bims-kimdis 2022-11-06 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2022–11–06
sixteen papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins

Regulation of gut microbiome by ketogenic diet in neurodegenerative diseases: A molecular crosstalk.
Branched-chain amino acid supplementation suppresses the detraining-induced reduction of mitochondrial content in mouse skeletal muscle.
A Literature Review of the Therapeutic Perspectives of Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitor-Induced Euglycemic Diabetic Ketoacidosis.
Remission of Prurigo Pigmentosa after Breaking Ketogenic Diet and Resuming Regular Diet.
Fuel Selection in Skeletal Muscle Exercising at Low Intensity; Reliance on Carbohydrate in Very Sedentary Individuals.
Mixed effects of moderate exercise and subsequent various food ingestion on breath acetone.
Kynurenic acid ameliorates NLRP3 inflammasome activation by blocking calcium mobilization via GPR35.
Activation of the NLRP3 inflammasome by CCl4 exacerbates hepatopathogenic diet-induced experimental NASH.
Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 Inhibitors and Reaffirmation of the Nutrient Deprivation Signaling/Autophagy Hypothesis.
ATF5 is a regulator of exercise-induced mitochondrial quality control in skeletal muscle.
Coffee reduces the risk of hepatocellular carcinoma probably through inhibition of NLRP3 inflammasome activation by caffeine.
Selective Cross-Ketonization of Carboxylic Acids Enabled by Metallaphotoredox Catalysis.
Inhibition of NLRP3 inflammasome activation by caffeine might be a potential mechanism to reduce the risk of squamous cell carcinoma of the oral cavity and oropharynx with coffee drinking.
A Rare Case of Severe Diabetic Ketoacidosis in a Patient With Metastatic Renal Cell Carcinoma Being Treated With Nivolumab.
Interleukin-18 in metabolism: From mice physiology to human diseases.
Common NLRP3 inflammasome inhibitors and Covid-19: Divide and conquer.

Front Aging Neurosci. 2022 ;14 1015837

Regulation of gut microbiome by ketogenic diet in neurodegenerative diseases: A molecular crosstalk.

Shobana Kaviyarasan, Edmund Lee Chung Sia, Thaarvena Retinasamy, Alina Arulsamy, Mohd Farooq Shaikh.

  The gut taxonomical profile is one of the contributory factors in maintaining homeostasis within the central nervous system (CNS). Of late, the efficacy of diet as a target of treatment, and how various dietary interventions may modulate gut microbiota differently have been an area of focus in research. The role of ketogenic diet (KD) in particular has been well-established in other diseases like intractable epilepsy due to its postulated effects on gut microbiome modulation, resulting in neuronal stability and prevention of epileptogenesis. Therefore, this systematic review aimed to critically evaluate the current available literature investigating the interplay between the three distinct entities: ketogenic diet, neurodegeneration, and gut microbiota, which may serve as a focus guide for future neurodegenerative diseases (ND) therapeutic research. A comprehensive literature search was performed on three databases; PubMed, Scopus, and Ovid Medline. A total of 12 articles were selected for critical appraisal, after subjecting to the inclusion and exclusion criteria in this study. The selected articles revealed that the hopes of KD as a treatment modality for ND are being ventured into as these individuals are said to acquire gut dysbiosis, primarily through increased colonization of phyla Proteobacteria and Firmicutes. Although positive effects including restoration of healthy gut microbes such as Akkermansia Muciphilia sp., improvement in cognitive functioning and decline in neuro-inflammatory markers were noted, this systematic review also depicted conflicting results such as decrease in alpha and beta species diversity as well as diminution of healthy gut commensals such as Bifidobacteriace. In addition, positive neuromodulation were also observed, notably an increase in cerebral blood perfusion to ventromedial hippocampal region via increased expression of eNOS and clearance of amyloid-beta proteins across the blood-brain-barrier via expression of p-glycoprotein. Neuroprotective mechanisms of ketogenic diet also included downregulation of mTOR expression, to prevention acceleration of pathological diseases such as Alzheimer's. Thus due to this conflicting/contrasting results demonstrated by ketogenic diet, such as a decline in gut species richness, diminution in beneficial microbes and decline cognition unless delivered in an intermittent fasting pattern, further studies may still be required before prior recommendation of a ketogenic diet therapeutic regime in ND patients.

Keywords:  brain-gut axis; gut microbiota; high-fat diet; ketogenic diet; neurodegeneration

DOI:  https://doi.org/10.3389/fnagi.2022.1015837
FASEB J. 2022 Dec;36(12): e22628

Branched-chain amino acid supplementation suppresses the detraining-induced reduction of mitochondrial content in mouse skeletal muscle.

Yutaka Matsunaga, Yuki Tamura, Kenya Takahashi, Yu Kitaoka, Yumiko Takahashi, Daisuke Hoshino, Tomoyasu Kadoguchi, Hideo Hatta.

