The D-mannose/L-galactose pathway plays a predominant role in ascorbate biosynthesis in the liverwort Marchantia polymorpha but is not regulated by light and oxidative stress.

Ascorbate plays an indispensable role in plants, functioning as both an antioxidant and a cellular redox buffer. It is widely acknowledged that the ascorbate biosynthesis in the photosynthetic tissues of land plants is governed by light-mediated regulation of the D-mannose/L-galactose (D-Man/L-Gal) pathway. At the core of this light-dependent regulation lies the VTC2 gene, encoding the rate-limiting enzyme GDP-L-Gal phosphorylase. The VTC2 expression is regulated by signals via the photosynthetic electron transport system. In this study, we directed our attention to the liverwort Marchantia polymorpha, representing one of the basal land plants, enabling us to conduct an in-depth analysis of its ascorbate biosynthesis. The M. polymorpha genome harbors a solitary gene for each enzyme involved in the D-Man/L-Gal pathway, including VTC2, along with three lactonase orthologs, which may be involved in the alternative ascorbate biosynthesis pathway. Through supplementation experiments with potential precursors, we observed that only L-Gal exhibited effectiveness in ascorbate biosynthesis. Furthermore, the generation of VTC2-deficient mutants through genome editing unveiled the inability of thallus regeneration in the absence of L-Gal supplementation, thereby revealing the importance of the D-Man/L-Gal pathway in ascorbate biosynthesis within M.  polymorpha. Interestingly, gene expression analyses unveiled a distinct characteristic of M. polymorpha, where none of the genes associated with the D-Man/L-Gal pathway, including VTC2, showed upregulation in response to light, unlike other known land plants. This study sheds light on the exceptional nature of M. polymorpha as a land plant that has evolved distinctive mechanisms concerning ascorbate biosynthesis and its regulation.

D-mannose facilitates immunotherapy and radiotherapy of triple-negative breast cancer via degradation of PD-L1.

Breast cancer is the most frequent malignancy in women worldwide, and triple-negative breast cancer (TNBC) patients have the worst prognosis and highest risk of recurrence. The therapeutic strategies for TNBC are limited. It is urgent to develop new methods to enhance the efficacy of TNBC treatment. Previous studies demonstrated that D-mannose, a hexose, can enhance chemotherapy in cancer and suppress the immunopathology of autoimmune diseases. Here, we show that D-mannose can significantly facilitate TNBC treatment via degradation of PD-L1. Specifically, D-mannose can activate AMP-activated protein kinase (AMPK) to phosphorylate PD-L1 at S195, which leads to abnormal glycosylation and proteasomal degradation of PD-L1. D-mannose-mediated PD-L1 degradation promotes T cell activation and T cell killing of tumor cells. The combination of D-mannose and PD-1 blockade therapy dramatically inhibits TNBC growth and extends the lifespan of tumor-bearing mice. Moreover, D-mannose-induced PD-L1 degradation also results in messenger RNA destabilization of DNA damage repair-related genes, thereby sensitizing breast cancer cells to ionizing radiation (IR) treatment and facilitating radiotherapy of TNBC in mice. Of note, the effective level of D-mannose can be easily achieved by oral administration in mice. Our study unveils a mechanism by which D-mannose targets PD-L1 for degradation and provides methods to facilitate immunotherapy and radiotherapy in TNBC. This function of D-mannose may be useful for clinical treatment of TNBC.

Effects of aging on urinary tract epithelial homeostasis and immunity.

