Sleep Loss Can Cause Death through Accumulation of Reactive Oxygen Species in the Gut.

The view that sleep is essential for survival is supported by the ubiquity of this behavior, the apparent existence of sleep-like states in the earliest animals, and the fact that severe sleep loss can be lethal. The cause of this lethality is unknown. Here we show, using flies and mice, that sleep deprivation leads to accumulation of reactive oxygen species (ROS) and consequent oxidative stress, specifically in the gut. ROS are not just correlates of sleep deprivation but drivers of death: their neutralization prevents oxidative stress and allows flies to have a normal lifespan with little to no sleep. The rescue can be achieved with oral antioxidant compounds or with gut-targeted transgenic expression of antioxidant enzymes. We conclude that death upon severe sleep restriction can be caused by oxidative stress, that the gut is central in this process, and that survival without sleep is possible when ROS accumulation is prevented. VIDEO ABSTRACT.

Radical S-Adenosylmethionine Enzymes in Human Health and Disease.

Radical S-adenosylmethionine (SAM) enzymes catalyze an astonishing array of complex and chemically challenging reactions across all domains of life. Of approximately 114,000 of these enzymes, 8 are known to be present in humans: MOCS1, molybdenum cofactor biosynthesis; LIAS, lipoic acid biosynthesis; CDK5RAP1, 2-methylthio-N(6)-isopentenyladenosine biosynthesis; CDKAL1, methylthio-N(6)-threonylcarbamoyladenosine biosynthesis; TYW1, wybutosine biosynthesis; ELP3, 5-methoxycarbonylmethyl uridine; and RSAD1 and viperin, both of unknown function. Aberrations in the genes encoding these proteins result in a variety of diseases. In this review, we summarize the biochemical characterization of these 8 radical S-adenosylmethionine enzymes and, in the context of human health, describe the deleterious effects that result from such genetic mutations.

Harmonizing the cyano-group and Na to enhance selective photocatalytic O2 activation on carbon nitride for refractory pollutant degradation.

Manipulating exciton dissociation and charge-carrier transfer processes to selectively generate free radicals of more robust photocatalytic oxidation capacity for mineralizing refractory pollutants remains challenging. Herein, we propose a strategy by simultaneously introducing the cyano-group and Na into graphitic carbon nitride (CN) to obtain CN-Cy-Na, which makes the charge-carrier transfer pathways the dominant process and consequently achieves the selective generation of free radicals. Briefly, the cyano-group intensifies the local charge density of CN, offering a potential well to attract the hole of exciton, which accelerates the exciton dissociation. Meanwhile, the separated electron transfers efficiently under the robust built-in electric field induced by the cyano-group and Na, and eventually accumulates in the heptazine ring of CN for the following O2 reduction due to the reinforced electron sink effect caused by Na. As a result, CN-Cy-Na exhibits 4.42 mmol L-1 h-1 productivity with 97.6% selectivity for free radicals and achieves 82.1% total organic carbon removal efficiency in the tetracycline photodegradation within 6 h. Additionally, CN-Cy-Na also shows outstanding photodegradation efficiency of refractory pollutants, including antibiotics, pesticide plastic additives, and dyes. This work presents an innovative approach to manipulating the exciton effect and enhancing charge-carrier mobility within two-dimensional photocatalysts, opening an avenue for precise control of free radical generation.

Tailoring the selective generation of oxidative organic radicals for toxic-by-product-free water decontamination.

Peracetic acid (PAA) is emerging as a versatile agent for generating long-lived and selectively oxidative organic radicals (R-O•). Currently, the conventional transition metal-based activation strategies still suffer from metal ion leaching, undesirable by-products formation, and uncontrolled reactive species production. To address these challenges, we present a method employing BiOI with a unique electron structure as a PAA activator, thereby predominantly generating CH3C(O)O• radicals. The specificity of CH3C(O)O• generation ensured the superior performance of the BiOI/PAA system across a wide pH range (2.0 to 11.0), even in the presence of complex interfering substances such as humic acids, chloride ions, bicarbonate ions, and real-world water matrices. Unlike conventional catalytic oxidative methods, the BiOI/PAA system degrades sulfonamides without producing any toxic by-products. Our findings demonstrate the advantages of CH3C(O)O• in water decontamination and pave the way for the development of eco-friendly water decontaminations based on organic peroxides.

