The role of GAPDH in the selective toxicity of CNP in melanoma cells.

BACKGROUND: Malignant melanoma is the most aggressive form of skin cancer with a rather poor prognosis. Standard chemotherapy often results in severe side effects on normal (healthy) cells finally being difficult to tolerate for the patients. Shown by us earlier, cerium oxide nanoparticles (CNP, nanoceria) selectively killed A375 melanoma cells while not being cytotoxic at identical concentrations on non-cancerous cells. In conclusion, the redox-active CNP exhibited both prooxidative as well as antioxidative properties. In that context, CNP induced mitochondrial dysfunction in the studied melanoma cells via generation of reactive oxygene species (primarily hydrogen peroxide (H2O2)), but that does not account for 100% of the toxicity. AIM: Cancer cells often show an increased glycolytic rate (Warburg effect), therefore we focused on CNP mediated changes of the glucose metabolism. RESULTS: It has been shown before that glyceraldehyde 3-phosphate dehydrogenase (GAPDH) activity is regulated via oxidation of a cysteine in the active center of the enzyme with a subsequent loss of activity. Upon CNP treatment, formation of cellular lactate and GAPDH activity were significantly lowered. The treatment of melanoma cells and melanocytes with the GAPDH inhibitor heptelidic acid (HA) decreased viability to a much higher extent in the cancer cells than in the studied normal (healthy) cells, highlighting and supporting the important role of GAPDH in cancer cells. CONCLUSION: We identified glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as a target protein for CNP mediated thiol oxidation.

Metabolic effects of SGLT2i and metformin on 3-hydroxybutyric acid and lactate in db/db mice.

Combining a Sodium-Glucose-Cotransporter-2-inhibitor (SGLT2i) with metformin is recommended for managing hyperglycemia in patients with type 2 diabetes (T2D) who have cardio-renal complications. Our study aimed to investigate the metabolic effects of SGLT2i and metformin, both individually and synergistically. We treated leptin receptor-deficient (db/db) mice with these drugs for two weeks and conducted metabolite profiling, identifying 861 metabolites across kidney, liver, muscle, fat, and plasma. Using linear regression and mixed-effects models, we identified two SGLT2i-specific metabolites, X-12465 and 3-hydroxybutyric acid (3HBA), a ketone body, across all examined tissues. The levels of 3HBA were significantly higher under SGLT2i monotherapy compared to controls and were attenuated when combined with metformin. We observed similar modulatory effects on metabolites involved in protein catabolism (e.g., branched-chain amino acids) and gluconeogenesis. Moreover, combination therapy significantly raised pipecolate levels, which may enhance mTOR1 activity, while modulating GSK3, a common target of SGLT2i and 3HBA inhibition. The combination therapy also led to significant reductions in body weight and lactate levels, contrasted with monotherapies. Our findings advocate for the combined approach to better manage muscle loss, and the risks of DKA and lactic acidosis, presenting a more effective strategy for T2D treatment.

Baicalin and N-acetylcysteine regulate choline metabolism via TFAM to attenuate cadmium-induced liver fibrosis.

(Background): Cadmium is an environmental pollutant associated with several liver diseases. Baicalin and N-Acetylcysteine have antioxidant and hepatoprotective effects. (Purpose): However, it is unclear whether baicalin and N-Acetylcysteine can alleviate Cadmium -induced liver fibrosis by regulating metabolism, or whether they exert a synergistic effect. (Study design): We treated Cadmium-poisoned mice with baicalin, N-Acetylcysteine, or baicalin+ N-Acetylcysteine. We studied the effects of baicalin and N-Acetylcysteine on Cadmium-induced liver fibers and their specific mechanisms. (Methods): We used C57BL/6 J mice, and AML12, and HSC-6T cells to establish in vitro assays and in vivo models. (Results): Metabolomics was used to detect the effect of baicalin and N-Acetylcysteine on liver metabolism, which showed that compared with the control group, the Cadmium group had increased fatty acid and amino acid levels, with significantly reduced choline and acetylcholine contents. Baicalin and N-Acetylcysteine alleviated these Cadmium-induced metabolic changes. We further showed that choline alleviated Cadmium -induced liver inflammation and fibrosis. In addition, cadmium significantly promoted extracellular leakage of lactic acid, while choline alleviated the cadmium -induced destruction of the cell membrane structure and lactic acid leakage. Western blotting showed that cadmium significantly reduced mitochondrial transcription factor A (TFAM) and Choline Kinase α(CHKα2) levels, and baicalin and N-Acetylcysteine reversed this effect. Overexpression of Tfam in mouse liver and AML12 cells increased the expression of CHKα2 and the choline content, alleviating and cadmium-induced lactic acid leakage, liver inflammation, and fibrosis. (Conclusion): Overall, baicalin and N-Acetylcysteine alleviated cadmium-induced liver damage, inflammation, and fibrosis to a greater extent than either drug alone. TFAM represents a target for baicalin and N-Acetylcysteine, and alleviated cadmium-induced liver inflammation and fibrosis by regulating hepatic choline metabolism.

