Biomolecules of Fermented Tropical Fruits and Fermenting Microbes as Regulators of Human Hair Loss, Hair Quality, and Scalp Microbiota.

Plant-derived secondary metabolites (polyphenols/terpenes/alkaloids) and microbial exometabolites/membrane components of fermented tropical fruits are known as highly bioavailable biomolecules causing skin and hair improvement effects (wound healing, anti-inflammatory, antioxidant, antidiabetic, antiacne, skin/hair microbiota balancing, hair growth-promoting, and hair loss-inhibiting). Caffein is considered as a hair growth promoter. A randomized placebo- and caffein-controlled clinical trial on the efficacy of fermented papaya (FP) plus fermented mangosteen (FM) towards human hair quality and loss was conducted. Shampoo and lotion hair care products containing FP, FM, and caffein as active agents were developed and applied to 154 subjects of both sexes with clinically confirmed androgenic or diffuse alopecia for 3 months. Their clinical efficacy was assessed subjectively by questionnaires filled in by dermatologists/trichologists, and by the objective trichomicroscopical calculations. Hair and scalp skin quality was determined by microbiota pattern and ATP, SH-groups, protein, and malonyl dialdehyde quantification. Comparative clinical data showed that the experimental hair care cosmetics significantly inhibited hair loss, increased hair density/thickness, and improved hair follicle structure versus placebo and caffein controls. The cosmetics with FP and FM substantially normalized the microbiota pattern and increased ATP content in hair follicle, while inhibiting lipid peroxidation in the scalp skin, and SH-group formation in the hair shaft.

Fermented Mangosteen (Garcinia mangostana L.) Supplementation in the Prevention of HPV-Induced Cervical Cancer: From Mechanisms to Clinical Outcomes.

In the observational clinical study, we identified the oxidative markers of HPV-associated cervical carcinogenesis and the local/circulating ligands of TNF-alpha-induced apoptosis. Cervical biopsies of 196 females infected with low-cancer-risk HPV10/13 or high-cancer-risk HPV16/18 (healthy, pre-cancerous CIN I and CIN II, and CIN III carcinoma) were analysed for OH radical scavenging, catalase, GSH-peroxidase, myeloperoxidase (MPO), nitrate/nitrite, nitrotyrosine, and isoprostane. Ligands of TNF-alpha-dependent apoptosis (TNF-alpha, TRAIL, IL-2, and sFAS) were determined in cervical fluid, biopsies, and serum. Cervical MPO was highly enhanced, while nitrotyrosine decreased in CIN III. Local/circulating TRAIL was remarkably decreased, and higher-than-control serum TNF-alpha and IL-2 levels were found in the CIN I and CIN III groups. Then, 250 females infected with HPV16/18 (healthy and with CIN I and CIN II) were recruited into a placebo-controlled clinical study of supplementation with fermented mangosteen (FM, 28g/day, daily) for three months. Post-trial colposcopy revealed normal patterns in 100% of the FM group versus 62% of the placebo group. Inflammatory cells in cervical fluid were found in 21% of the FM group versus 40% of the placebo group. Locally, FM drastically diminished MPO and NO2/NO3, while it remarkably increased TRAIL. Additionally, FM supplementation normalised serum TRAIL, TNF-alpha, and IL-2.

Fermented Carica papaya and Morinda citrifolia as Perspective Food Supplements for the Treatment of Post-COVID Symptoms: Randomized Placebo-Controlled Clinical Laboratory Study.

Food supplements based on fermented Carica papaya and Morinda citrifolia, known for their immune modulating, redox balancing, and anti-inflammatory effects, were added to conventional treatment protocols prescribed to patients recovering after severe and moderate COVID-19 disease in order to alleviate long-lasting post-COVID symptoms. A randomized single-center placebo-controlled clinical laboratory study was designed and performed (total number of participants 188, with delta variant of virus 157, with omicron 31). Clinical statuses were assessed using computer tomography, electrocardiography, a questionnaire, and physical endurance. Plasma cytokines (IL-6, IL-8, IL-17A, and INF-gamma), nitrate/nitrite ratio, antioxidant activity (AOA), and polymorphonuclear leukocyte (PMN) ATP levels were determined before and 20 days following the addition of 28 g of fermented supplements twice per day. The capacity of PMN to phagocyte and the oral-nasal-pharyngeal microbiota were assessed. Clinical symptoms, IL-6, IL-8, and nitric oxide metabolites diminished significantly compared to the placebo group and their background expression. The PMN capacity to phagocyte, AOA, and ATP content remarkably increased. The oral-nasal-pharyngeal microbiota were unchanged. On these grounds, we suggest that fermented tropical fruits could efficiently diminish post-COVID clinical symptoms through several immune-modulating, redox balancing, and pro-energy mechanisms.