Elucidating the photodissociation fingerprint and quantifying the determination of organic hydroperoxides in gas-phase autoxidation.

Hydroperoxides are formed in the atmospheric oxidation of volatile organic compounds, in the combustion autoxidation of fuel, in the cold environment of the interstellar medium, and also in some catalytic reactions. They play crucial roles in the formation and aging of secondary organic aerosols and in fuel autoignition. However, the concentration of organic hydroperoxides is seldom measured, and typical estimates have large uncertainties. In this work, we developed a mild and environmental-friendly method for the synthesis of alkyl hydroperoxides (ROOH) with various structures, and we systematically measured the absolute photoionization cross-sections (PICSs) of the ROOHs using synchrotron vacuum ultraviolet-photoionization mass spectrometry (SVUV-PIMS). A chemical titration method was combined with an SVUV-PIMS measurement to obtain the PICS of 4-hydroperoxy-2-pentanone, a typical molecule for combustion and atmospheric autoxidation ketohydroperoxides (KHPs). We found that organic hydroperoxide cations are largely dissociated by loss of OOH. This fingerprint was used for the identification and accurate quantification of the organic peroxides, and it can therefore be used to improve models for autoxidation chemistry. The synthesis method and photoionization dataset for organic hydroperoxides are useful for studying the chemistry of hydroperoxides and the reaction kinetics of the hydroperoxy radicals and for developing and evaluating kinetic models for the atmospheric autoxidation and combustion autoxidation of the organic compounds.

Spontaneous dark formation of OH radicals at the interface of aqueous atmospheric droplets.

Hydroxyl radical (OH) is a key oxidant that triggers atmospheric oxidation chemistry in both gas and aqueous phases. The current understanding of its aqueous sources is mainly based on known bulk (photo)chemical processes, uptake from gaseous OH, or related to interfacial O3 and NO3 radical-driven chemistry. Here, we present experimental evidence that OH radicals are spontaneously produced at the air-water interface of aqueous droplets in the dark and the absence of known precursors, possibly due to the strong electric field that forms at such interfaces. The measured OH production rates in atmospherically relevant droplets are comparable to or significantly higher than those from known aqueous bulk sources, especially in the dark. As aqueous droplets are ubiquitous in the troposphere, this interfacial source of OH radicals should significantly impact atmospheric multiphase oxidation chemistry, with substantial implications on air quality, climate, and health.

In situ electrogenerated Cu(III) triggers hydroxyl radical production on the Cu-Sb-SnO2 electrode for highly efficient water decontamination.

The electrochemical oxidation process has the unique advantage of in-situ •OH generation for deep mineralization of organic pollutants, which is expected to provide a solution for the globally decentralized wastewater treatment and reuse. However, it is still a great challenge to develop low-cost anodes with ultrahigh •OH yield and low energy consumption. Here, a low-cost and stable mixed metal oxide (MMO) anode (Cu-Sb-SnO2) developed by a simple and scalable preparation process presents extremely high organic pollutants degradation efficiency and low energy consumption. The tetracycline degradation kinetics constant of the Cu-Sb-SnO2 system (0.362 min-1) was 9 to 45 times higher than that of other prepared anodes, which is superior to the existing anodes reported so far. The experimental results and theoretical calculations indicate that the Cu-Sb-SnO2 has moderate oxygen evolution potential, larger water adsorption energy, and lower reaction energy barrier, which is conducive to selective water oxidation to generate •OH. Notably, it is systematically and comprehensively confirmed that the generation of •OH triggered by in situ electrogenerated Cu(III) increased •OH steady-state concentration by over four times. Furthermore, the doped Cu species can play a key role in promoting charge transfer as an "electronic porter" between Sn and Sb in the electrocatalytic process by adjusting the electronic structure of the Sb-SnO2 electrode. This work paves the way for the development of MMO anodes utilizing the advantage of the Cu redox shuttle.