Optimal Changes Seen in Patients After Treatment With Poly- l -Lactic Acid: A Retrospective Descriptive Study.

BACKGROUND: Poly- l -lactic acid (PLLA) is a biostimulator that enhances collagen production and leads to volume restoration. It became popular because of its improvement of facial wrinkles and long-lasting effect, although the specific visible changes it causes in the facial area are not fully described. OBJECTIVE: To identify and characterize the visible changes resulting from injecting PLLA into the facial area. METHODS: A list of 678 patients who underwent 2 to 3 treatments with PLLA injections in this center between 2021 and 2022 were retrieved. After 2 rounds of evaluations, 31 independent international evaluators described the 3 main changes they observed in the before-and-after images (taken approximately 7 months after the last injection session) of the 12 patients with the most significant improvement. RESULTS: A total of 1,015 descriptions were received. They were divided into categories based upon similarity. The main detected changes were better contouring and enhancement of the lateral face, a lifting effect and secondary impact on the nasolabial fold, and improvement of skin texture and skin firmness. CONCLUSION: Poly- l -lactic acid injections were judged to be effective for contouring, lifting, and improving skin texture in the facial area. Further research is needed to validate these results and create an assessment scale for PLLA injections.

Shikonin reverses cancer-associated fibroblast-induced gemcitabine resistance in pancreatic cancer cells by suppressing monocarboxylate transporter 4-mediated reverse Warburg effect.

BACKGROUND: Gemcitabine is a first-line chemotherapeutic agent for pancreatic cancer (PC); however, most patients who receive adjuvant gemcitabine rapidly develop resistance and recurrence. Cancer-associated fibroblasts (CAFs) are a crucial component of the tumor stroma that contribute to gemcitabine-resistance. There is thus an urgent need to find a novel therapeutic strategy to improve the efficacy of gemcitabine in PC cells under CAF-stimulation. PURPOSE: To investigate if shikonin potentiates the therapeutic effects of gemcitabine in PC cells with CAF-induced drug resistance. METHODS: PC cell-stimulated fibroblasts or primary CAFs derived from PC tissue were co-cultured with PC cells to evaluate the ability of shikonin to improve the chemotherapeutic effects of gemcitabine in vitro and in vivo. Glucose uptake assay, ATP content analysis, lactate measurement, real-time PCR, immunofluorescence staining, western blot, and plasmid transfection were used to investigate the underlying mechanism. RESULTS: CAFs were innately resistant to gemcitabine, but shikonin suppressed the PC cell-induced transactivation and proliferation of CAFs, reversed CAF-induced resistance, and restored the therapeutic efficacy of gemcitabine in the co-culture system. In addition, CAFs underwent a reverse Warburg effect when co-cultured with PC cells, represented by enhanced aerobic glycolytic metabolism, while shikonin reduced aerobic glycolysis in CAFs by reducing their glucose uptake, ATP concentration, lactate production and secretion, and glycolytic protein expression. Regarding the mechanism underlying these sensitizing effects, shikonin suppressed monocarboxylate transporter 4 (MCT4) expression and cellular membrane translocation to inhibit aerobic glycolysis in CAFs. Overexpression of MCT4 accordingly reversed the inhibitory effects of shikonin on PC cell-induced transactivation and aerobic glycolysis in CAFs, and reduced its sensitizing effects. Furthermore, shikonin promoted the effects of gemcitabine in reducing the growth of tumors derived from PC cells and CAF co-inoculation in BALB/C mice, with no significant systemic toxicity. CONCLUSION: These results indicate that shikonin reduced MCT4 expression and activation, resulting in inhibition of aerobic glycolysis in CAFs and overcoming CAF-induced gemcitabine resistance in PC. Shikonin is a promising chemosensitizing phytochemical agent when used in combination with gemcitabine for PC treatment. The results suggest that disrupting the metabolic coupling between cancer cells and stromal cells might provide an attractive strategy for improving gemcitabine efficacy.