Effects of Heavy Isotopes (2H1 and 18O16) Depleted Water Con-Sumption on Physical Recovery and Metabolic and Immunological Parameters of Healthy Volunteers under Regular Fitness Load.

Water depleted of heavy isotopes, such as 2H1 and 18O16 (HIDW), has shown numerous biological/health effects in vitro, in vivo, and in epidemiological studies. Major observations were related to cell growth/differentiation, immune/nervous system responses, endurance/adaptation, mitochondrial electron transfer, energy production, glucose metabolism, etc. No human studies to confirm physiological, metabolic, and immune responses to the consumption of HIDW have been performed. A placebo-controlled study on healthy volunteers (n = 50) under fitness load who consumed 1.5 L HIDW (58 ppm 2H and 1780 ppm 18O) or normal water for 60 days was carried out. Plasma content of 2H1 and 18O16, markers of energy, lipid, and glucose metabolism, anthropometric, cardio-vascular, oxidant/antioxidant, and immunological parameters were determined. Significant decrease in plasma heavy isotopes in the group consuming HIDW was observed in concomitance with an increase in ATP, insulin, and LDH, and diminished plasma lactate. Several anthropometric and cardio-vascular parameters were improved as compared to placebo group. Lipid markers demonstrated antiatherogenic effects, while oxidant/antioxidant parameters revealed HIDW-induced hormesis. Antibacterial/antiviral immunity was remarkably higher in HIDW versus placebo group. Conclusions: HIDW consumption by humans under fitness load could be a valid approach to improve their adaptation/recovery through several mechanisms.

Anti-Bacterial and Anti-Inflammatory Effects of Toothpaste with Swiss Medicinal Herbs towards Patients Suffering from Gingivitis and Initial Stage of Periodontitis: from Clinical Efficacy to Mechanisms.

OBJECTIVE: To distinguish clinical effects and mechanisms of sodium monofluorophosphate plus xylitol and herbal extracts of Swiss medicinal plants (Chamomilla recutita, Arnica montana, Echinacea purpurea, and Salvia officinalis). MATERIALS AND METHODS: A 2-month-long comparative clinical study of toothpaste containing 1450 ppm sodium monofluorophosphate and xylitol (control, 15 patients) and toothpaste additionally containing extracts of the medicinal herbs (experiment, 35 patients) was performed on patients with gingivitis and the initial stage of periodontitis. Clinical indices of gingivitis/periodontitis were quantified by Loe & Silness's, CPITN, OHI-S, and PMA indexes. The pro-inflammatory and anti-inflammatory interleukins, nitrites/nitrates, total antioxidant activity, and bacterial pattern characteristic for gingivitis and periodontitis were quantified in the gingival crevicular fluid and plaque. In the in vitro tests, direct anti-bacterial effects, inhibition of catalase induction in Staphylococcus aureus, in response to oxidative burst of phagocytes, and intracellular bacterial killing were determined for the toothpastes, individual plant extracts, and their mixture. RESULTS: Experimental toothpaste was more efficient clinically and in the diminishing of bacterial load specific for gingivitis/periodontitis. Although the control toothpaste exerted a direct moderate anti-bacterial effect, herbal extracts provided anti-inflammatory, anti-oxidant, direct, and indirect anti-bacterial actions through inhibition of bacterial defence against phagocytes. CONCLUSIONS: Chemical and plant-derived anti-bacterials to treat gingivitis and periodontitis at the initial stage should be used in combination amid their different mechanisms of action. Plant-derived actives for oral care could substitute toxic chemicals due to multiple modes of positive effects.

Mucin adsorbed by E. coli can affect neutrophil activation in vitro.