A mineral-based origin of Earth's initial hydrogen peroxide and molecular oxygen.

Terrestrial reactive oxygen species (ROS) may have played a central role in the formation of oxic environments and evolution of early life. The abiotic origin of ROS on the Archean Earth has been heavily studied, and ROS are conventionally thought to have originated from H2O/CO2 dissociation. Here, we report experiments that lead to a mineral-based source of oxygen, rather than water alone. The mechanism involves ROS generation at abraded mineral-water interfaces in various geodynamic processes (e.g., water currents and earthquakes) which are active where free electrons are created via open-shell electrons and point defects, high pressure, water/ice interactions, and combinations of these processes. The experiments reported here show that quartz or silicate minerals may produce reactive oxygen-containing sites (≡SiO•, ≡SiOO•) that initially emerge in cleaving Si-O bonds in silicates and generate ROS during contact with water. Experimental isotope-labeling experiments show that the hydroxylation of the peroxy radical (≡SiOO•) is the predominant pathway for H2O2 generation. This heterogeneous ROS production chemistry allows the transfer of oxygen atoms between water and rocks and alters their isotopic compositions. This process may be pervasive in the natural environment, and mineral-based production of H2O2 and accompanying O2 could occur on Earth and potentially on other terrestrial planets, providing initial oxidants and free oxygen, and be a component in the evolution of life and planetary habitability.

Chemiexcitation and melanin in photoreceptor disc turnover and prevention of macular degeneration.

Age-related macular degeneration, Stargardt disease, and their Abca4-/- mouse model are characterized by accelerated accumulation of the pigment lipofuscin, derived from photoreceptor disc turnover in the retinal pigment epithelium (RPE); lipofuscin accumulation and retinal degeneration both occur earlier in albino mice. Intravitreal injection of superoxide (O2•-) generators reverses lipofuscin accumulation and rescues retinal pathology, but neither the target nor mechanism is known. Here we show that RPE contains thin multi-lamellar membranes (TLMs) resembling photoreceptor discs, which associate with melanolipofuscin granules in pigmented mice but in albinos are 10-fold more abundant and reside in vacuoles. Genetically over-expressing tyrosinase in albinos generates melanosomes and decreases TLM-related lipofuscin. Intravitreal injection of generators of O2•- or nitric oxide (•NO) decreases TLM-related lipofuscin in melanolipofuscin granules of pigmented mice by ~50% in 2 d, but not in albinos. Prompted by evidence that O2•- plus •NO creates a dioxetane on melanin that excites its electrons to a high-energy state (termed "chemiexcitation"), we show that exciting electrons directly using a synthetic dioxetane reverses TLM-related lipofuscin even in albinos; quenching the excited-electron energy blocks this reversal. Melanin chemiexcitation assists in safe photoreceptor disc turnover.

Dual-functional single-atomic Mo/Fe clusters-decorated C3N5 via three electron-pathway in oxygen reduction reaction for tandemly removing contaminants from water.

Inspired by the development of single-atom catalysts (SACs), the fabrication of multimetallic SACs can be a promising technical approach for the in situ electro-Fenton (EF) process. Herein, dual-functional atomically dispersed Mo-Fe sites embedded in carbon nitride (C3N5) (i.e., MoFe/C3N5) were synthesized via a facile SiO2 template method. The atomically isolated bimetallic configuration in MoFe/C3N5 was identified by combining the microscopic and spectroscopic techniques. The MoFe/C3N5 catalyst on the cathode exhibited a remarkable catalytic activity toward the three electron-dominated oxygen reduction reaction in sodium sulfate, leading to a highly effective EF reaction with a low overpotential for the removal of organic contaminants from wastewater. The new catalyst showed a superior performance over its conventional counterparts, owing to the dual functions of the dual-metal active sites. Density functional theory (DFT) analysis revealed that the dual-functional 50-MoFe/C3N5 catalyst enabled a synergistic action of the Mo-Fe dual single atomic centers, which can alter the adsorption/dissociation behavior and decrease the overall reaction barriers for effective organic oxidation during the EF process. This study not only sheds light on the controlled synthesis of atomically isolated catalyst materials but also provides deeper understanding of the structure-performance relationship of the nanocatalysts with dual active sites for the catalytic EF process. Additionally, the findings will promote the advanced catalysis for the treatment of emerging organic contaminants in water and wastewater.