A global increase in older individuals creates an increasing demand to understand numerous healthcare challenges related to aging. This population is subject to changes in tissue physiology and the immune response network. Older individuals are particularly susceptible to infectious diseases, with one of the most common being urinary tract infections (UTIs). Postmenopausal and older women have the highest risk of recurrent UTIs (rUTIs); however, why rUTIs become more frequent after menopause and during old age is incompletely understood. This increased susceptibility and severity among older individuals may involve functional changes to the immune system with age. Aging also has substantial effects on the epithelium and the immune system that led to impaired protection against pathogens, yet heightened and prolonged inflammation. How the immune system and its responses to infection changes within the bladder mucosa during aging has largely remained poorly understood. In this review, we highlight our understanding of bladder innate and adaptive immunity and the impact of aging and hormones and hormone therapy on bladder epithelial homeostasis and immunity. In particular, we elaborate on how the cellular and molecular immune landscape within the bladder can be altered during aging as aged mice develop bladder tertiary lymphoid tissues (bTLT), which are absent in young mice leading to profound age-associated change to the immune landscape in bladders that might drive the significant increase in UTI susceptibility. Knowledge of host factors that prevent or promote infection can lead to targeted treatment and prevention regimens. This review also identifies unique host factors to consider in the older, female host for improving rUTI treatment and prevention by dissecting the age-associated alteration of the bladder mucosal immune system.

Injectable Ozone-Rich Nanocomposite Hydrogel Loaded with D-Mannose for Anti-Inflammatory and Cartilage Protection in Osteoarthritis Treatment.

Osteoarthritis (OA) is a dynamic condition characterized by cartilage damage and synovial inflammation. Ozone (O3) shows potential therapeutic effects owing to its anti-inflammatory properties; however, its high reactivity and short half-life substantially limit its effectiveness in OA treatment. In this study, an ozone-rich thermosensitive nanocomposite hydrogel loaded with D-mannose is developed for OA treatment. Briefly, O3 is encapsulated in nanoparticles (NPs) composed of perfluorotributylamine and fluorinated hyaluronic acid to improve its stability. Next, D-mannose is conjugated with α-amino of the hydroxypropyl chitin (HPCH) via Schiff base to prepare MHPCH. These nanoparticles are encapsulated in MHPCH to produce O3 NPs@MHPCH. In vitro cell experiments demonstrate that the O3 NPs@MHPCH treatment significantly reduced VEGF and inflammation levels, accompanied by a decrease in inflammatory factors such as IL-1ß, IL-6, TNF-α, and iNOS. Furthermore, O3 NPs@MHPCH promotes the expression of collagen II and aggrecan and stimulates chondrocyte proliferation. Additionally, in vivo studies show that O3 NPs@MHPCH significantly alleviated OA by reducing synovial inflammation, cartilage destruction, and subchondral bone remodeling. O3 NPs@MHPCH offers a promising option for improving the efficacy of O3 therapy and reducing the risk of synovial inflammation and cartilage degeneration in OA.

Structural insights into the Smirnoff-Wheeler pathway for vitamin C production in the Amazon fruit camu-camu.

l-Ascorbic acid (AsA, vitamin C) is a pivotal dietary nutrient with multifaceted importance in living organisms. In plants, the Smirnoff-Wheeler pathway is the primary route for AsA biosynthesis, and understanding the mechanistic details behind its component enzymes has implications for plant biology, nutritional science, and biotechnology. As part of an initiative to determine the structures of all six core enzymes of the pathway, the present study focuses on three of them in the model species Myrciaria dubia (camu-camu): GDP-d-mannose 3',5'-epimerase (GME), l-galactose dehydrogenase (l-GalDH), and l-galactono-1,4-lactone dehydrogenase (l-GalLDH). We provide insights into substrate and cofactor binding and the conformational changes they induce. The MdGME structure reveals a distorted substrate in the active site, pertinent to the catalytic mechanism. Mdl-GalDH shows that the way in which NAD+ association affects loop structure over the active site is not conserved when compared with its homologue in spinach. Finally, the structure of Mdl-GalLDH is described for the first time. This allows for the rationalization of previously identified residues which play important roles in the active site or in the formation of the covalent bond with FAD. In conclusion, this study enhances our understanding of AsA biosynthesis in plants, and the information provided should prove useful for biotechnological applications.

