAs) possess anti-cancer action both in vitro and in vivo. In the present study, we detected cell viability with methyl thiazolyl tetrazolium (MTT) assay and cell membrane permeability with propidium iodide (PI) fluorescence dyeing, and calculated cell membrane fluidity change as fluorescence anisotropy. Fatty acid content in cells was measured by gas chromatography/mass spectroscopy (GC/MS), and the relationship between fatty acid composition and cell viability was studied. We observed that n-6 PUFA linoleic acid (LA) inhibited tumor cell growth at high concentrations (≥300 µmol/L), while low concentrations (100-200 µmol/L) seemed to promote cell proliferation. Analyses of cell membrane permeability, cell membrane fluidity, and cell fatty acid composition suggested that the anti-cancer action of LA could be related to changes in the ratio of n-6 to n-3 PUFAs. We observed that pre-incubation of cancer cells with 100 µmol/L LA for 24 h enhanced cell sensitivity to the cytotoxic action of LA, whereas undifferentiated cell line LoVo seemed to have a distinct path in LA-induced death. These results showed that one of the mechanisms by which supplementation of LA induces cancer cell death could be altering the ratio of n-6/n-3 PUFAs, and this may be related to cell differentiation status.

Novel cathelicidin-derived antimicrobial peptides from Equus asinus.

In the present study, EA-CATH1 and EA-CATH2 were identified from a constructed lung cDNA library of donkey (Equus asinus) as members of cathelicidin-derived antimicrobial peptides, using a nested PCR-based cloning strategy. Composed of 25 and 26 residues, respectively, EA-CATH1 and EA-CATH2 are smaller than most other cathelicidins and have no sequence homology to other cathelicidins identified to date. Chemically synthesized EA-CATH1 exerted potent antimicrobial activity against most of the 32 strains of bacteria and fungi tested, especially the clinically isolated drug-resistant strains, and minimal inhibitory concentration values against Gram-positive bacteria were mostly in the range of 0.3-2.4 microg mL(-1). EA-CATH1 showed an extraordinary serum stability and no haemolytic activity against human erythrocytes in a dose up to 20 microg mL(-1). CD spectra showed that EA-CATH1 mainly adopts an alpha-helical conformation in a 50% trifluoroethanol/water solution, but a random coil in aqueous solution. Scanning electron microscope observations of Staphylococcus aureus (ATCC2592) treated with EA-CATH1 demonstrated that EA-CATH could cause rapid disruption of the bacterial membrane, and in turn lead to cell lysis. This might explain the much faster killing kinetics of EA-CATH1 than conventional antibiotics revealed by killing kinetics data. In the presence of CaCl(2), EA-CATH1 exerted haemagglutination activity, which might potentiate an inhibition against the bacterial polyprotein interaction with the host erythrocyte surface, thereby possibly restricting bacterial colonization and spread.

Investigations of the cytotoxicity of epigallocatechin-3-gallate against PC-3 cells in the presence of Cd2+ in vitro.

The epidemiological studies and recent data have provided convinced evidence that green tea and its major constituent epigallocatechin gallate (EGCG) might have the potential to lower the risk of cancers in humans. Metal ions, such as zinc and cadmium, which are necessary to our health, are important factors inducing many diseases including prostate cancer in the condition of absence or excess. EGCG can satisfactorily exhibit complex chemistry with metal ions because of multiple hydroxyl states, which in turn changes their bioactivities and metabolism pathways. This paper presents the results of an investigation of the cytotoxicity of EGCG against PC-3 prostate cancer cells in the presence and absence of Cd2+ in vitro. The results showed that both EGCG and Cd2+ suppressed viability and clonegenecity of PC-3 cells, and the suppression effect was enhanced when EGCG added with Cd2+. Although Cd2+ up-regulated the 67 kDa laminin receptor (67LR), which is a migration-associated protein, the cell migration ability was not significantly increased after each treatment. We also found that EGCG and Cd2+ directly interacted with mitochondrial, and the mixture of EGCG and Cd2+ (EGCG+Cd2+) significantly caused loss of the mitochondrial membrane potential, decrease of the ATP content and activation of caspase-9 compared with EGCG treated alone. Taken together, these findings suggest that Cd2+ enhanced the cytotoxicity of EGCG to PC-3 cells by up-regulating the 67LR and the mitochondria-mediated apoptosis pathway.

Effects of metal ions, catechins, and their interactions on prostate cancer.

