Oral preparation of hyaluronic acid, chondroitin sulfate, N-acetylglucosamine, and vitamin C improves sexual and urinary symptoms in participants with recurrent urinary tract infections: a randomized crossover trial.

BACKGROUND: Intravesical instillation of hyaluronic acid (HA) has been associated with reduced sexual dysfunction in participants with recurrent urinary tract infections (rUTIs), but the efficacy of an oral treatment has never been investigated. AIM: To investigate the efficacy of an oral preparation of HA, chondroitin sulfate, N-acetylglucosamine, and vitamin C in improving sexual and urinary symptoms in a cohort of reproductive-age participants with rUTI. METHODS: In a monocentric randomized crossover pilot trial, participants with rUTI who were referred to our institute between March 2022 and April 2023 were randomized 1:1 in 2 groups: intervention vs control. All participants had an oral preparation of cranberry, D-mannose, propolis extract, turmeric, and Boswellia twice a day for 3 months. The intervention group also included an oral preparation of HA, chondroitin sulfate, N-acetylglucosamine, and vitamin C once a day for 3 months. Crossover of treatment occurred at 3 months for an additional 3 months. At baseline and 3 and 6 months, participants were evaluated clinically and with the International Prostate Symptom Score (IPSS) and Female Sexual Function Index (FSFI). Descriptive statistics and logistic regression models tested the impact of the intervention on urinary and sexual symptoms at each follow-up assessment. OUTCOMES: Improvement in sexual and urinary symptoms as measured by the FSFI and IPSS. RESULTS: Overall, 27 (54%) participants had an FSFI score <26.5 at enrollment. At 3 months, FSFI scores were higher in the intervention group vs control (P < .001), but IPSS scores were lower (P = .03). After crossover of treatment, FSFI and IPSS scores remained stable in the intervention group. However, after crossover, the control group showed a significant improvement in IPSS and FSFI scores (all P < .01) vs the 3-month assessment. At last follow-up, urinary and sexual symptoms were comparable between groups. In logistic regression analyses, the intervention group was associated with early improvement in sexual symptoms (odds ratio, 3.9; P = .04) and urinary symptoms (odds ratio, 5.1; P = .01) after accounting for clinical confounders. CLINICAL IMPLICATIONS: Combination treatment with HA, chondroitin sulfate, N-acetylglucosamine, and vitamin C is effective if started immediately or even after a few months from symptoms in participants with rUTI. STRENGTHS AND LIMITATIONS: The main limitation is the lack of long-term follow-up. CONCLUSION: The oral formulation of HA, chondroitin sulfate, N-acetylglucosamine, and vitamin C could be an effective therapy against urinary and sexual distress in participants with rUTI (NCT06268483; ClinicalTrials.gov).

Mannosylation of budesonide palmitate nanoprodrugs for improved macrophage targeting.

In a strategy to improve macrophage targeting of glucocorticoids (GCs) for anti-inflammatory therapy, a so-called nanoprodrug of budesonide palmitate decorated by mannose moieties was designed. The synthesis of budesonide palmitate (BP) was obtained by esterification and mannosylated lipid (DSPE-PEG-Man) by reacting 1,2-Distearoyl-sn-Glycero-3-Phosphoethanolamine (DSPE)-polyethylene glycol-amine and α-D-mannopyranosylphenyl isothiocyanate (MPITC). Nanoparticles were formulated by emulsion-evaporation and different ratios of mannosylated lipid were introduced in the formulation of BP nanoprodrugs. Using up to 75% of DSPE-PEG-man (75/25) led to 200 nm particles with a polydispersity index below 0.2, a negative zeta potential ranging from -10 to -30 mV, and one-month stability at 4 °C. The encapsulation efficiency of BP approached 100% proving that the prodrug was associated with the particles, leading to a final BP loading of 50-to 60% (w/w). The lectin agglutination test confirmed the availability of mannose on the nanoprodrug surface. Nanoprodrug uptake by RAW 264.7 macrophages was observed by confocal microscopy and flow cytometry. After 24 and 48 h of incubation, a significantly greater internalization of mannosylated nanoparticles as compared to PEGylated nanoparticles was achieved. The mannose receptor-mediated uptake was confirmed by a mannan inhibition study. After LPS-induced inflammation, the anti-inflammatory effect of mannosylated nanoparticles was assessed. After 48 h of incubation, cytokines (MCP-1 and TNFα) were reduced demonstrating that the functionalization of nanoprodrugs is possible and efficient.