Serum sickness-like reaction to D-supplement: a case report.

BACKGROUND: Serum Sickness-Like Reaction (SSLR) is an immune response characterized by rash, polyarthralgias, inflammation, and fever. Serum sickness-like reaction is commonly attributed to antibiotics, anticonvulsants, and anti-inflammatory agents. CASE PRESENTATION: A 16-year-old female with a history of overactive bladder and anemia presented with a diffuse urticarial rash, headaches, joint pain, and swelling for three days. Her medications included oral contraceptive pills, iron, mirabegron, UQora, and a probiotic. Physical examination revealed a diffuse urticarial rash, and her musculoskeletal exam revealed swelling and tenderness in her wrists. She was evaluated by her pediatrician and started on a 7-day course of prednisone, as well as antihistamines. Her CBC, basic metabolic panel, liver function panel, Lyme titers, and urinalysis were all within normal limits. With concern for hypersensitivity reaction to medication, all medications were discontinued. Nine days after symptom onset, the patient was evaluated by an allergist, who confirmed her presentation was consistent with serum sickness-like reaction. Her symptoms resolved, and her medications were re-introduced sequentially over several months. Restarting UQora, however, triggered a recurrence of her symptoms, and it was identified as the culprit medication. Consequently, UQora was permanently discontinued, and the patient has remained symptom-free. CONCLUSIONS: This case report describes the first documented case of serum sickness-like reaction caused by UQora (active ingredient D-mannose). D-mannose is a monosaccharide, and it is frequently promoted to prevent urinary tract infections. While the clinical features and timeline in this case were typical of serum sickness-like reaction, UQora as the trigger was highly unusual. Clinicians should be aware of the diverse triggers of serum sickness-like reaction and the importance of prompt identification and management to enhance patient safety. Further research is necessary to better understand the potential therapeutic applications of D-mannose, as well as the potential risks and interactions.

d-mannose suppresses oxidative response and blocks phagocytosis in experimental neuroinflammation.

Inflammation drives the pathology of many neurological diseases. d-mannose has been found to exert an antiinflammatory effect in peripheral diseases, but its effects on neuroinflammation and inflammatory cells in the central nervous system have not been studied. We aimed to determine the effects of d-mannose on key macrophage/microglial functions-oxidative stress and phagocytosis. In murine experimental autoimmune encephalomyelitis (EAE), we found d-mannose improved EAE symptoms compared to phosphate-buffered saline (PBS)-control mice, while other monosaccharides did not. Multiagent molecular MRI performed to assess oxidative stress (targeting myeloperoxidase [MPO] using MPO-bis-5-hydroxytryptamide diethylenetriaminepentaacetate gadolinium [Gd]) and phagocytosis (using cross-linked iron oxide [CLIO] nanoparticles) in vivo revealed that d-mannose-treated mice had smaller total MPO-Gd+ areas than those of PBS-control mice, consistent with decreased MPO-mediated oxidative stress. Interestingly, d-mannose-treated mice exhibited markedly smaller CLIO+ areas and much less T2 shortening effect in the CLIO+ lesions compared to PBS-control mice, revealing that d-mannose partially blocked phagocytosis. In vitro experiments with different monosaccharides further confirmed that only d-mannose treatment blocked macrophage phagocytosis in a dose-dependent manner. As phagocytosis of myelin debris has been known to increase inflammation, decreasing phagocytosis could result in decreased activation of proinflammatory macrophages. Indeed, compared to PBS-control EAE mice, d-mannose-treated EAE mice exhibited significantly fewer infiltrating macrophages/activated microglia, among which proinflammatory macrophages/microglia were greatly reduced while antiinflammatory macrophages/microglia increased. By uncovering that d-mannose diminishes the proinflammatory response and boosts the antiinflammatory response, our findings suggest that d-mannose, an over-the-counter supplement with a high safety profile, may be a low-cost treatment option for neuroinflammatory diseases such as multiple sclerosis.