Bacteria colonizing human intestine adhere to the gut mucosa and avoid the innate immune system. We previously demonstrated that Escherichia coli isolates can adsorb mucin from a diluted solution in vitro. Here, we evaluated the effect of mucin adsorption by E. coli cells on neutrophil activation in vitro. Activation was evaluated based on the detection of reactive oxygen species production by a chemiluminescent reaction (ChL), observation of morphological alterations in neutrophils and detection of exocytosis of myeloperoxidase and lactoferrin. We report that mucin adsorbed by cells of SharL1 isolate from Crohn's disease patient's inflamed ileum suppressed the potential for the activation of neutrophils in whole blood. Also, the binding of plasma complement proteins and immunoglobulins to the bacteria was reduced. Desialylated mucin, despite having the same adsorption efficiency to bacteria, had no effect on the blood ChL response. The effect of mucin suggests that it shields epitopes that interact with neutrophils and plasma proteins on the bacterial outer membrane. Potential candidates for these epitopes were identified among the proteins within the bacterial outer membrane fraction by 2D-PAGE, fluorescent mucin binding on a blot and HPLC-MS/MS. In vitro, the following proteins demonstrated mucin adsorption: outer membrane porins (OmpA, OmpC, OmpD and OmpF), adhesin OmpX, the membrane assembly factor OmpW, cobalamine transporter, ferrum uptake protein and the elongation factor Ef Tu-1. In addition to their other functions, these proteins are known to be bacterial surface antigens. Therefore, the shielding of epitopes by mucin may affect the dynamics and intensity of an immune response.

Effects of Standardised Fermented Papaya Gel on Clinical Symptoms, Inflammatory Cytokines, and Nitric Oxide Metabolites in Patients with Chronic Periodontitis: An Open Randomised Clinical Study.

The clinical efficacy of topical administration of standardised fermented papaya gel (SFPG), known to have antioxidant and anti-inflammatory properties, versus conventional therapy was evaluated in a group of 84 patients with moderate-to-severe periodontitis, randomly assigned to control group (n = 45) undergoing traditional pharmacologic/surgical protocols or to experimental group (n = 39), additionally treated with intragingival pocket SFPG (7 g) applications (15 min daily for 10 days). Patients undergoing SFPG treatment showed significant (P < 0.05), durable improvement of three major clinical indices of disease severity: reduced bleeding (day 7), plaque and gingival conditions (day 14), and consistent gingival pocket depth reduction (day 45). Proinflammatory nitric oxide metabolites reached normal values in plasma (day 14) and gingival crevicular fluid (GCF) at day 45 with SFPG applications compared to controls that did not reach normalisation. Levels of highly increased proinflammatory (IL-1B, IL-6) and suppressed anti-inflammatory (IL-10) cytokines normalised in the SFPG group by days 14 (plasma) and 45 (GCF), but never in the control group. Although not acting directly as antibiotic, SFPG acted in synergy with human granulocytes blocking adaptive catalase induction in S. aureus in response to granulocyte-derived oxidative stress, thus enhancing intracellular bacterial killing.

Is there a role for antioxidants in the prevention of infection-associated carcinogenesis and in the treatment of infection-driven tumors?

Causative connections between infections and cancer are ascertained for several types of viruses, bacteria, and parasites. The mechanisms of cancer induction in chronically infected inflamed tissues strongly implicate oxygen- and nitrogen-centered reactive species, and an impairment of redox-sensitive molecular pathways involved in the tumorigenic transformation, tumor growth, altered immune defense, and in the mechanisms of tumor cell death and survival. Here, we briefly reviewed mechanistic data on carcinogenesis and tumor progression of three major infection-associated tumors, human papillomavirus-induced cervical cancer, hepatitis B virus-positive hepatocarcinoma, and Helicobacter pylori-positive gastric cancer. Notwithstanding the contradictory results of clinical studies on cancer chemoprevention with long-term, high dosage antioxidant vitamin/micronutrient supplementation, natural and synthetic agents with proven capacity to affect redox-dependent molecular pathways still hold the promise for preventing/delaying carcinogenesis initiation, as well as the overt malignancy evolution from dysplastic/ aplastic stages. Novel directions for a targeted antioxidant-based approach to the reduction of persistent infection-driven cancer risk stems from the current knowledge of critical factors in the host-microbe interaction leading to oncogenesis. An emerging role of redox active substances in the chemotherapy of tumors relies on their stimulating effects towards TRAIL-related apoptosis and the induction of intracellular oxidative stress.