Gut Lactobacillus contribute to the progression of breast cancer by affecting the anti-tumor activities of immune cells in the TME of tumor-bearing mice.

Studies have proven that gut microbiota dysbiosis may influence the carcinogenesis and outcomes of multiple cancers. However, it is still unclear whether gut microbiota dysbiosis affect the progression of breast cancer, especially triple-negative breast cancer. In the present study, by using gut microbiota dysbiosis murine model established by treatment of mice with streptomycin, we found Lactobacillus and the metabolite-lactic acid are the pivotal factors for 4T1 tumor progression. In fact, streptomycin-treated mice exhibited slower tumor growth, in parallel with less abundance of Lactobacillus in the gut. Supplementation with Lactobacillus resulted in a rapid tumor growth, following a decrease in the expression of mRNAs for anti-tumor-related factors but an increase in the M2 polarization. The elevated percentages of IFN-γ-producing CD4+T cells and CD8+T cells in the tumor microenvironment of streptomycin-treated tumor-bearing mice may be vanished by supplementation of Lactobacillus. It seems likely that lactobacillus-mediated pro-tumor effect is related to the production of lactic acid. A decrease in the levels of lactic acid in the cecal feces and tumor tissues were observed in streptomycin-treated tumor bearing mice. However, supplementation of Lactobacillus can restore streptomycin-reduced concentration of lactic acid in the tumor tissues, suggesting that gut Lactobacillus are the source of lactic acid. Bioinformatics analysis result suggests high concentration of lactic acid in tumor sites may be related to the diminished anti-tumor immunity in the TME. This study reveals a correlation between gut Lactobacillus and tumor progression in a murine 4T1 tumor model, providing experimental evidence for clinical treatment of breast cancer.

Lactic acid-induced M2-like macrophages facilitate tumor cell migration and invasion via the GPNMB/CD44 axis in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is the most prevalent form of oral and maxillofacial malignancies, characterized by a low five-year survival rate primarily caused by invasion and metastasis. The progression of OSCC is influenced by macrophage-mediated immunosuppression, which contributes to both local invasion and distant metastasis. Herein, it is of great necessity to explore the molecular mechanisms underlying the crosstalk between OSCC cells and macrophages, as it remains unclear. In the present study, we found that lactic acid orchestrated intracellular communication in the tumor microenvironment. Glycoprotein non-metastatic protein B (GPNMB), a remarkable molecule preferentially expressed by tumor-associated macrophages (TAMs), was significantly highly expressed in the OSCC tissue. The results showed that lactic acid induced macrophage polarization towards an M2-like phenotype and orchestrated GPNMB secretion from macrophages. Furthermore, paracrine GPNMB played a critical role in triggering tumor-promoting activities such as facilitating tumor cell migration, invasion, and epithelial-mesenchymal transition (EMT). In terms of molecular mechanism, GPNMB functionally interacted with the CD44 receptor, and then partially activated the PI3K/AKT/mTOR signaling cascade. Silencing of CD44 could attenuate the tumor-promoting effects of GPNMB in OSCC cells. Collectively, our findings decipher a positive feedback loop in which tumor cells metabolically interact with macrophages in the OSCC microenvironment, highlighting the potential for therapeutic targeting of the GPNMB/CD44 axis as a promising strategy for treating OSCC.

Molecular Complex of HSIM-loaded Polymeric Nanoparticles: Potential Carriers in Osteoporosis.