The Impact of Glycolysis and Its Inhibitors on the Immune Response to Inflammation and Autoimmunity.

Glucose metabolism is a crucial biological pathway maintaining the activation of extra- and intracellular signaling pathways involved in the immune response. Immune cell stimulation via various environmental factors results in their activation and metabolic reprogramming to aerobic glycolysis. Different immune cells exhibit cell-type-specific metabolic patterns when performing their biological functions. Numerous published studies have shed more light on the importance of metabolic reprogramming in the immune system. Moreover, this knowledge is crucial for revealing new ways to target inflammatory pathologic states, such as autoimmunity and hyperinflammation. Here, we discuss the role of glycolysis in immune cell activity in physiological and pathological conditions, and the potential use of inhibitors of glycolysis for disease treatment.

Inhibition of bleomycin-induced pulmonary fibrosis in SD rats by sea cucumber peptides.

BACKGROUND: Pulmonary fibrosis (PF) is the terminal manifestation of a type of pulmonary disease, which seriously affects the respiratory function of the body, and with no effective cure for treatment. This study evaluated the effect of sea cucumber peptides (SCP) on bleomycin-induced SD rat PF. RESULTS: SCP can inhibit the PF induced by bleomycin. PF and SCP did not affect the food intake of rats, but PF reduced the body weight of rats, and SCP could improve the weight loss. SCP reduced lung index in PF rats in a dose-dependent manner. SCP significantly reduced IL-1ß, IL-6, TNF-α, α-SMA and VIM expression levels in lung tissue (P < 0.05), significantly decreased TGF-ß1 expression level in serum (P < 0.01) and the LSCP group and MSCP group had better inhibitory effects on PF than the HSCP group. Histomorphological results showed that SCP could ameliorate the structural damage of lung tissue, alveolar wall rupture, inflammatory cell infiltration, fibroblast proliferation and deposition of intercellular matrix and collagen fibers caused by PF. The improvement effect of the MSCP group was the most noteworthy in histomorphology. Metabolomics results showed that SCP significantly downregulated catechol, N-acetyl-l-histidine, acetylcarnitine, stearoylcarnitine, d-mannose, l-threonine, l-alanine, glycine, 3-guanidinopropionic acid, prostaglandin D2 and embelic acid d-(-)-ß-hydroxybutyric acid expression levels in lung tissue. CONCLUSION: SCP ameliorate bleomycin-induced SD rat PF. KEGG pathway analysis proved that SCP intervened in PF mainly via the lysosome pathway, with d-mannose as the key factor. © 2023 Society of Chemical Industry.

D-Mannose prevents bone loss under weightlessness.

BACKGROUND: Astronauts undergo significant microgravity-induced bone loss during space missions, which has become one of the three major medical problems hindering human's long-term space flight. A risk-free and antiresorptive drug is urgently needed to prevent bone loss during space missions. D-mannose is a natural C-2 epimer of D-glucose and is abundant in cranberries. This study aimed to investigate the protective effects and potential mechanisms of D-mannose against bone loss under weightlessness. METHODS: The hind legs of tail-suspended (TS) rats were used to mimic weightlessness on Earth. Rats were administered D-mannose intragastrically. The osteoclastogenic and osteogenic capacity of D-mannose in vitro and in vivo was analyzed by micro-computed tomography, biomechanical assessment, bone histology, serum markers of bone metabolism, cell proliferation assay, quantitative polymerase chain reaction, and western blotting. RNA-seq transcriptomic analysis was performed to detect the underlying mechanisms of D-mannose in bone protection. RESULTS: The TS rats showed lower bone mineral density (BMD) and poorer bone morphological indices. D-mannose could improve BMD in TS rats. D-mannose inhibited osteoclast proliferation and fusion in vitro, without apparent effects on osteoblasts. RNA-seq transcriptomic analysis showed that D-mannose administration significantly inhibited the cell fusion molecule dendritic cell-specific transmembrane protein (DC-STAMP) and two indispensable transcription factors for osteoclast fusion (c-Fos and nuclear factor of activated T cells 1 [NFATc1]). Finally, TS rats tended to experience dysuria-related urinary tract infections (UTIs), which were suppressed by treatment with D-mannose. CONCLUSION: D-mannose protected against bone loss and UTIs in rats under weightlessness. The bone protective effects of D-mannose were mediated by inhibiting osteoclast cell fusion. Our findings provide a potential strategy to protect against bone loss and UTIs during space missions.

