The macrophage odorant receptor Olfr78 mediates the lactate-induced M2 phenotype of tumor-associated macrophages

Expression and function of odorant receptors (ORs), which account for more than 50% of G protein–coupled receptors, are being increasingly reported in nonolfactory sites. However, ORs that can be targeted by drugs to treat diseases remain poorly identified. Tumor-derived lactate plays a crucial role in multiple signaling pathways leading to generation of tumor-associated macrophages (TAMs). In this study, we hypothesized that the macrophage OR Olfr78 functions as a lactate sensor and shapes the macrophage–tumor axis. Using Olfr78+/+ and Olfr78−/− bone marrow–derived macrophages with or without exogenous Olfr78 expression, we demonstrated that Olfr78 sensed tumor-derived lactate, which was the main factor in tumor-conditioned media responsible for generation of protumoral M2-TAMs. Olfr78 functioned together with Gpr132 to mediate lactate-induced generation of protumoral M2-TAMs. In addition, syngeneic Olfr78-deficient mice exhibited reduced tumor progression and metastasis together with an increased anti- versus protumoral immune cell population. We propose that the Olfr78–lactate interaction is a therapeutic target to reduce and prevent tumor progression and metastasis.

Monitoring of Lactate in Interstitial Fluid, Saliva and Sweat by Electrochemical Biosensor: The Uncertainties of Biological Interpretation

Lactate electrochemical biosensors were fabricated using Pediococcus sp lactate oxidase (E.C. 1.1.3.2), an external polyurethane membrane laminate diffusion barrier and an internal ionomeric polymer barrier (sulphonated polyether ether sulphone polyether sulphone, SPEES PES). In a needle embodiment, a Pt wire working electrode was retained within stainless steel tubing serving as pseudoreference. The construct gave linearity to at least 25 mM lactate with 0.17 nA/mM lactate sensitivity. A low permeability inner membrane was also unexpectedly able to increase linearity. Responses were oxygen dependent at pO2 < 70 mmHg, irrespective of the inclusion of an external diffusion barrier membrane. Subcutaneous tissue was monitored in Sprague Dawley rats, and saliva and sweat during exercise in human subjects. The tissue sensors registered no response to intravenous Na lactate, indicating a blood-tissue lactate barrier. Salivary lactate allowed tracking of blood lactate during exercise, but lactate levels were substantially lower than those in blood (0–3.5 mM vs. 1.6–12.1 mM), with variable degrees of lactate partitioning from blood, evident both between subjects and at different exercise time points. Sweat lactate during exercise measured up to 23 mM but showed highly inconsistent change as exercise progressed. We conclude that neither tissue interstitial fluid nor sweat are usable as surrogates for blood lactate, and that major reappraisal of lactate sensor use is indicated for any extravascular monitoring strategy for lactate.

Multisensing Wearable Technology for Sweat Biomonitoring

This work describes a multisensing wearable platform for monitoring biomarkers in sweat during the practice of exercise. Five electrochemical sensors for pH, potassium, sodium, chloride, and lactate were implemented in a flexible patch approach, together with a paper microfluidic component, to continuously measure sweat composition. The sensors are fabricated with silicon technologies: ion selective field effect transistors (ISFETs) for pH and ionic species; and a gold thin-film microelectrode for lactate. The latter includes a polymeric membrane based on an electropolymerized polypyrroled structure, where all the biocomponents required for carrying out the lactate analyses are entrapped. The flexible patch is fabricated using hybrid integration technologies, including printed pads defined on a polyimide (Kapton®) substrate and wire bonding encapsulation of silicon chips. To fix and align the sensors to the flexible substrate, different laminated materials, such as polymethyl methacrylate (PMMA), polydimethylsiloxane (PDMS), and silicone-based adhesive, were used. The first results show good performance of the sensors—ISFETS sensitivity between 54–59 mV dec−1 for ion ranges in sweat from 2 to 100 mM and lactate sensor sensitivity of −135 × 102 µA M−1 cm−2 for the range of 2–50 mM. The microfluidic platform has been tested in terms of adequate sensor wettability and rapid response during the time span of exercise activity (2 h) showing excellent results.