BACKGROUND: Statins, especially simvastatin promote bone formation by stimulating the activity of osteoblasts and suppressing osteoclast activity via the BMP-Smad signaling pathway. Statins present the liver first-pass metabolism. This study attempts to fabricate and evaluate simvastatin functionalized hydroxyapatite encapsulated in poly(lactic-co-glycolic) acid (PLGA) nanoparticles (HSIM-PLGA NPs) administered subcutaneously with sustained release properties for effective management of osteoporosis. METHODS: Simvastatin functionalized hydroxyapatite (HSIM) was prepared by stirring and validated by docking studies, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and X-ray diffraction (XRD). Further, HSIM-loaded PLGA nanoparticles (HSIM-PLGA NPs) were developed via the solvent emulsification method. The nanoparticles were evaluated for zeta potential, particle size, entrapment efficiency, stability studies, and in vitro drug release studies. in vitro binding affinity of nanoparticles for hydroxyapatite was also measured. Bone morphology and its effect on bone mineral density were examined by using a glucocorticoid-induced osteoporosis rat model. RESULTS: The optimized nanoparticles were found to be amorphous and showed no drug-polymer interaction. The particle size of formulated nanoparticles varied from 196.8 ± 2.27nm to 524.8 ± 5.49 nm and the entrapment efficiency of nanoparticles varied from 41.9 ± 3.44% to 70.8 ± 4.46%, respectively. The nanoparticles showed sustained release behaviour (75% in 24 hr) of the drug followed by non-fickian drug release. The nanoparticles exhibited high binding affinity to bone cell receptors, increasing bone mineral density. A significant difference in calcium and phosphorous levels was observed in disease and treatment rats. Porous bone and significant improvement in porosity were observed in osteoporotic rats and treated rats, respectively (P < 0.05). CONCLUSION: Bone-targeting nanoparticles incorporating functionalized simvastatin can target bone. Thus, in order to distribute simvastatin subcutaneously for the treatment of osteoporosis, the developed nanoparticles may act as a promising approach.

Applications of poly(lactic acid) in bone tissue engineering: A review article.

BACKGROUND: Bone tissue engineering is a promising approach to large-scale bone regeneration. This involves the use of an artificial extracellular matrix or scaffold and osteoblasts to promote osteogenesis and ossification at defect sites. Scaffolds are constructed using biomaterials that typically have properties similar to those of natural bone. METHOD: In this study, which is a review of the literature, various evidences have been discussed in the field of Poly Lactic acid (PLA) polymer application and modifications made on it in order to induce osteogenesis and repair bone lesions. RESULTS: PLA is a synthetic aliphatic polymer that has been extensively used for scaffold construction in bone tissue engineering owing to its good processability, biocompatibility, and flexibility in design. However, PLA has some drawbacks, including low osteoconductivity, low cellular adhesion, and the possibility of inflammatory reactions owing to acidic discharge in a living environment. To overcome these issues, a combination of PLA and other biomaterials has been introduced. CONCLUSIONS: This short review discusses PLA's characteristics of PLA, its applications in bone regeneration, and its combination with other biomaterials.

Neutrophil hitchhiking for drug delivery to the bone marrow.

Pharmaceuticals have been developed for the treatment of a wide range of bone diseases and disorders, but suffer from problematic delivery to the bone marrow. Neutrophils are naturally trafficked to the bone marrow and can cross the bone marrow-blood barrier. Here we report the use of neutrophils for the targeted delivery of free drugs and drug nanoparticles to the bone marrow. We demonstrate how drug-loaded poly(lactic-co-glycolic acid) nanoparticles are taken up by neutrophils and are then transported across the bone marrow-blood barrier to boost drug concentrations in the bone marrow. We demonstrate application of this principle to two models. In a bone metastasis cancer model, neutrophil delivery is shown to deliver cabazitaxel and significantly inhibit tumour growth. In an induced osteoporosis model, neutrophil delivery of teriparatide is shown to significantly increase bone mineral density and alleviate osteoporosis indicators.

EFFECT OF MAGNESIUM L-LACTATE SUPPLEMENT ON BLOOD PRESSURE AND CORRECTED QT INTERVAL IN A SAMPLE OF IRAQI WOMEN WITH METABOLIC SYNDROME.