A chemical timer approach to delayed chemiluminescence.

Although the onset time of chemical reactions can be manipulated by mechanical, electrical, and optical methods, its chemical control remains highly challenging. Herein, we report a chemical timer approach for manipulating the emission onset time of chemiluminescence (CL) reactions. A mixture of Mn2+, NaHCO3, and a luminol analog with H2O2 produced reactive oxygen species (ROS) radicals and other superoxo species (superoxide containing complex) with high efficiency, accompanied by strong and immediate CL emission. Surprisingly, the addition of thiourea postponed CL emission in a concentration-dependent manner. The delay was attributed to a slow-generation-scavenging mechanism, which was found to be generally applicable not only to various types of CL reagents and ROS radical scavengers but also to popular chromogenic reactions. The precise regulation of CL kinetics was further utilized in dynamic chemical coding with improved coding density and security. This approach provides a powerful platform for engineering chemical reaction kinetics using chemical timers, which is of application potential in bioassays, biosensors, CL microscopic imaging, microchips, array chips, and informatics.

Severe hypoxaemic hypercapnia compounds cerebral oxidative-nitrosative stress during extreme apnoea: Implications for cerebral bioenergetic function.

We examined the extent to which apnoea-induced extremes of oxygen demand/carbon dioxide production impact redox regulation of cerebral bioenergetic function. Ten ultra-elite apnoeists (six men and four women) performed two maximal dry apnoeas preceded by normoxic normoventilation, resulting in severe end-apnoea hypoxaemic hypercapnia, and hyperoxic hyperventilation designed to ablate hypoxaemia, resulting in hyperoxaemic hypercapnia. Transcerebral exchange of ascorbate radicals (by electron paramagnetic resonance spectroscopy) and nitric oxide metabolites (by tri-iodide chemiluminescence) were calculated as the product of global cerebral blood flow (by duplex ultrasound) and radial arterial (a) to internal jugular venous (v) concentration gradients. Apnoea duration increased from 306 ± 62 s during hypoxaemic hypercapnia to 959 ± 201 s in hyperoxaemic hypercapnia (P ≤ 0.001). Apnoea generally increased global cerebral blood flow (all P ≤ 0.001) but was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose (P = 0.015-0.044). This was associated with a general net cerebral output (v > a) of ascorbate radicals that was greater in hypoxaemic hypercapnia (P = 0.046 vs. hyperoxaemic hypercapnia) and coincided with a selective suppression in plasma nitrite uptake (a > v) and global cerebral blood flow (P = 0.034 to <0.001 vs. hyperoxaemic hypercapnia), implying reduced consumption and delivery of nitric oxide consistent with elevated cerebral oxidative-nitrosative stress. In contrast, we failed to observe equidirectional gradients consistent with S-nitrosohaemoglobin consumption and plasma S-nitrosothiol delivery during apnoea (all P ≥ 0.05). Collectively, these findings highlight a key catalytic role for hypoxaemic hypercapnia in cerebral oxidative-nitrosative stress. KEY POINTS: Local sampling of blood across the cerebral circulation in ultra-elite apnoeists determined the extent to which severe end-apnoea hypoxaemic hypercapnia (prior normoxic normoventilation) and hyperoxaemic hypercapnia (prior hyperoxic hyperventilation) impact free radical-mediated nitric oxide bioavailability and global cerebral bioenergetic function. Apnoea generally increased the net cerebral output of free radicals and suppressed plasma nitrite consumption, thereby reducing delivery of nitric oxide consistent with elevated oxidative-nitrosative stress. The apnoea-induced elevation in global cerebral blood flow was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose. Cerebral oxidative-nitrosative stress was greater during hypoxaemic hypercapnia compared with hyperoxaemic hypercapnia and coincided with a lower apnoea-induced elevation in global cerebral blood flow, highlighting a key catalytic role for hypoxaemia. This applied model of voluntary human asphyxia might have broader implications for the management and treatment of neurological diseases characterized by extremes of oxygen demand and carbon dioxide production.