Glucose and mannose analogs inhibit KSHV replication by blocking N-glycosylation and inducing the unfolded protein response.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent for Kaposi's sarcoma (KS), an HIV/AIDS-associated malignancy. Effective treatments against KS remain to be developed. The sugar analog 2-deoxy- d-glucose (2-DG) is an anticancer agent that is well-tolerated and safe in patients and was recently demonstrated to be a potent antiviral, including KSHV and severe acute respiratory syndrome coronavirus 2. Because 2-DG inhibits glycolysis and N-glycosylation, identifying its molecular targets is challenging. Here we compare the antiviral effect of 2-DG with 2-fluoro-deoxy- d-glucose, a glycolysis inhibitor, and 2-deoxy-fluoro- d-mannose (2-DFM), a specific N-glycosylation inhibitor. At doses similar to those clinically achievable with 2-DG, the three drugs impair KSHV replication and virion production in iSLK.219 cells via downregulation of viral structural glycoprotein expression (K8.1 and gB), being 2-DFM the most potent KSHV inhibitor. Consistently with the higher potency of 2-DFM, we found that d-mannose rescues KSHV glycoprotein synthesis and virus production, indicating that inhibition of N-glycosylation is the main antiviral target using d-mannose competition experiments. Suppression of N-glycosylation by the sugar drugs triggers ER stress. It activates the host unfolded protein response (UPR), counteracting KSHV-induced inhibition of the protein kinase R-like endoplasmic reticulum kinase branch, particularly activating transcription factor 4 and C/EBP homologous protein expression. Finally, we demonstrate that sugar analogs induce autophagy (a prosurvival mechanism) and, thus, inhibit viral replication playing a protective role against KSHV-induced cell death, further supporting their direct antiviral effect and potential therapeutic use. Our work identifies inhibition of N-glycosylation leading to ER stress and UPR as an antienveloped virus target and sugar analogs such as 2-DG and the newly identified 2-DFM as antiviral drugs.

d-mannosuria levels measured 1 h after d-mannose intake can select out favorable responders: A pilot study.

BACKGROUND: d-mannose is used as preventive measure against recurrent urinary tract infections (RUTIs). We studied d-mannosuria after a challenge test to identify favorable responders that could be targeted for long-term preventive therapy. MATERIAL AND METHODS: Following institutional review board approval, women attending a specialized tertiary care center urology clinic with a history of RUTIs were invited to participate by providing a urine sample (baseline), followed by the intake of home-dose d-mannose, and a second urine sample 1 h later (post). Urine samples were processed according to a d-mannosuria assay technique reported previously by our group. d-mannose concentrations were normalized to urinary creatinine. RESULTS: From July 2020 to March 2021, 26 patients met study criteria. Thirteen had a lower or unchanged ratio of baseline to post d-mannose, whereas 13 were responders. Among 19 taking 2 g, 12 had a lower or unchanged trend and 7 were responders with >20% increase in the d-mannose/creatinine ratio. Comparison of urinary baseline d-mannose/creatinine ratios was significantly different between the responder (mean = 0.337 ± 0.158) and nonresponder (mean = 0.692 ± 0.444; p = 0.016) groups. Urinary post d-mannose/creatinine ratios did not significantly differ between the two groups (p = 0.46). d-mannose-naïve patients had few responders, and age and urinary creatinine did not affect the findings. CONCLUSION: This preliminary study on d-mannose challenge tests indicates a urine response if urinary d-mannose/creatinine ratio is low, which it was in some women with a history of RUTIs.