Mannose and phosphomannose isomerase regulate energy metabolism under glucose starvation in leukemia.

Diverse metabolic changes are induced by various driver oncogenes during the onset and progression of leukemia. By upregulating glycolysis, cancer cells acquire a proliferative advantage over normal hematopoietic cells; in addition, these changes in energy metabolism contribute to anticancer drug resistance. Because leukemia cells proliferate by consuming glucose as an energy source, an alternative nutrient source is essential when glucose levels in bone marrow are insufficient. We profiled sugar metabolism in leukemia cells and found that mannose is an energy source for glycolysis, the tricarboxylic acid (TCA) cycle, and the pentose phosphate pathway. Leukemia cells express high levels of phosphomannose isomerase (PMI), which mobilizes mannose to glycolysis; consequently, even mannose in the blood can be used as an energy source for glycolysis. Conversely, suppression of PMI expression or a mannose load exceeding the processing capacity of PMI inhibited transcription of genes related to mitochondrial metabolism and the TCA cycle, therefore suppressing the growth of leukemia cells. High PMI expression was also a poor prognostic factor for acute myeloid leukemia. Our findings reveal a new mechanism for glucose starvation resistance in leukemia. Furthermore, the combination of PMI suppression and mannose loading has potential as a novel treatment for driver oncogene-independent leukemia.

Mannosylation of pH-sensitive liposomes promoted cytoplasmic delivery of protein to macrophages: green fluorescent protein (GFP) performed as an endosomal escape tracer.

Conventional non-pH-sensitive liposomes for cytoplasmic delivery of protein suffer from poor efficiency. Here we investigated mannosylated pH-sensitive liposomes (MAN-PSL) for cytoplasmic delivery of protein to macrophages RAW 264.7 using PSL and non-pH-sensitive liposomes for comparison. We characterised the pH-dependent fluorescence of green fluorescent protein (GFP) and encapsulated it in liposomes as an intracellular trafficking tracer. GFP showed a reversed 'S'-shaped pH-fluorescence curve with a dramatic signal loss at acidic pH. GFP stored at 4 °C with light protection showed a half-life of 10 days (pH 5-8). The entrapment efficiency of GFP was dominated by the volume ratio of intraliposomal core to external medium for thin-film hydration. Mannosylation did not affect the pH-responsiveness of PSL. Confocal microscopy elucidated that mannosylation promoted the cellular uptake of PSL. For both these liposomes, the strongest, homogeneously distributed GFP fluorescence in the cytoplasm was found at 3 h, confirming efficient endosomal escape of GFP. Conversely, internalisation of non-pH-sensitive liposomes was slow (peaked at 12 h) and both Nile Red and GFP signals remained weak and punctuated in the cytosol. In conclusion, GFP performed as a probe for endosome escape of liposomal cargo. Mannosylation facilitated the internalisation of PSL without compromising their endosomal escape ability.

Pharmacological Strategies to Improve Dendritic Spines in Alzheimer's Disease.

To deeply understand late onset Alzheimer's disease (LOAD), it may be necessary to change the concept that it is a disease exclusively driven by aging processes. The onset of LOAD could be associated with a previous peripheral stress at the level of the gut (changes in the gut microbiota), obesity (metabolic stress), and infections, among other systemic/environmental stressors. The onset of LOAD, then, may result from the generation of mild peripheral inflammatory processes involving cytokine production associated with peripheral stressors that in a second step enter the brain and spread out the process causing a neuroinflammatory brain disease. This hypothesis could explain the potential efficacy of Sodium Oligomannate (GV-971), a mixture of acidic linear oligosaccharides that have shown to remodel gut microbiota and slowdown LOAD. However, regardless of the origin of the disease, the end goal of LOAD-related preventative or disease modifying therapies is to preserve dendritic spines and synaptic plasticity that underlay and support healthy cognition. Here we discuss how systemic/environmental stressors impact pathways associated with the regulation of spine morphogenesis and synaptic maintenance, including insulin receptor and the brain derived neurotrophic factor signaling. Spine structure remodeling is a plausible mechanism to maintain synapses and provide cognitive resilience in LOAD patients. Importantly, we also propose a combination of drugs targeting such stressors that may be able to modify the course of LOAD by acting on preventing dendritic spines and synapsis loss.