Multiple oxidative post-translational modifications of human glutamine synthetase mediate peroxynitrite-dependent enzyme inactivation and aggregation.

Glutamine synthetase (GS), which catalyzes the ATP-dependent synthesis of L-glutamine from L-glutamate and ammonia, is a ubiquitous and conserved enzyme that plays a pivotal role in nitrogen metabolism across all life domains. In vertebrates, GS is highly expressed in astrocytes, where its activity sustains the glutamate-glutamine cycle at glutamatergic synapses and is thus essential for maintaining brain homeostasis. In fact, decreased GS levels or activity have been associated with neurodegenerative diseases, with these alterations attributed to oxidative post-translational modifications of the protein, in particular tyrosine nitration. In this study, we expressed and purified human GS (HsGS) and performed an in-depth analysis of its oxidative inactivation by peroxynitrite (ONOO-) in vitro. We found that ONOO- exposure led to a dose-dependent loss of HsGS activity, the oxidation of cysteine, methionine, and tyrosine residues and also the nitration of tryptophan and tyrosine residues. Peptide mapping by LC-MS/MS through combined H216O/H218O trypsin digestion identified up to 10 tyrosine nitration sites and five types of dityrosine cross-links; these modifications were further scrutinized by structural analysis. Tyrosine residues 171, 185, 269, 283, and 336 were the main nitration targets; however, tyrosine-to-phenylalanine HsGS mutants revealed that their sole nitration was not responsible for enzyme inactivation. In addition, we observed that ONOO- induced HsGS aggregation and activity loss. Thiol oxidation was a key modification to elicit aggregation, as it was also induced by hydrogen peroxide treatment. Taken together, our results indicate that multiple oxidative events at various sites are responsible for the inactivation and aggregation of human GS.

The nexus between reactive oxygen species and the mechanism of action of herbicides.

Herbicides are small molecules that act by inhibiting specific molecular target sites within primary plant metabolic pathways resulting in catastrophic and lethal consequences. The stress induced by herbicides generates reactive oxygen species (ROS), but little is known about the nexus between each herbicide mode of action (MoA) and their respective ability to induce ROS formation. Indeed, some herbicides cause dramatic surges in ROS levels as part of their primary MoA, whereas other herbicides may generate some ROS as a secondary effect of the stress they imposed on plants. In this review, we discuss the types of ROS and their respective reactivity and describe their involvement for each known MoA based on the new Herbicide Resistance Action Committee classification.

Screening seven-electron boron-centered radicals for dinitrogen activation.

The activation of dinitrogen is significant as nitrogen-containing compounds play an important role in industries. However, the inert NN triple bond caused by its large HOMO-LUMO gap (10.8 eV) and high bond dissociation energy (945 kJ mol-1 ) renders its activation under mild conditions particularly challenging. Recent progress shows that a few main group species can mimic transition metal complexes to activate dinitrogen. Here, we demonstrate that a series of seven-electron (7e) boron-centered radical can be used to activate N2 via density functional theory calculations. It is found that boron-centered radicals containing amine ligand perform best on the thermodynamics of dinitrogen activation. In addition, when electron-donating groups are introduced at the boron atom, these radicals can be used to activate N2 with low reaction barriers. Further analysis suggests that the electron transfer from the boron atom to the π* orbitals of dinitrogen is essential for its activation. Our findings suggest great potential of 7e boron radicals in the field of dinitrogen activation.