  Exercise training enhances oxidative capacity whereas detraining reduces mitochondrial content in skeletal muscle. The strategy to suppress the detraining-induced reduction of mitochondrial content has not been fully elucidated. As previous studies reported that branched-chain amino acid (BCAA) ingestion increased mitochondrial content in skeletal muscle, we evaluated whether BCAA supplementation could suppress the detraining-induced reduction of mitochondrial content. Six-week-old male Institute of Cancer Research (ICR) mice were randomly divided into four groups as follows: control (Con), endurance training (Tr), detraining (DeTr), and detraining with BCAA supplementation (DeTr + BCAA). Mice in Tr, DeTr, and DeTr + BCAA performed treadmill running exercises [20-30 m/min, 60 min, 5 times/week, 4 weeks]. Then, mice in DeTr and DeTr + BCAA were administered with water or BCAA [0.6 mg/g of body weight, twice daily] for 2 weeks of detraining. In whole skeletal muscle, mitochondrial enzyme activities and protein content were decreased after 2 weeks of detraining, but the reduction was suppressed by BCAA supplementation. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) protein content, a master regulator of mitochondrial biogenesis, was decreased by detraining irrespective of BCAA ingestion. Regarding mitochondrial degradation, BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), a mitophagy-related protein, was significantly higher in the Tr group than in the DeTr + BCAA group, but not different from in the DeTr group. With respect to mitochondrial quality, BCAA ingestion did not affect oxygen consumption rate (OCR) and reactive oxygen species (ROS) production in isolated mitochondria. Our findings suggest that BCAA ingestion suppresses the detraining-induced reduction of mitochondrial content partly through inhibiting mitophagy.

Keywords:  branched-chain amino acid; detraining; mitochondria; mitochondrial biogenesis; mitophagy; skeletal muscle

DOI:  https://doi.org/10.1096/fj.202200588R
Cureus. 2022 Sep;14(9): e29652

A Literature Review of the Therapeutic Perspectives of Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitor-Induced Euglycemic Diabetic Ketoacidosis.

Khyati Patel, Arun Nair.

  Euglycemic diabetic ketoacidosis (DKA), a side effect of sodium-glucose cotransporter-2 (SGLT2) inhibitors, is a triad of high metabolic anion gap acidosis, raised serum and urine ketones, and serum glucose <250 mg/dl. SGLT2 inhibitors cause a carbohydrate deficit by glucosuria, which leads to an increased glucagon/insulin ratio, the metabolic shift from glucose to lipid utilization causing ketogenesis, and hence euglycemic DKA. Additional factors like the ketogenic diet, illness, surgery, and pregnancy contribute to precipitating these episodes. Keywords search included "Euglycemic DKA and SGLT2 inhibitors" in PubMed and Google Scholar, to compile data from existing articles that provide information on the withholding and restarting period of the drug after a euglycemic DKA episode. SGLT2 inhibitors, used in the treatment of type 2 DM, have an average half-life of 11-13 hours, so most articles suggested withholding the drug three days before any elective surgery but some articles suggested a longer withholding period based on other precipitating factors contributing to euglycemic DKA. Hence, we came up with patient inclusion criteria and concomitant therapies review that we need to consider in making this decision. In addition, a multidisciplinary approach is required when laying out guidelines for restarting the drug to have a unanimous approach. After reviewing the existing literature, it is clear that concrete guidelines are required to decide on drug withholding and restarting periods after a euglycemic DKA episode, as they vary among different institutions and different specialties. We believe it is crucial to consider patient inclusion criteria and concomitant therapies in forming those guidelines.

Keywords:  diabetes mellitus type 2; diabetic ketoacidosis (dka); dka with normal blood glucose; euglycaemic diabetic ketoacidosis; euglycemic dka; precipitating factors for euglycemic dka; sglt 2 inhibitor; sodium-glucose cotransporter 2 (sglt-2) inhibitors; treatment of euglycaemic diabetic ketoacidosis; withholding period of sglt2 inhibitor

DOI:  https://doi.org/10.7759/cureus.29652
Adv Biomed Res. 2022 ;11 70

Remission of Prurigo Pigmentosa after Breaking Ketogenic Diet and Resuming Regular Diet.

Maryam Daneshpazhooh, Zahra Nikyar, Kambiz Kamyab Hesari, Ehsan Rostami, Shirin Taraz Jamshidi, Fatemeh Mohaghegh.

  Prurigo pigmentosa (PP) is a rare skin disorder presenting as erythematous urticarial papules on the chest and leaving reticulated pigmentation. Although the etiology of PP is unknown, conditions associated with ketosis such as diabetes mellitus, ketogenic diet (KD), and anorexia nervosa are implicated. Herein, we report a 21-year-old woman who developed PP after adhering to a KD and responded to resuming a regular diet.