Atractylodin targets GLA to regulate D-mannose metabolism to inhibit osteogenic differentiation of human valve interstitial cells and ameliorate aortic valve calcification.

Atractylodin (ATL) has been reported to exert anti-inflammatory effects. Osteogenic changes induced by inflammation in valve interstitial cells (VICs) play a key role in the development of calcified aortic valve disease (CAVD). This study aimed to investigate the anti-calcification effects of ATL on aortic valves. Human VICs (hVICs) were exposed to osteogenic induction medium (OM) containing ATL to investigate cell viability, osteogenic gene and protein expression, and anti-calcification effects. Gas chromatography-mass spectroscopy (GC-MS) metabolomics analysis was used to detect changes in the metabolites of hVICs stimulated with OM before and after ATL administration. The compound-reaction-enzyme-gene network was used to identify drug targets. Gene interference was used to verify the targets. ApoE-/- mice fed a high-fat (HF) diet were used to evaluate the inhibition of aortic valve calcification by ATL. Treatment with 20 µM ATL in OM prevented calcified nodule accumulation and decreases in the gene and protein expression levels of ALP, RUNX2, and IL-1ß. Differential metabolite analysis showed that D-mannose was highly associated with the anti-calcification effect of ATL. The addition of D-mannose prevented calcified nodule accumulation and inhibited succinate-mediated HIF-1α activation and IL-1ß production. The target of ATL was identified as GLA. Silencing of the GLA gene (si-GLA) reversed the anti-osteogenic differentiation of ATL. In vivo, ATL ameliorated aortic valve calcification by preventing decreases in GLA expression and the up-regulation of IL-1ß expression synchronously. In conclusion, ATL is a potential drug for the treatment of CAVD by targeting GLA to regulate D-mannose metabolism, thereby inhibiting succinate-mediated HIF-1α activation and IL-1ß production.

D-Mannose Plus Saccharomyces boulardii to Prevent Urinary Tract Infections and Discomfort after Cystoscopy: A Single-Center Prospective Randomized Pilot Study.

Background and Objectives: Patients undergoing cystoscopy can experience discomfort or pain during the procedure. In some cases, a urinary tract infection (UTI) with storage lower urinary tract symptoms (LUTS) may occur in the days following the procedure. This study aimed to assess the efficacy of D-mannose plus Saccharomyces boulardii in the prevention of UTIs and discomfort in patients undergoing cystoscopy. Materials and Methods: A single-center prospective randomized pilot study was conducted between April 2019 and June 2020. Patients undergoing cystoscopy for suspected bladder cancer (BCa) or in the follow-up for BCa were enrolled. Patients were randomized into two groups: D-Mannose plus Saccharomyces boulardii (Group A) vs. no treatment (Group B). A urine culture was prescribed regardless of symptoms 7 days before and 7 days after cystoscopy. The International Prostatic Symptoms Score (IPSS), 0-10 numeric rating scale (NRS) for local pain/discomfort, and EORTC Core Quality of Life questionnaire (EORTC QLQ-C30) were administered before cystoscopy and 7 days after. Results: A total of 32 patients (16 per group) were enrolled. No urine culture was positive in Group A 7 days after cystoscopy, while 3 patients (18.8%) in Group B had a positive control urine culture (p = 0.044). All patients with positive control urine culture reported the onset or worsening of urinary symptoms, excluding the diagnosis of asymptomatic bacteriuria. At 7 days after cystoscopy, the median IPSS of Group A was significantly lower than that of Group B (10.5 vs. 16.5 points; p = 0.021), and at 7 days, the median NRS for local discomfort/pain of Group A was significantly lower than that for Group B (1.5 vs. 4.0 points; p = 0.012). No statistically significant difference (p > 0.05) in the median IPSS-QoL and EORTC QLQ-C30 was found between groups. Conclusions: D-Mannose plus Saccharomyces boulardii administered after cystoscopy seem to significantly reduce the incidence of UTI, the severity of LUTS, and the intensity of local discomfort.