Is there a Role For Antioxidants in the Prevention of Infection-Associated Carcinogenesis and in the Treatment of Infection-Driven Tumors?

Causative connections between infections and cancer are ascertained for several types of viruses, bacteria, and parasites. The mechanisms of cancer induction in chronically infected inflamed tissues strongly implicate oxygen- and nitrogen-centered reactive species, and an impairment of redox-sensitive molecular pathways involved in the tumorigenic transformation, tumor growth, altered immune defense, and in the mechanisms of tumor cell death and survival. Here, we briefly reviewed mechanistic data on carcinogenesis and tumor progression of three major infection-associated tumors, human papillomavirus-induced cervical cancer, hepatitis B virus-positive hepatocarcinoma, and Helicobacter pylori-positive gastric cancer. Notwithstanding the contradictory results of clinical studies on cancer chemoprevention with long-term, high dosage antioxidant vitamin/micronutrient supplementation, natural and synthetic agents with proven capacity to affect redox-dependent molecular pathways still hold the promise for preventing/delaying carcinogenesis initiation, as well as the overt malignancy evolution from dysplastic/aplastic stages. Novel directions for a targeted antioxidant-based approach to the reduction of persistent infection-driven cancer risk stems from the current knowledge of critical factors in the host-microbe interaction leading to oncogenesis. An emerging role of redox active substances in the chemotherapy of tumors relies on their stimulating effects towards TRAIL-related apoptosis and the induction of intracellular oxidative stress.

Coenzyme Q(10), vitamin E, selenium, and methionine in the treatment of chronic recurrent viral mucocutaneous infections.

OBJECTIVE: Host defense and latency determinants in viral recurrent dermatologic infections are not entirely understood, as conventional protocols are inadequate to achieve fast healing and relapse prevention. Endogenously produced oxygen/nitrogen reactive species (ROS/RNS) are essential for antiviral immune defense, while their excess may aggravate skin inflammation. Here, we sought a nutritional approach capable of controlling ROS/RNS balance to accelerate recovery and inhibit recurrences of two mucocutaneous chronic DNA-virus infections. METHODS: Two controlled clinical trials evaluated the feasibility of ROS/RNS-modulating nutriceutical dosages of coenzyme Q(10), RRR-α-tocopherol, selenium aspartate, and L-methionine associated with established therapies. Clinical trial 1 evaluated 68 patients with relapsing human papillomavirus skin warts treated with cryotherapy followed by 180 d of nutriceutical/placebo administration. Clinical trial 2 compared the combination of acyclovir followed by 90 d of nutriceutical administration versus acyclovir alone in patients with recurrences of herpes simplex genitalis (n = 60) or herpes zoster (n = 29). Viral DNA levels were assessed by polymer chain reaction, biomarkers of antiviral defense (peroxynitrite and IFNα/γ) and antioxidant capacity (lipophilic antioxidants and glutathione) were assayed by biochemical/enzyme-linked immunosorbent assay techniques in blood fractions. RESULTS: In both trials, the nutriceutical induced significantly faster healing (P < 0.01-0.05) with reduced incidence of relapses (P < 0.05) as compared to control groups, which was confirmed by decreased viral load and increased antiviral cytokine and peroxynitrite plasma levels. Plasma antioxidant capacity was higher (P < 0.01) in the experimental versus control groups. CONCLUSIONS: Results document positive clinical outcomes of the selected nutriceutical associated with conventional protocols in the management of relapsing mucocutaneous human papillomavirus and herpes infections.

Wide-spectrum profile of inflammatory mediators in the plasma and scales of patients with psoriatic disease.

Psoriasis is a chronic recurrent inflammatory disorder of the skin. Clinical subtypes include psoriasis vulgaris (PV), psoriatic arthropathy, and erythrodermic psoriasis. Aim of this study was to analyse relevant inflammatory mediators in the plasma of patients with distinct subtypes of active psoriasis, and in the scales of mild-to-moderate PV patients, and correlation to disease severity. Compared to healthy controls (n=10), patients affected by very severe forms of psoriasis (n=30) were characterized by increased plasma levels of IL-4, IL-6, MCP-1, VEGF and in particular PDGFbb. Each group with severe psoriasis had distinct characteristic features of plasma cytokine profile. Mild-to-moderate PV patients (n=35) showed higher levels of IL-4, IL-6, IL-10, and IL-13 when compared to healthy controls. No correlation was found between PV severity assessed by PASI (Psoriasis Area and Severity Index) and levels of these mediators. By contrast, disease severity correlated to scale levels of IP-10. For the first time, we found exaggerated circulating levels of the pro-angiogenic PDGFbb and VEGF in severe psoriasis. Evidence that the severity of skin symptoms correlated exclusively with scale levels of IP-10, but not with any up-regulated inflammatory mediator in plasma, suggests that distinct skin-independent processes contribute to the circulating cytokine profile in psoriasis.