Prostate cancer is threatening human health heavily, for its causes are related to diet, genetic factors, and lifestyle. Metal ions, which are necessary to our health, are important factors inducing many diseases including prostate cancer in the condition of absence or excess. Epidemiological and laboratory studies provide convincing evidence that green tea prevents and cures prostate cancer. Practically, interactions of catechins, which are the main bioactive components in green tea or GTP, with metal ions have a new aspect to investigate their mechanism in preventing and curing prostate cancer. In the present paper, we summarize some research about the effects of catechins with metal ions related to prostate cancer and their interactions on prostate cancer.

Role of Zn2+ in epigallocatechin gallate affecting the growth of PC-3 cells.

Green tea has chemo-preventive effects to human carcinoma including prostate cancer. Epigallocatechin gallate (EGCG) is the major active component in green tea. Zn(2+) is indispensable to our health, and plays an important role in the normal function and pathology of the prostate gland, and might be a good marker for diagnosing prostate cancer. Effects of Zn(2+), EGCG and their interactions on the growth of androgen-insensitive prostate cancer cell (PC-3) were investigated in the present paper. The results show that Zn(2+) and EGCG inhibited the growth of PC-3 cells in a time- and dose-dependent manner, but effects of interactions of EGCG with Zn(2+) were extremely dependent on their concentrations and added orders. Inhibitory effects of Zn(2+) were significantly decreased in the presence of EGCG on PC-3 cell growth. Therefore, we hypothesize that complexation of EGCG with Zn(2+) might be responsible for the observed decrease of the bioactivities of Zn(2+) against PC-3 cells.

Fatty acids in tea shoots (Camellia sinensis (L.) O. Kuntze) and their effects on the growth of retinal RF/6A endothelial cell lines.

Chemo-protective effects of tea on ocular diseases were recorded in Chinese pharmacopoeia about 2000 years ago by eating tea. In the present study, contents of fatty acids (FAs) in tea shoots were determined by capillary GC; and the growth of RF/6A cells was also investigated by exposure to various representative FAs existing in tea shoots with pathologically relevant concentrations (40-500 microM) by ameliorated MTT assay and flow cytometry. Electron spin resonance (ESR) was used to measure oxygen consumption and investigate the free radical scavenging ability of linoleic acid (LA). Results showed that the most abundant long chain FAs were palmitic, linoleic, and alpha-linolenic acid in tea shoots; some RF/6A cells became suspended in culture medium treated by a high dose of both saturated and unsaturated FAs, but no apoptosis was observed. Moreover, it seemed that those FAs with different structure had various effects on the cell proliferation at their relatively low concentrations, LA expressed antioxidant activity in this study, which might be an important mechanism on the protection of eyes.

Effects of interactions of EGCG and Cd(2+) on the growth of PC-3 cells and their mechanisms.

The preventive and therapeutic effects of a major component of catechins of green tea, epigallocatechin-3-gallate (EGCG), on prostate cancer have been demonstrated in many studies. It is well known that metal ions are necessary for human health, but an imbalance in metal ions metabolism can lead to many diseases including prostate cancer. Understanding the interactions of EGCG with metal ions might elucidate its mechanism in preventing and curing prostate cancer. The present study focused on the effects of Cd(2+) and EGCG on the growth of androgen-insensitive prostate cancer cell PC-3 investigated by MTT assay, the effects of EGCG and Cd(2+) on absorption of Cd(2+) and Zn(2+) by PC-3 cells were detected by atomic absorption spectroscopy (AAS), and the interactions of EGCG with Cd(2+) were determined by distribution coefficient and UV-Vis spectroscopy detection. The results showed that Cd(2+) suppressed viability of PC-3 cells in concentration- and time-dependent manner, and EGCG enhanced the effect of Cd(2+) on PC-3 cells. EGCG was shown to decrease the absorption Cd(2+) and increase the absorption of Zn(2+) by PC-3 cells, while the effects of Cd(2+) on the absorption of Cd(2+) and Zn(2+) were opposite to that of EGCG. In the presence of both EGCG and Cd(2+), absorption of Cd(2+) and Zn(2+) by PC-3 cells was dependent on concentrations of EGCG, Cd(2+) and its order of addition. Results from the distribution coefficient determination and UV-Vis spectroscopy analysis indicated that Cd(2+) might affect conformation of EGCG, while no complex of EGCG with Cd(2+) was observed in the system.