[Prevention of the development of catheter-associated urinary system infections in the early postoperative period].

BACKGROUND: Bladder catheterization is a common medical manipulation that is associated with the risk of complications, including catheter-associated urinary tract infection (CAUTI), which accounts for 80% of all nosocomial infections of the urological profile. AIM: To evaluate the combined use of the biologically active additive Uronext and ceftriaxone in the prevention of the development of CAUTI in the early postoperative period in 120 patients aged 20-80 years with a Foley indwelling catheter. MATERIALS AND METHODS: The patients were divided into 2 groups: in group I (n=60), D-mannose with cranberry extract and vitamin D3 as part of Uronext dietary supplement was administered orally in the form of sachets 48 hours before surgery and after surgery until urethral catheter was placed, as well as intravenous ceftriaxone 1000 mg 2 hours before surgery and in the postoperative period within 7 days. In group II (n=60), ceftriaxone monotherapy was prescribed in a similar way. RESULTS: According to the results of bacteriological examination of the removed urinary catheter on 3-7 days in Uronext group, bacterial growth was absent in 40 patients (66.67%, p<0.05), versus 23 cases (38.33%) in the control group. CONCLUSIONS: The data obtained confirm the efficiency of the use of the biologically active additive Uronext in combination with an antibacterial drug, which allows to recommend this scheme in patients with an indwelling urinary catheter for the prevention of the development of CAUTI.

The d-mannose/l-galactose pathway is the dominant ascorbate biosynthetic route in the moss Physcomitrium patens.

Ascorbate is an abundant and indispensable redox compound in plants. Genetic and biochemical studies have established the d-mannose/l-galactose (d-Man/l-Gal) pathway as the predominant ascorbate biosynthetic pathway in streptophytes, while the d-galacturonate (d-GalUA) pathway is found in prasinophytes and euglenoids. Based on the presence of the complete set of genes encoding enzymes involved in the d-Man/l-Gal pathway and an orthologous gene encoding aldonolactonase (ALase) - a key enzyme for the d-GalUA pathway - Physcomitrium patens may possess both pathways. Here, we have characterized the moss ALase as a functional lactonase and evaluated the ascorbate biosynthesis capability of the two pathways using knockout mutants. Physcomitrium patens expresses two ALase paralogs, namely PpALase1 and PpALase2. Kinetic analyses with recombinant enzymes indicated that PpALase1 is a functional enzyme catalyzing the conversion of l-galactonic acid to the final precursor l-galactono-1,4-lactone and that it also reacts with dehydroascorbate as a substrate. Interestingly, mutants lacking PpALase1 (Δal1) showed 1.2-fold higher total ascorbate content than the wild type, and their dehydroascorbate content was increased by 50% compared with that of the wild type. In contrast, the total ascorbate content of mutants lacking PpVTC2-1 (Δvtc2-1) or PpVTC2-2 (Δvtc2-2), which encode the rate-limiting enzyme GDP-l-Gal phosphorylase in the d-Man/l-Gal pathway, was markedly decreased to 46 and 17%, respectively, compared with that of the wild type. Taken together, the dominant ascorbate biosynthetic pathway in P. patens is the d-Man/l-Gal pathway, not the d-GalUA pathway, and PpALase1 may play a significant role in ascorbate metabolism by facilitating dehydroascorbate degradation rather than ascorbate biosynthesis.

d-mannose administration improves autoimmune hepatitis by upregulating regulatory T cells.