PDA-Based Glyconanomicelles for Hepatocellular Carcinoma Cells Active Targeting Via Mannose and Asialoglycoprotein Receptors.

Hepatocellular carcinoma (HCC) is the sixth most common neoplasia and the fourth most common cause of cancer-related mortality worldwide. Sorafenib is the first-line molecular therapy for patients in an advanced stage of HCC. However, the recommended clinical dose of Sorafenib is associated with several complications, which derive from its lack of cell specificity and its very low water solubility. To circumvent these drawbacks, in the present study we developed two sugar-coated polydiacetylene-based nanomicelles-Sorafenib carriers targeting mannose and asialoglycoprotein receptors (MR and ASGPR, respectively). The strategies allowed the inducement of apoptosis and reduction of cell proliferation at a nanomolar, instead of micromolar, range in liver cancer cells. The study showed that, contrary to literature data, Sorafenib included into the pMicMan (Man = mannose) vector (targeting MR) is more efficient than pMicGal (Gal = galactose) (targeting ASGPR). Indeed, pMicMan increased the endosomal incorporation with an increased intracellular Sorafenib concentration that induced apoptosis and reduced cell proliferation at a low concentration range (10-20 nM).

Long term outcome of MPI-CDG patients on D-mannose therapy.

Mannose phosphate isomerase MPI-CDG (formerly CDG-1b) is a potentially fatal inherited metabolic disease which is readily treatable with oral D-mannose. We retrospectively reviewed long-term outcomes of patients with MPI-CDG, all but one of whom were treated with D-mannose. Clinical, biological, and histological data were reviewed at diagnosis and on D-mannose treatment. Nine patients were diagnosed with MPI-CDG at a median age of 3 months. The presenting symptoms were diarrhea (n = 9), hepatomegaly (n = 9), hypoglycemia (n = 8), and protein loosing enteropathy (n = 7). All patients survived except the untreated one who died at 2 years of age. Oral D-mannose was started in eight patients at a median age of 7 months (mean 38 months), with a median follow-up on treatment of 14 years 9 months (1.5-20 years). On treatment, two patients developed severe portal hypertension, two developed venous thrombosis, and 1 displayed altered kidney function. Poor compliance with D-mannose was correlated with recurrence of diarrhea, thrombosis, and abnormal biological parameters including coagulation factors and transferrin profiles. Liver fibrosis persisted despite treatment, but two patients showed improved liver architecture during follow-up. This study highlights (i) the efficacy and safety of D-mannose treatment with a median follow-up on treatment of almost 15 years (ii) the need for life-long treatment (iii) the risk of relapse with poor compliance, (iii) the importance of portal hypertension screening (iv) the need to be aware of venous and renal complications in adulthood.

Amplio estudio (283 mujeres) sobre la eficacia de Manosar(R): 2 g de d-manosa + 140 mg de proantocianidinas (PAC), de liberación prolongada frente a 240 mg de PAC de liberación prolongada en la prevención a 6 meses por vía oral de las infecciones urinarias recurrentes / Large study (283 women) on the effectiveness of Manosar(R): 2 g of d-mannose + 140 mg of proanthocyanidins (PAC), of prolonged release