MOFs-Based Nanoagents Enable Sequential Damage to Cancer-Associated Fibroblast and Tumor Cells for Phototriggered Tumor Microenvironment Regulation.

A composite nanoagent capable of phototriggered tumor microenvironment (TME) regulation is developed based on copper (II) metal-organic frameworks (MOFs) with encapsulation of blebbistatin (Bb) and surface modification of fibroblast activation protein-αtargeted peptide (Tp). Tp enables active targeting of the nanoagents to cancer-associated fibroblast (CAF) while near-infrared light triggers Cu2+ -to-Cu+ photoreduction in MOFs, which brings about the collapse of MOFs and the release of Bb and Cu+ . Bb mediates photogeneration of hydroxyl radicals (•OH) and therefore inhibits extracellular matrix production by inducing CAF apoptosis, which facilitates the penetration of nanoagent to deep tumor tissue. The dual-channel generation of •OH based on Bb and the Cu+ species, via distinct mechanisms, synergistically reinforces oxidative stress in TME capable of inducing immunogenic cell death, which activates the antitumor immune response and therefore reverses the immunosuppressive TME. The synergistic antitumor phototherapy efficacy of such a type of nanoagent based on the abovementioned TME remodeling is unequivocally verified in a cell-derived tumor xenograft model.

Construction of Embedded Sulfur-Doped g-C3N4/BiOBr S-Scheme Heterojunction for Highly Efficient Visible Light Photocatalytic Degradation of Organic Compound Rhodamine B.

Constructing S-scheme heterojunction catalysts is a key challenge in visible-light catalysed degradation of organic pollutants. Most heterojunction materials are reported to face significant obstacles in the separation of photogenerated electron-hole pairs owing to differences in the material size and energy barriers. In this study, sulfur-doped g-C3N4 oxidative-type semiconductor materials are synthesized and then coupled with BiOBr reductive-type semiconductor to form S-g-C3N4/BiOBr S-scheme heterojunction. A strong and efficient internal electric field is established between the two materials, facilitating the separation of photogenerated electron-hole pairs. Notably, in situ XPS proved that after visible light irradiation, Bi3+ is converted into Bi(3+ɑ)+, and a large number of photogenerated holes are produced on the surface of BiOBr, which oxidized and activated H2O into •OH.  â€¢OH cooperated with •O2 - and 1O2 to attack Rhodamine B (RhB) molecules to achieve deep oxidation mineralization. The composite material is designed with a LUMO energy level higher than that of RhB, promoting the sensitization of RhB by injecting photogenerated electrons into the heterojunction, thereby enhancing the photocatalytic performance to 22.44 times that of pure g-C3N4. This study provides a new perspective on the efficient degradation of organic molecules using visible light catalysis.

AIBI Modified Mesoporous Copper Sulfide Nanocomposites for Efficient Non-Oxygen Dependent Free Radicals-Assisted Photothermal Therapy in Uveal Melanoma.

Uveal melanoma (UM) is an ocular cancer predominantly affecting adults, characterized by challenging diagnostic outcomes. This research endeavors to develop an innovative multifunctional nanocomposite system sensitive to near-infrared (NIR) radiation, serving as both a non-oxygen free-radical generator and a photothermal agent. The designed system combines azobis isobutyl imidazoline hydrochloride (AIBI) with mesoporous copper sulfide (MCuS) nanoparticles. MCuS harnesses NIR laser energy to induce photothermal therapy, converting light energy into heat to destroy cancer cells. Simultaneously, AIBI is activated by the NIR laser to produce alkyl radicals, which induce DNA damage in remaining cancer cells. This distinctive feature equips the designed system to selectively eliminate cancers in the hypoxic tumor microenvironment. MCuS is also beneficial to scavenge the overexpressed glutathione (GSH) in the tumor microenvironment. GSH generally consumes free radicals and hiders the PDT effect. To enhance control over AIBI release in cancer cells, 1-tetradecyl alcohol (TD), a phase-changing material, is introduced onto the surface of MCuS nanoparticles to create the final AMPT nanoparticle system. In vitro and in vivo experiments confirm the remarkable anti-tumor efficacy of AMPT. Notably, the study introduces an orthotopic tumor model for UM, demonstrating the feasibility of precise and effective targeted treatment within the ocular system.