A novel device for detecting anaerobic threshold using sweat lactate during exercise

The lactate threshold (LT1), which is defined as the first rise in lactate concentration during incremental exercise, has not been non-invasively and conveniently determined in a clinical setting. We aimed to visualize changes in lactate concentration in sweat during exercise using our wearable lactate sensor and investigate the relationship between the lactate threshold (LT1) and ventilatory threshold (VT1). Twenty-three healthy subjects and 42 patients with cardiovascular diseases (CVDs) were enrolled. During exercise, the dynamic changes in lactate values in sweat were visualized in real-time with a sharp continuous increase up to volitional exhaustion and a gradual decrease during the recovery period. The LT1 in sweat was well correlated with the LT1 in blood and the VT1 (r = 0.92 and 0.71, respectively). In addition, the Bland–Altman plot described no bias between the mean values (mean differences: − 4.5 and 2.5 W, respectively). Continuous monitoring of lactate concentrations during exercise can provide additional information for detecting the VT1.

Abstract 13134: A Novel Device for Detecting Anaerobic Threshold Using Sweat Lactate Acid During Exercise

Background: Continuous monitoring of lactate acid (LA) levels during exercise has not been possible. We aimed to visualize real-time changes in LA levels in sweat during exercise and to investigate the relationship between the lactate threshold in sweat (sLT) and LT in blood (bLT) and the ventilatory threshold (VT). Methods: Twenty-three healthy subjects (age: median; 20 [interquartile range; 20, 21] years old) and 22 consecutive patients (age: 65 [57, 73] years old) with cardiovascular diseases (CVDs) underwent exercise tests with a RAMP protocol ergometer, simultaneously monitoring changes in the LA values in sweat using a wearable lactate sensor. The sLT was identified as the first significant increase in LA above baseline based on the graphical plots and change finder scores calculated by the Change Finder algorithm using the time-series data of the LA values during exercise. We applied the Bland-Altman method to verify similarities for each threshold. Results: During exercise, the dynamic changes in LA values in sweat were successfully visualized in real-time with a sharp continuous increase up to volitional exhaustion and a gradual decrease in the recovery period. In healthy subjects, the work rate (WR) at the sLT (WR-sLT) was substantially correlated with the WR at the bLT (r=0.90). The Bland-Altman plot described a strong agreement (the mean difference: -3.0 watt). Among 22 patients, there were 8 patients whose LA values in sweat were not measured due to a non-response in the sensor. In the remaining 13 cases, except for a patient in whom the VT could not be detected, the sLT was well correlated with bLT and VT (r=0.81 and 0.65, respectively); the mean differences were -8.3 and 3.4, and there was no bias between the mean values. Finally, the logistic regression analysis revealed that a non-response in the sensor was associated with NYHA 3/4 and low peak VO2 (Odds ratio [OR] 0.01 [95% confidence interval (CI); 0.00-0.13], OR 1.45 [95% CI; 1.09-2.20], respectively) Conclusions: Our wearable device enabled a continuous and real-time LA measurement in sweat during incremental exercise in a subset of patients with CVDs as well as healthy subjects. This can provide additional information for detecting the VT.

Selective Nonenzymatic Amperometric Detection of Lactic Acid in Human Sweat Utilizing a Multi-Walled Carbon Nanotube (MWCNT)-Polypyrrole Core-Shell Nanowire

Lactic acid plays an important role as a biochemical indicator for sports medicine and clinical diagnosis. The detection of lactic acid in sweat is a promising technique without any intrusive inconvenience or risk of infection. In this study, we present a selective nonenzymatic amperometric detection method for lactic acid in human sweat utilizing a multi-wall carbon nanotube (MWCNT)-polypyrrole core-shell nanowire. Because polypyrrole is a p-type conducting polymer, onto which anions are exclusively doped, leading to charge transfer, it offers selective detection for lactate anions at a specific potential, while being inert to the neutral and cationic species contained in human sweat. A chronoamperometric study reveals good sensing performance for lactic acid with a high sensitivity of 2.9 μA mM−1 cm−2 and detection limit of 51 μM. Furthermore, the MWCNT-polypyrrole nanowire exhibits excellent selectivity for lactic acid over interfering species, such as sodium chloride, glucose, urea, and riboflavin, which coexist with lactic acid in sweat. Finally, a nonenzymatic amperometric sensor for the selective detection of lactic acid in human sweat is demonstrated on commercial flexible electrodes. The results demonstrate the potential applications of the MWCNT-polypyrrole core-shell nanowire as a nonenzymatic amperometric lactate sensor.