OBJETIVO: Comparar la eficacia y seguridad de la profilaxis de las infecciones del tracto urinario (ITUs) con un complemento alimenticio que contiene D-manosa como principio activo principal (Manosar(R)), en comparación con otro preparado cuyo principio activo único son las proantocianidinas (PAC), ambos de liberación continuada, tras su administración durante24 semanas. MÉTODOS: Estudio experimental multicéntrico, aleatorizado y doble ciego. Se incluyeron 283 mujeres con historia de ITUs recurrentes sin evidencias de complicación. Se randomizaron 1:1 en dos grupos. En un grupo se administró 1 sobre diario oral de Manosar®, y en el otro 1 sobre diario oral de un compuesto de 240 mg de PAC de liberación continuada. Previo a la inclusión en el estudio se confirmó el episodio de ITU al menos por la sintomatología clínica y positividad del test de Combur. RESULTADOS: Se obtuvieron datos válidos de 184 pacientes con edad media de 49,5 años: 90 recibieron Manosar(R) y 94 PAC aislado. Un total de 72 pacientes padecieron una ITU por E.coli: 25 pacientes en el brazo con Manosar(R) frente a 47 pacientes en el grupo de PAC aislado, siendo esta diferencia estadísticamente significativa (p = 0,002). El tiempo libre de nuevas recurrencias de ITU fue de 98,6 días en el grupo tratado con Manosar(R) y de 84,6 días en el grupo con PAC aislado. CONCLUSIÓN: La toma oral de un sobre al día de Manosar(R) es eficaz y segura en la prevención de las ITUs recurrentes en la mujer, siendo superior a la toma oral de PAC aislado

OBJECTIVE: To compare the efficacy and safety in the prophylasis of urinary tract infections (UTIs) with a food supplement that contains D-mannose like active ingredient (Manosar(R)), in comparison to another preparation in which the active ingredient are the proanthocyanidins (PAC), both of them, in prolonged released, after, they was administered for 24 weeks. METHODS: A multicenter, randomized and double blind experimental study was carried out. 283 women with a history of recurrent UTIs without evidence of complication were included. They were randomized 1: 1 in two groups. In one group, 1 oral sachet of Manosar(R) a day was administered, and in the other group 1 oral sachet of a compound of 240 mg of continuous-release PAC. Prior to inclusion in the study, the episode of UTI was confirmed at least by the clinical symptoms and positivity of the Combur test. RESULTS: Valid data were obtained from 184 patients with an average age of 49.5 years: 90 received Manosar(R) and 94 isolated PAC. A total of 72 patients suffered an UTI due to E.coli: 25 patients in the arm with Manosar(R) versus 47 patients in the isolated PAC group, this difference being statistically significant (p = 0.002). The free time of new UTI recurrences was 98.6 days in the group treated with Manosar(R) and 84.6 days in the group with isolated PAC. CONCLUSION: The oral taking of a daily sachet of Manosar(R) is effective and safe in preventing recurrent UTIs in women, being superior to the oral taking of isolated PAC

Mannosylated glycoliposomes for the delivery of a peptide kappa opioid receptor antagonist to the brain.

Dynantin is a potent and selective synthetic polypeptide kappa opioid receptor antagonist which has potential antidepressant and anxiolytic-like therapeutic applications, however its clinical development has been hampered by plasma stability issues and poor penetration of the blood brain barrier. Targeted liposome delivery systems represent a promising and non-invasive approach to improving the delivery of therapeutic agents across the blood brain barrier. As part of our work focused on targeted drug delivery, we have developed a novel mannosylated liposome system. Herein, we investigate these glycoliposomes for the targeted delivery of dynantin to the central nervous system. Cholesterol was tested and optimized as a formulation excipient, where it improved particle stability as measured via particle size, entrapment and ex vivo plasma stability of dynantin. The in vitro PRESTO-TANGO assay system was used to confirm that glycoliposomal entrapment did not impact the affinity or activity of the peptide at its receptor. Finally, in vivo distribution studies in mice showed that the mannosylated glycoliposomes significantly improved delivery of dynantin to the brain. Overall, the results clearly demonstrate the potential of our glycoliposomes as a targeted delivery system for therapeutic agents of the central nervous system.

Effectiveness of a novel oral combination of D-Mannose, pomegranate extract, prebiotics and probiotics in the treatment of acute cystitis in women.