Constructing Nano-Heterostructure with Dual-Site to Boost H2 O2 Activation and Regulate the Transformation of Free Radicals.

A major issue with Fenton-like reaction is the excessive consumption of H2 O2 caused by the sluggish regeneration rate of low-valent metal, and how to improve the activation efficiency of H2 O2 has become a key in current research. Herein, a nano-heterostructure catalyst (1.0-MnCu/C) based on nano-interface engineering is constructed by supporting Cu and MnO on carbon skeleton, and its kinetic rate for the degradation of tetracycline hydrochloride is 0.0436 min-1 , which is 2.9 times higher than that of Cu/C system (0.0151 min-1 ). The enhancement of removal rate results from the introduced Mn species can aggregate and transfer electrons to Cu sites through the electron bridge Mn-N/O-Cu, thus preventing Cu2+ from oxidizing H2 O2 to form O2 •- , and facilitating the reduction of Cu2+ and generating more reactive oxygen species (1 O2 and ·OH) with stronger oxidation ability, resulting in H2 O2 utilization efficiency is 1.9 times as much as that of Cu/C. Additionally, the good and stable practical application capacity in different bodies demonstrates that it has great potential for practical environmental remediation.

Cannabinoid 2 receptor activation protects against diabetic cardiomyopathy through inhibition of AGE/RAGE-induced oxidative stress, fibrosis, and inflammasome activation.

Oxidative stress, fibrosis, and inflammasome activation from AGE-RAGE interaction contribute to diabetic cardiomyopathy (DCM) formation and progression. Our study revealed the impact of ß-caryophyllene (BCP) on activating CB2 receptors against diabetes complications and investigated the underlying cell signaling pathways in mice. The murine model of DCM was developed by feeding high-fat diet with streptozotocin injections. After the development of diabetes, the animals received a 12-week oral BCP treatment at a dosage of 50 mg/kg/body weight. BCP treatment showed significant improvement in glucose tolerance, insulin resistance, and enhanced serum insulin levels in diabetic animals. BCP treatment effectively reversed the heart remodeling and restored the phosphorylated troponin I and SERCA2a expression. Ultrastructural examination showed reduced myocardial cell injury in DCM mice treated with BCP. The preserved myocytes were found associated with reduced expression of AGE/RAGE in DCM mice hearts. BCP treatment mitigated oxidative stress by inhibiting expression of NOX4 and activating PI3K/AKT/Nrf2 signaling. BCP suppressed cardiac fibrosis and endothelial-to-mesenchymal transition (EndMT) in DCM mice by inhibiting TGF-ß/Smad signaling. Further, BCP treatment suppressed NLRP3 inflammasome activation in DCM mice and alleviated cellular injury to the pancreatic tissues evidenced by significant elevation of the number of insulin-positive cells. To demonstrate CB2 receptor dependent mechanism of BCP, another group of DCM mice were pretreated with AM630, a CB2 receptor antagonist AM630 and AM630 was observed to abrogate the beneficial effects of BCP in DCM mice. Taken together, BCP showed the potential to protect the myocardium and pancreas of DCM mice mediating CB2 receptor dependent mechanisms. Significance Statement 1. ß-caryophyllene (BCP), a cannabinoid type 2 receptor (CB2R) agonist. 2. BCP attenuates diabetic cardiomyopathy via activating CB2R in mice 3. CB2R activation by BCP shows strong protection against fibrosis and inflammasome activation 4. It regulates AGE/RAGE and PI3K/Nrf2/Akt signaling in mice.