OBJECTIVE: The aim: The current study was designed for evaluation the effect of oral magnesium l-lactate supplementation on blood pressure and corrected QT interval in a sample of Iraqi women. PATIENTS AND METHODS: Materials and methods: In this interventional prospective randomized trial, 58 female patients diagnosed with MetS according to the International Diabetic Federation (IDF) criteria and were randomly allocated to receive either placebo or magnesium l-lactate 84 mg, twice daily. RESULTS: Results: O#ce blood pressure showed a signi$cant drop in systolic blood pressure (SBP) (P<0.05), non-significant decline in diastolic blood pressure (DBP), heart rate (HR), and pulse pressure (PP) (P>0.05), while ambulatory blood pressure monitoring (ABPM) recorded a signi$cant reduction in HR in patients on magnesium supplement. Also, there was a signi$cant decline in the SBP (P<0.05) and non-signi$cant decline in DBP and PP (P>0.05) in patients with masked hypertension on Mg supplement. The changes in corrected QT- interval had no signi$cant e"ect within Mg group (P>0.05). CONCLUSION: Conclusions: From above results, one can conclude that oral Mg l-lactate supplement can improve, to a certain extent, blood pressure of women with MetS. Further studies in this aspect may be required.

Tumor lactic acid: a potential target for cancer therapy.

Tumor development is influenced by circulating metabolites and most tumors are exposed to substantially elevated levels of lactic acid and low levels of nutrients, such as glucose and glutamine. Tumor-derived lactic acid, the major circulating carbon metabolite, regulates energy metabolism and cancer cell signaling pathways, while also acting as an energy source and signaling molecule. Recent studies have yielded new insights into the pro-tumorigenic action of lactic acid and its metabolism. These insights suggest an anti-tumor therapeutic strategy targeting the oncometabolite lactic acid, with the aim of improving the efficacy and clinical safety of tumor metabolism inhibitors. This review describes the current understanding of the multifunctional roles of tumor lactic acid, as well as therapeutic approaches targeting lactic acid metabolism, including lactate dehydrogenase and monocarboxylate transporters, for anti-cancer therapy.

Recurrent Sensory-Motor Neuropathy Mimicking CIDP as Predominant Presentation of PDH Deficiency.

INTRODUCTION: Pyruvate dehydrogenase complex (PDH) deficiency (Online Mendelian Inheritance in Man # 312170) is a relatively common mitochondrial disorder, caused by mutations in the X-linked PDHA1 gene and presenting with a variable phenotypic spectrum, ranging from severe infantile encephalopathy to milder chronic neurological disorders.Isolated peripheral neuropathy as predominant clinical presentation is uncommon. RESULTS: We report on a patient, now 21 years old, presenting at the age of 2 years with recurrent symmetric weakness as first symptom of a PDH deficiency. Neurophysiological evaluation proving a sensory-motor polyneuropathy with conduction blocks and presence of elevated cerebrospinal fluid proteins, suggested a chronic inflammatory demyelinating polyneuropathy. The evidence of high serum lactate and the alterations in oxidative metabolism in muscle biopsy pointed toward the final diagnosis. After starting nutritional supplements, no further episodes occurred. A hemizygous mutation in PDHA1 (p.Arg88Cys) was identified. This mutation has been previously described in five patients with a similar phenotype. A three-dimensional reconstruction demonstrated that mutations affecting this arginine destabilize the interactions between the subunits of the E1 complex. CONCLUSION: We summarize the clinical and genetic characteristics of one patient with PDH deficiency presenting isolated peripheral nervous system involvement. This study highlights that the diagnosis of PDH deficiency should be considered in children with unexplained peripheral neuropathy, even with features suggestive of acquired forms, especially in case of early onset and limited response to treatment. A simple analysis of lactic acid could help to target the diagnosis.In addition, we suggest that the residue Arg88 is the most frequently involved in this specific phenotype of PDH deficiency.

Interaction of gentamicin and gentamicin-AOT with poly-(lactide-co-glycolate) in a drug delivery system - density functional theory calculations and molecular dynamics simulation.