OBJECTIVE: Urinary tract infections (UTIs) are defined as the symptomatic presence of pathogens in the urinary tract that are typically diagnosed by microscopy and culture of urine samples. Over the long-term antibiotic courses, alternative prophylactic methods as probiotics, cranberry juices and D-mannose have been introduced for recurrence prevention. The present study aimed to determine whether a new combination of D-Mannose, Pomegranate extract, Prebiotics and Probiotics is effective in modifying symptoms reported by women with acute uncomplicated acute cystitis. MATERIAL AND METHODS: This is a pilot study, performed between September 2018 and November 2018 at the Department of Urology of Villa Stuart Private Hospital. A dose of a new combination of agents was administered twice daily for 5 days and then once a day for 10 days. Together with the compound, forced hydration (> 2 liters/day) has been strongly suggested. Antibiotics were permitted only in case of clinical worsening. Changes in patients' symptoms, the therapeutic effects and changes in quality of life (QoL) were evaluated clinically and through a validated questionnaire, the Acute Cystitis Symptom Score (ACSS) at the first visit (T0), 15 (T1) and 30 (T2) days later. RESULTS: Thirty-three patients were enrolled in the study (mean age 38,1 ± 11.2 years) and all completed the treatment protocol. At T1 visit, all symptoms or the majority of symptoms went off in 10 women (30.3%) and at T2 in 30 women (90.9%); some symptoms still remained in 16 women (48.5%) at T1 and in 3 women (9.1%) at T2; the persistence of all symptoms or the worsening of the condition was observed in 7 patients (21.2%) at T1 and in none at T2. The mean score reported at all the ACSS sub-scales significantly decreased between baseline and T1 and T2. Typical symptoms decreased from 11.5 (10.5-12.6) to 4.9 (4.0-5.9) and to 2.7 (2.1-3.3) (p-values < 0.0001); differential symptoms decreased from 3.1 (2.6-3.6) to 0.6 (0.3-0.9) and to 0.3 (0.1-0.5) (p-values 0.009 to < 0.0001); QoL mean score also decrease from 7.2 (6.7- 7.7) to 4.0 (3.3-4.6) and to 1.7 (1.2-2.1) (p-values < 0.0001). Six patients required antibiotics and no adverse events were recorded. CONCLUSIONS: Our study suggests that the action of the compounds, administered in this new combination, could help in an effective management of symptoms of acute cystitis in women, without antibiotics, in a wide majority of the cases. Lack of microbiological assessment is a clear limitation of the study. Moreover, lack of a control group is another important limitation. Finally, hyperhydration could have been a confounding factor in interpretation of results.

Cranberry, D-mannose and anti-inflammatory agents prevent lower urinary tract symptoms in women undergoing prolapse surgery.

Objective: We assessed the effect on lower urinary tract symptoms (LUTS) of a supplement containing cranberry, D-mannose and anti-inflammatory molecules in postmenopausal women undergoing surgery for cystocele.Study design: Forty postmenopausal women were randomized 1:1 to an active group receiving the nutritional supplement twice a day for 2 weeks starting from surgery, or to a control group receiving surgery only. Primary outcomes were the effectiveness in the postoperative LUTS and urinary tract infections (UTI). LUTS were investigated by a validated questionnaire (ICIQ-FLUTS) at baseline and at week 4. Secondary outcomes were the safety and tolerability of the supplement and other perioperative outcomes.Results: No significant differences were found in perioperative outcomes and in incidence of UTI. After surgery, women treated with the supplement experienced significantly better scores on the filling domain of the questionnaire. A non-significant decrease in voiding scores was also found. No adverse events were detected.Conclusion: The use of an oral supplement containing cranberry, D-mannose and anti-inflammatory molecules decreases the perception of LUTS in postmenopausal women after anterior colporraphy. Our data suggest that perioperative use of nutritional supplements may be useful in the management of postoperative LUTS.

Mannose-Modified PLGA Nanoparticles for Sustained and Targeted Delivery in Hepatitis B Virus Immunoprophylaxis.