Clinical and biochemical effects of coenzyme Q(10), vitamin E, and selenium supplementation to psoriasis patients.

OBJECTIVE: The aim of the present study was to evaluate clinical effects of supplementation with antioxidants to patients with severe erythrodermic (EP) and arthropathic (PsA) forms of psoriasis. METHODS: Fifty-eight patients were hospitalized, treated by conventional protocols, and randomly assigned to four groups. Groups EP1 and PsA1 were supplemented with coenzyme Q(10) (ubiquinone acetate, 50 mg/d), vitamin E (natural alpha-tocopherol, 50 mg/d), and selenium (aspartate salt, 48 mug/d) dissolved in soy lecithin for 30-35 d. Groups EP2 and PsA2 (placebo) received soy lecithin. Clinical conditions were assessed by severity parameters. Markers of oxidative stress included superoxide production, copper/zinc-superoxide dismutase, and catalase activities in the circulating granulocytes, in the affected epidermis, and plasma levels of nitrites/nitrates. RESULTS: At baseline patients had an increased superoxide release from granulocytes (10.0 +/- 0.5, 2.9 +/- 0.2, and 1.5 +/- 0.1 nmol/L per 10(6) cells/h for EP, PsA, and donors, respectively), increased copper/zinc-superoxide dismutase and catalase activities in granulocytes in EP patients and decreased in PsA patients, decreased activity of copper/zinc-superoxide dismutase (0.3 +/- 0.0, 1.8 +/- 0.1, and 2.2 +/- 0.2 U/mg protein for EP, PsA, and donors, respectively), and altered activity of catalase in psoriatic epidermis. Plasma levels of nitrites/nitrates were greater than normal in psoriatic patients. Supplementation resulted in significant improvement of clinical conditions, which corresponded to the faster versus placebo normalization of the oxidative stress markers. CONCLUSION: Supplementation with antioxidants coenzyme Q(10), vitamin E, and selenium could be feasible for the management of patients with severe forms of psoriasis.

Effect of cytokines on the level of free radicals in the blood of patients with systemic and local staphylococcus infection.

An increased extracellular production of free radicals with bactericidal activity does not improve the efficacy of intracellular digestion of Staphylococci. The amount of intracellular oxygen reactive species generated by the neutrophils from patients with an infectious condition has been found considerably decreased as compared to healthy donors. On the other hand, the excess of secretion of free radicals into the extracellular space leads inevitably to the adaptive increase of antioxidant enzymes and, as a result, to an increase in the total antioxidant capacity of the blood plasma. Indeed, patients with septicemia at its highest peak (at the moment of hospitalization) showed a significant increase (more than twice) in the parameters of catalase and superoxide dismutase activity; the antioxidant capacity of the plasma was elevated as well. The patients of the other two groups in our study (with a localized infection) did not show any statistically significant rise in these parameters. On the second day after the initiation of an intensive treatment the activity of the enzymes and the total antioxidant capacity of the plasma dropped sharply below the normal level. Therefore, the staphylococcus infection, especially its generalized from, is characterized by an increased extracellular secretion of radicals together with a decreased generation of intracellular radicals. On one hand this leads to the failure of the intracellular killing, on the other--to the inflammatory free radical-mediated damage of the host cells and tissues. Cytokines, such as interleukins and interferons, can regulate the free radical-mediated processes during the staphylococcus infections. The effect of the two recombinant cytokines (IL-1 beta, IFN-gamma) on the character of free radical production and intracellular killing of Staphylococci by neutrophils isolated from the blood of patients and healthy donors has been studied. The analysis of the effect of cytokines on the radical production by phagocytes revealed a redistribution of the extracellular and intracellular fractions of free radicals rather than a general increase of the oxygen active metabolite production. As expected, the increment in the number of intracellular radicals improved significantly the process of phagocytosis.