Gentamicin is used to treat brucellosis, an infectious disease caused by the Brucella species but the drug faces several issues such as low efficacy, instability, low solubility, and toxicity. It also has a very short half-life, therefore, requiring frequent dosing. Consequently, several other antibiotics are also being used for the treatment of brucellosis as a single dose as well as in combination with other antibiotics but none of these therapies are satisfactory. Nanoparticles in particular polymer-based ones utilizing polymers that are biodegradable and biocompatible for instance PLGA are a method of choice to overcome such drug delivery issues and enable potential targeted delivery. The current study focuses on the evaluation of the structural and dynamical properties of a drug-polymer system consisting of gentamicin drug and PLGA polymer nanoparticles in the water representing a targeted drug delivery system for the treatment of brucellosis. For this purpose, all-atom molecular dynamics simulations were carried out on the drug-polymer systems in the absence and presence of the surfactant bis(2-Ethylhexyl) sulfosuccinate (AOT) to determine the structural and dynamical properties as well as the effect of the surfactant on these properties. We also investigated systems in which the polymer constituents were in the form of monomeric units toward decoupling the primary interactions of the monomer units and polymer effects. The simulation results explain the nature of the interactions between the drug and the polymer as well as transport properties in terms of drug diffusion coefficients, which characterize the molecular behavior of gentamicin-polymer nanoparticles for use in brucellosis.

[Therapy of sepsis]. / Therapie der Sepsis.

Sepsis as a development of an acute infection-related organ dysfunction significantly increases the risk of death for the patient. Therefore, fast and consistent management is required. The sepsis bundle is a convenient algorithm for initial sepsis therapy within the first hour of sepsis diagnosis consisting of blood cultures, lactate measurement, antibiotics, fluid resuscitation, and vasopressor therapy. Cristalloid solutions are first choice for fluid therapy but albumin and gelatine may be considered if colloid solutions are required. Norepinephrine is the vasopressor of first choice. After initial therapy, further fluid resuscitation should be guided by dynamic criteria. Vasopressin may be added as an additional vasopressor. Goal of resuscitation is to achieve lactate clearance. In shock refractory to therapy, addition of hydrocortisone (200 mg/day) should be considered. Further additional therapies such as immunoglobulins, blood purification, and metabolic resuscitation (combination of hydrocortisone, thiamine, vitamine C) are currently not supported by studies and should not be considered as standard therapy.

Engineering lactate-modulating nanomedicines for cancer therapy.

Lactate in tumors has long been considered "metabolic junk" derived from the glycolysis of cancer cells and utilized only as a biomarker of malignancy, but is presently believed to be a pivotal regulator of tumor development, maintenance and metastasis. Indeed, tumor lactate can be a "fuel" for energy supply and functions as a signaling molecule, which actively contributes to tumor progression, angiogenesis, immunosuppression, therapeutic resistance, etc., thus providing promising opportunities for cancer treatment. However, the current approaches for regulating lactate homeostasis with available agents are still challenging, which is mainly due to the short half-life, low bioavailability and poor specificity of these agents and their unsatisfactory therapeutic outcomes. In recent years, lactate modulation nanomedicines have emerged as a charming and efficient strategy for fighting cancer, which play important roles in optimizing the delivery of lactate-modulating agents for more precise and effective modulation and treatment. Integrating specific lactate-modulating functions in diverse therapeutic nanomedicines may overcome the intrinsic restrictions of different therapeutic modalities by remodeling the pathological microenvironment for achieving enhanced cancer therapy. In this review, the most recent advances in the engineering of functional nanomedicines that can modulate tumor lactate for cancer therapy are summarized and discussed, and the fundamental mechanisms by which lactate modulation benefits various therapeutics are elucidated. Finally, the challenges and perspectives of this emerging strategy in the anti-tumor field are highlighted.

Monodisperse CaCO3-loaded gelatin microspheres for reversing lactic acid-induced chemotherapy resistance during TACE treatment.

Transarterial chemoembolization (TACE) is an important approach for the treatment of unresectable hepatocellular carcinoma (HCC). However, the lactic acid-induced acidic tumor microenvironment (TME) may reduce the therapeutic outcome of TACE. Herein, monodispersed gelatin microspheres loaded with calcium carbonate nanoparticles (CaNPs@Gel-MS) as novel embolic agents were prepared by a simplified microfluidic device. It was found that the particle size and homogeneity of as-prepared CaNPs@Gel-MS were strongly dependent on the flow rates of continuous and dispersed phases, and the inner diameter of syringe needle. The introduction of CaNPs provided the gelatin microspheres with an enhanced ability to encapsulate the chemotherapeutic drug of DOX, as well as a pH-responsive sustained drug release behavior. In vitro results revealed that CaNPs@Gel-MS could largely increase the cellular uptake and chemotoxicity of DOX by neutralizing the lactic acid in the culture medium. In addition, CaNPs@Gel-MS exhibited an excellent and persistent embolic efficiency in a rabbit renal model. Finally, we found that TACE treatment with DOX-loaded CaNPs@Gel-MS (DOX/CaNPs@Gel-MS) had a much stronger ability to inhibit tumor growth than the DOX-loaded gelatin microspheres without CaNPs (DOX@Gel-MS). Overall, CaNPs@Gel-MS could be a promising embolic microsphere that can significantly improve anti-HCC ability by reversing lactic acid-induced chemotherapy resistance during TACE treatment.