The launched hepatitis B vaccine could induce powerful antibodies, whereas it failed to improve potent cellular immune responses due to that the Th2-type response-induced aluminum adjuvant was adopted. Here, to target antigen-presenting cells under the epidermis and induce potent cellular and humoral immune responses, mannose-modified poly D,L-lactide-co-glycolic acid (PLGA) was synthesized and nanoparticle (MNP)-loaded hepatitis B surface antigen (HBsAg) protein was prepared. HBsAg could be slowly released and highly presented to lymphocytes which facilitated to produce long-lasting immunity based on characters of PLGA. In vitro uptake test results showed that MNPs could enhance internalization in bone marrow-derived dendritic cells (BMDCs) and RAW 264.7 cells. Subcutaneous delivery of MNPs into mice kept humoral immune and strengthened cellular immune responses. Experimental results indicated that MNPs showed significantly modified properties compared with parental PLGA nanoparticles. Thus, the obtained MNPs could be a promising vehicle for hepatitis B vaccine delivery.

Unsuccessful intravenous D-mannose treatment in PMM2-CDG.

BACKGROUND: PMM2-CDG (Phosphomannomutase 2 - Congenital disorder of glycosylation-Ia; CDG-Ia) is the most common glycosylation defect, often presenting as a severe multisystem disorder that can be fatal within the first years of life. While mannose treatment has been shown to correct glycosylation in vitro and in vivo in mice, no convincing effects have been observed in short-term treatment trials in single patients so far. RESULTS: We report on a boy with a severe PMM2-CDG who received a continuous intravenous mannose infusion over a period of 5 months during the first year of life in a dose of 0.8 g/kg/day. N-glycosylation of serum glycoproteins and mannose concentrations in serum were studied regularly. Unfortunately, no biochemical or clinical improvement was observed, and the therapy was terminated at age 9 months. CONCLUSION: Postnatal intravenous D-mannose treatment seems to be ineffective in PMM2-CDG.

Azido-galactose outperforms azido-mannose for metabolic labeling and targeting of hepatocellular carcinoma.

Metabolic glycoengineering of unnatural monosaccharides provides a facile method to label cancer cells with chemical tags for glycan imaging and cancer targeting. Multiple types of monosaccharides have been utilized for metabolic cell labeling. However, the comparison of different types of monosaccharides in labeling efficiency and selectivity has not been reported. In this study, we compared N-azidoacetylgalactosamine (GalAz) and N-azidoacetylmannosamine (ManAz) for metabolic labeling of HepG2 hepatocellular carcinoma in vitro and in vivo. GalAz showed higher labeling efficiency at low concentrations, and outperformed ManAz in metabolic labeling of HepG2 tumors in vivo. GalAz mediated labeling of HepG2 tumors with azido groups significantly improved the tumor accumulation of dibenzocyclooctyne (DBCO)-Cy5 and DBCO-doxorubicin conjugate via efficient Click chemistry. This study, for the first time, uncovered the distinct labeling efficiency and selectivity of different unnatural monosaccharides in liver cancers.

Modular core-shell polymeric nanoparticles mimicking viral structures for vaccination.

Recent advances in the development of protein-based vaccines have expanded the opportunities for preventing and treating both infectious diseases as well as cancer. However, the development of readily and efficient antigen delivery systems capable of stimulating strong cytotoxic T-lymphocyte (CTL) responses remains a challenge. With the attempt to closely mimic the properties of viruses in terms of their size and molecular organization, we constructed RNA (which is a ligand for Toll-like receptor 7 (TLR7) and TLR8) and antigen-loaded nanoparticles resembling the structural organization of viruses. Cationic polymers containing either azide or bicyclo[6.1.0]nonyne (BCN) groups were synthesized as electrostatic glue that binds negatively charged single stranded RNA (PolyU) to form a self-crosslinked polyplex core. An azide-modified model antigen (ovalbumin, OVA) and a BCN-modified mannosylated or galactosylated polymer were sequentially conjugated to the RNA core via disulfide bonds using copper free click chemistry to form the shell of the polyplexes. The generated reducible virus mimicking particles (VMPs) with a diameter of 200 nm and negatively surface charge (-14 mV) were colloidally stable in physiological conditions. The immunogenicity of these VMP vaccines was evaluated both in vitro and in vivo. The surface mannosylated VMPs (VMP-Man) showed 5 times higher cellular uptake by bone marrow derived DCs (BMDCs) compared to galactosylated VMP (VMP-Gal) counterpart. Moreover, VMP-Man efficiently activated DCs and greatly facilitated MHC I Ag presentation in vitro. Vaccination of mice with VMP-Man elicited strong OVA-specific CTL responses as well as humoral immune responses. These results demonstrate that the modular core-shell polymeric nanoparticles described in this paper are superior in inducing strong and durable immune responses compared to adjuvanted protein subunit vaccines and offer therefore a flexible platform for personalized vaccines.