A recent study revealed that d-mannose suppressed immunopathology in mouse models of autoimmune diabetes and airway inflammation and increased the proportion of regulatory T cells (Tregs) in mice. We investigated the effect of d-mannose on liver injury in murine autoimmune hepatitis (AIH) models induced by concanavalin A (ConA) and α-galactosylceramide (GalCer). Mouse models of AIH were created by intraperitoneal injection of GalCer or intravenous injection of ConA. Drinking water was supplemented with d-mannose and biochemically and pathologically examined over time. The administration of d-mannose to AIH model mice significantly reduced liver injury and reduced inflammatory cytokine expression. In addition, Tregs among splenocytes and intrahepatic lymphocytes were significantly increased by the administration of d-mannose. These results indicate that treatment with d-mannose reduced the inflammatory response in the liver and suppressed liver damage by increasing Tregs.

Role of D-mannose in urinary tract infections - a narrative review.

Urinary tract infections (UTIs) are one of the most prevalent bacterial diseases worldwide. Despite the efficacy of antibiotics targeted against UTI, the recurrence rates remain significant among the patients. Furthermore, the development of antibiotic resistance is a major concern and creates a demand for alternative treatment options. D-mannose, a monosaccharide naturally found in fruits, is commonly marketed as a dietary supplement for reducing the risk for UTIs. Research suggests that supplemented D-mannose could be a promising alternative or complementary remedy especially as a prophylaxis for recurrent UTIs. When excreted in urine, D-mannose potentially inhibits Escherichia coli, the main causative organism of UTIs, from attaching to urothelium and causing infection. In this review, we provide an overview of UTIs, E. coli pathogenesis and D-mannose and outline the existing clinical evidence of D-mannose in reducing the risk of UTI and its recurrence. Furthermore, we discuss the potential effect mechanisms of D-mannose against uropathogenic E.coli.

Membrane-bound D-mannose isomerase of acetic acid bacteria: finding, characterization, and application.

D-Mannose isomerase (EC 5.3.1.7) catalyzing reversible conversion between D-mannose and D-fructose was found in acetic acid bacteria. Cell fractionation confirmed the enzyme to be a typical membrane-bound enzyme, while all sugar isomerases so far reported are cytoplasmic. The optimal enzyme activity was found at pH 5.5, which was clear contrast to the cytoplasmic enzymes having alkaline optimal pH. The enzyme was heat stable and the optimal reaction temperature was observed at around 40 to 60˚C. Purified enzyme after solubilization from membrane fraction showed the total molecular mass of 196 kDa composing of identical four subunits of 48 kDa. Washed cells or immobilized cells were well functional at nearly 80% of conversion ratio from D-mannose to D-fructose and reversely 20-25% of D-fructose to D-mannose. Catalytic properties of the enzyme were discussed with respect to the biotechnological applications to high fructose syrup production from konjac taro.

Non-antibiotic Approaches to Preventing Pediatric UTIs: a Role for D-Mannose, Cranberry, and Probiotics?

PURPOSE OF REVIEW: While antibiotics have been a staple in the management and even prevention of urinary tract infections (UTIs), it is not without significant consequences due to intolerance and development of antibiotic resistant bacteria. These concerns necessitate alternatives to antibiotic use in the management of pediatric UTIs. This review seeks to evaluate non-antibiotic means of preventing UTI in the pediatric population. RECENT FINDINGS: The search for preventative alternatives to antibiotics has included D-mannose, cranberry, and probiotics. These products similarly work through competitive inhibition of uropathogens in the urinary tract. Pediatric studies exist highlighting the use of cranberry extract/juice and probiotics in UTI prevention, although significant heterogeneity amongst studies have limited overarching recommendations for their use. Data of D-mannose use is extrapolated from adult literature. More studies are required in the utility of each treatment, with some emphasis on larger sample sizes and clarifications regarding dosing and formulation.