Cyanide Poisoning and Lactate in Smoke Inhalation.

House fires can lead to cyanide poisoning and an associated elevated serum lactate level. Because of delays in obtaining serum cyanide levels, clinical symptoms and serum lactate are often used to guide clinical decision making and antidote administration. However, as this case report identifies, lower levels of serum lactate may in fact correlate with higher levels of serum cyanide that could benefit from treatment with an antidote.

Lactate modulates microglia polarization via IGFBP6 expression and remodels tumor microenvironment in glioblastoma.

Lactic acidosis has been reported in solid tumor microenvironment (TME) including glioblastoma (GBM). In TME, several signaling molecules, growth factors and metabolites have been identified to induce resistance to chemotherapy and to sustain immune escape. In the early phases of the disease, microglia infiltrates TME, contributing to tumorigenesis rather than counteracting its growth. Insulin-like Growth Factor Binding Protein 6 (IGFBP6) is expressed during tumor development, and it is involved in migration, immune-escape and inflammation, thus providing an attractive target for GBM therapy. Here, we aimed at investigating the crosstalk between lactate metabolism and IGFBP6 in TME and GBM progression. Our results show that microglia exposed to lactate or IGFBP6 significantly increased the Monocarboxylate transporter 1 (MCT1) expression together with genes involved in mitochondrial metabolism. We, also, observed an increase in the M2 markers and a reduction of inducible nitric oxide synthase (iNOS) levels, suggesting a role of lactate/IGFBP6 metabolism in immune-escape activation. GBM cells exposed to lactate also showed increased levels of IGFBP6 and vice-versa. Such a phenomenon was coupled with a IGFBP6-mediated sonic hedgehog (SHH) ignaling increase. We, finally, tested our hypothesis in a GBM zebrafish animal model, where we observed an increase in microglia cells and igfbp6 gene expression after lactate exposure. Our results were confirmed by the analysis of human transcriptomes datasets and immunohistochemical assay from human GBM biopsies, suggesting the existence of a lactate/IGFBP6 crosstalk in microglial cells, so that IGFBP6 expression is regulated by lactate production in GBM cells and in turn modulates microglia polarization.

Dietary lactate supplementation can alleviate DSS-induced colitis in piglets.

Colitis is a common and complex intestinal inflammatory disease in which lactate, a metabolite of anaerobic glycolysis, plays a crucial role. Our study aimed to investigate the alleviated effect of lactate in colitis, and to provide a nutritional measure to alleviate colitis injury. The variations in colonic lactate in piglets with DSS-induced colitis were investigated in Experiment 1 (Exp.1). Thirty weaned pigs were allotted into three groups and sampled at different stages of DSS-induced colitis (days 0, 5, and 7). The colonic level of lactate and interleukin 10 (IL-10) was significantly decreased on day 5 when compared to day 0. Colonic lactate, IL-10, and G protein receptor 81 (GPR81) levels were significantly increased on day 7 when compared to day 5. Sixty weaned piglets were assigned to control (basal diet), DSS (basal diet with DSS gavage), or lactate (2% lactate supplementation diet with DSS gavage) groups to investigate the effects of lactate on DSS-induced colitis in Experiment 2 (Exp.2). Lactate reduced the disease activity index (DAI), DSS-induced impairment of colonic structure in response to the critical inflammatory cytokines interleukin 1ß (IL-1ß) and interleukin 18 (IL-18) when compared with the DSS group. Furthermore, GPR-81 levels, colonic M2 macrophages, and IL-10 levels, the colonic antioxidant capacity, colonic butyrate levels were increased, and eventually improved growth performance post-colitis. The results of this study show that lactate was decreased at the peak of colitis, accumulated in subsidized colitis. Furthermore, dietary lactate supplementation helped to alleviate DSS-induced colitis injury.