Mannose impairs tumour growth and enhances chemotherapy.

It is now well established that tumours undergo changes in cellular metabolism1. As this can reveal tumour cell vulnerabilities and because many tumours exhibit enhanced glucose uptake2, we have been interested in how tumour cells respond to different forms of sugar. Here we report that the monosaccharide mannose causes growth retardation in several tumour types in vitro, and enhances cell death in response to major forms of chemotherapy. We then show that these effects also occur in vivo in mice following the oral administration of mannose, without significantly affecting the weight and health of the animals. Mechanistically, mannose is taken up by the same transporter(s) as glucose3 but accumulates as mannose-6-phosphate in cells, and this impairs the further metabolism of glucose in glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway and glycan synthesis. As a result, the administration of mannose in combination with conventional chemotherapy affects levels of anti-apoptotic proteins of the Bcl-2 family, leading to sensitization to cell death. Finally we show that susceptibility to mannose is dependent on the levels of phosphomannose isomerase (PMI). Cells with low levels of PMI are sensitive to mannose, whereas cells with high levels are resistant, but can be made sensitive by RNA-interference-mediated depletion of the enzyme. In addition, we use tissue microarrays to show that PMI levels also vary greatly between different patients and different tumour types, indicating that PMI levels could be used as a biomarker to direct the successful administration of mannose. We consider that the administration of mannose could be a simple, safe and selective therapy in the treatment of cancer, and could be applicable to multiple tumour types.

Targeted delivery of p-coumaric acid encapsulated mannosylated liposomes to the synovial macrophages inhibits osteoclast formation and bone resorption in the rheumatoid arthritis animal model.

The current study aimed to target the delivery of p-coumaric acid (CA), a dietary polyphenol to the synovial macrophages of AIA rats via mannose incorporated liposomal delivery system (ML) with reference to osteoclastogenesis and bone resorption. In vivo imaging and in vitro drug release study indicated the efficiency of mannosylated liposomes to localize at the site of inflammation and increased sustain drug release respectively. Morphological assessment of isolated synovial macrophages with respect to CD86 (synovial macrophages) and CD51 (pre-/osteoclast) indicated that p-coumaric acid encapsulated mannosylated liposomes (ML-CA) inhibited the osteoclasts differentiation. ML-CA treatment inhibited the TRAP staining, downregulated the expression of MMP-9 and NFATc1 and inflammatory cytokines. The ex-vivo study specified the ability of CA to induce the OPG production in bone marrow stromal cell triggered macrophage-osteoclasts differentiation and to preserve the calcium content. Taken together, our results demonstrated that ML-CA could intervene in the osteoclast formation.

Effect of mannose targeting of hydroxyl PAMAM dendrimers on cellular and organ biodistribution in a neonatal brain injury model.

Neurotherapeutics for the treatment of central nervous system (CNS) disorders must overcome challenges relating to the blood-brain barrier (BBB), brain tissue penetration, and the targeting of specific cells. Neuroinflammation mediated by activated microglia is a major hallmark of several neurological disorders, making these cells a desirable therapeutic target. Building on the promise of hydroxyl-terminated generation four polyamidoamine (PAMAM) dendrimers (D4-OH) for penetrating the injured BBB and targeting activated glia, we explored if conjugation of targeting ligands would enhance and modify brain and organ uptake. Since mannose receptors [cluster of differentiation (CD) 206] are typically over-expressed on injured microglia, we conjugated mannose to the surface of multifunctional D4-OH using highly efficient, atom-economical, and orthogonal Cu(I)-catalyzed alkyne-azide cycloaddition (CuAAC) click chemistry and evaluated the effect of mannose conjugation on the specific cell uptake of targeted and non-targeted dendrimers both in vitro and in vivo. In vitro results indicate that the conjugation of mannose as a targeting ligand significantly changes the mechanism of dendrimer internalization, giving mannosylated dendrimer a preference for mannose receptor-mediated endocytosis as opposed to non-specific fluid phase endocytosis. We further investigated the brain uptake and biodistribution of targeted and non-targeted fluorescently labeled dendrimers in a maternal intrauterine inflammation-induced cerebral palsy (CP) rabbit model using quantification methods based on fluorescence spectroscopy and confocal microscopy. We found that the conjugation of mannose modified the distribution of D4-OH throughout the body in this neonatal rabbit CP model without lowering the amount of dendrimer delivered to injured glia in the brain, even though significantly higher glial uptake was not observed in this model. Mannose conjugation to the dendrimer modifies the dendrimer's interaction with cells, but does not minimize its inherent inflammation-targeting abilities.

[Efficacy and safety of D-mannose (2 g), 24h prolonged release, associated with Proanthocyanidin (PAC), versus isolate PAC, in the management of a series of women with recurrent urinary infections.] / Eficacia y tolerancia terapéutica de la D­manosa (2 g) de liberación prolongada 24 horas (asociada a proantocianidinas), frente a proantocianidinas aisladas en el manejo de una serie de mujeres con infecciones urinarias recurrentes.

OBJECTIVE: To compare the efficacy and safety of dietary supplement "Manosar®" composed of D-mannose (2 g), 24 h prolonged release, associated with Proanthocyanidin (PAC) (140 mg), ursolic acid (7.98 mg), A, C, and D vitamins and the oligoelement zinc, versus 240 mg of PAC in recurrent urinary tract infections (UTI), for a designed follow-up of 24 weeks, in women. METHODS: A multicenter randomized experimental double-blind study was carried out. The study was approved by review board of "Complejo Hospitalario de Toledo" (Spain), and all patients gave informed consent. A total of 150 women with non complicated UTI were screened for participation. Valid data was obtained from 93, with mean age of 48 years. Fortyfour patients were assigned to the Manosar® group and 51 patients to the PAC group. Patients were followed during six months. A previous UTI was defined based on a combination of symptoms and a positive reactive urine trip. Confirmation of a new UTI was based on symptoms, reactive urine strip and urine culture. RESULTS: Thirty-three patients (35%) had an UTI during the six months follow-up. The percentage of UTI of the Manosar® group during this period was 24%, while the percentage of the PAC group was 45% (p〈0.05). The disease-free time for the Manosar® group was 95 days, while this time was 79 days for the PAC group. The incidence of side effects was low. Diarrhea was the most frequent side-effect in both groups. CONCLUSION: Manosar® (oral once a day) is more effective than single dose PAC (240 mg daily orally) to prevent recurrent UTI in women.

Mannose-functionalized solid lipid nanoparticles are effective in targeting alveolar macrophages.

Mannose receptor is highly expressed on alveolar macrophages, being a potential target to promote the specific local drug delivery of anti-tuberculosis agents through the use of functionalized nanocarriers. In this work, isoniazid (Isn)-loaded solid lipid nanoparticles (SLN), reinforced with stearylamine (SA) were produced by double emulsion technique and further surface-functionalized with mannose in a straightforward chemical approach. Upon pre-formulation assessment, SLN close to 500 nm average size, positively charged and with association efficiency of ISN close to 50% were obtained. Functionalization with mannose was performed after SLN production and confirmed by Fourier transform infrared spectroscopy (FTIR). Both functionalized and non-functionalized SLN demonstrated to devoid of toxicity when tested in human lung epithelial cell line (NCI-H441) and differentiated THP-1 (dTHP-1), reducing the intrinsic cytotoxicity of Isn when incorporated into SLN. Uptake studies were conducted on same macrophage-like cells and the results showed that fluorescent mannosylated SLN (M-SLN) were more efficient in be internalized comparatively to SLN. Moreover, the uptake of M-SLN was reduced when cells were pre-incubated with mannose, demonstrating the receptor-dependence internalization of functionalized SLN. These functionalized nanocarriers may represent a useful platform to target alveolar macrophages for delivering anti-infective drugs.