Keywords:  Ketogenic diet; prurigo pigmentosa; treatment

DOI:  https://doi.org/10.4103/abr.abr_138_21
Metab Syndr Relat Disord. 2022 Nov 01.

Fuel Selection in Skeletal Muscle Exercising at Low Intensity; Reliance on Carbohydrate in Very Sedentary Individuals.

Neusha Barakati, Rocio Zapata Bustos, Dawn K Coletta, Paul R Langlais, Lindsay N Kohler, Moulun Luo, Janet L Funk, Wayne T Willis, Lawrence J Mandarino.

  Background: Resting skeletal muscle in insulin resistance prefers to oxidize carbohydrate rather than lipid, exhibiting metabolic inflexibility. Although this is established in resting muscle, complexities involved in directly measuring fuel oxidation using indirect calorimetry across a muscle bed have limited studies of this phenomenon in working skeletal muscle. During mild exercise and at rest, whole-body indirect calorimetry imperfectly estimates muscle fuel oxidation. We provide evidence that a method termed "ΔRER" can reasonably estimate fuel oxidation in skeletal muscle activated by exercise. Methods: Completely sedentary volunteers (n = 20, age 31 ± 2 years, V̇O2peak 24.4 ± 1.5 mL O2 per min/kg) underwent glucose clamps to determine insulin sensitivity and graded exercise consisting of three periods of mild steady-state cycle ergometry (15, 30, 45 watts, or 10%, 20%, and 30% of maximum power) with measurements of whole-body gas exchange. ΔRER, the RER in working muscle, was calculated as (V̇CO2exercise -V̇CO2rest)/(V̇O2exercise - V̇O2rest), from which the fraction of fuel accounted for by lipid was estimated. Results: Lactate levels were low and stable during steady-state exercise. Muscle biopsies were used to estimate mitochondrial content. The rise of V̇O2 at onset of exercise followed a monoexponential function, with a time constant of 51 ± 7 sec, typical of skeletal muscle; the average O2 cost of work was about 12 mL O2/watt/min, representing a mechanical efficiency of about 24%. At work rates of 30 or 45 watts, active muscle relied predominantly on carbohydrate, independent of insulin sensitivity within this group of very sedentary volunteers. Conclusions: The fraction of muscle fuel oxidation from fat was predicted by power output (P < 0.001) and citrate synthase activity (P < 0.05), indicating that low mitochondrial content may be the main driver of fuel choice in sedentary people, independent of insulin sensitivity.

Keywords:  exercise; indirect calorimetry; metabolic flexibility; skeletal muscle

DOI:  https://doi.org/10.1089/met.2022.0062
J Breath Res. 2022 Oct 31.

Mixed effects of moderate exercise and subsequent various food ingestion on breath acetone.

Koichiro Nagamine, Daiki Mineta, Koji Ishida, Keisho Katayama, Takaharu Kondo.

  Acetone, which is exhaled with breath, is a by-product of lipolysis and could be used as a simple, useful indicator of lipolysis in the body because, unlike blood sampling, it can be measured non-invasively and repeatedly. Breath acetone concentration, however, is known to be affected by several factors such as exercise and food. We designed the experiments to evaluate the mixed effect on breath acetone of exercise and food ingestion in order to enhance the usefulness of breath acetone for monitoring fat loss. Seven healthy males performed moderate exercise for twice of 45 minutes with an interval of 15 minutes then rested for 4 hours. Exhaled air was sampled every 15 minutes throughout the experiment. The subjects took one of four types, sugar-rich, balanced, protein-rich and fat-rich, of food as lunch one hour after the exercises or kept fasting. In the case of fasting, breath acetone kept increasing significantly (p<0.05) compared with the rest value after the exercises until the end of the experiment. In contrast, in the case of taking any type of food, the change in breath acetone varied according to the food type. In the case of taking sugar-rich food, breath acetone significantly decreased (p<0.05) compared with the fasting case. This decrease might be due to a suppression of acetone production when carbohydrates such as sugar are supplied to a body in the fasting condition. In contrast, in the case of taking fat-rich food, breath acetone showed the higher level than the fasting case. This additional increase might be attributable to the promotion of ketone bodies production, including acetone, due to the ingestion of medium chain triglycerides (MCT) contained in the fat-rich food. We should therefore consider exercise and food ingestion in using breath acetone as a non-invasive indicator of lipolysis.

Keywords:  breath acetone; exercise; food ingestion; lipolysis

DOI:  https://doi.org/10.1088/1752-7163/ac9ed4
Front Immunol. 2022 ;13 1019365

Kynurenic acid ameliorates NLRP3 inflammasome activation by blocking calcium mobilization via GPR35.

Tianyin Sun, Ruiqian Xie, Hongbin He, Qianqian Xie, Xueqin Zhao, Guijie Kang, Chen Cheng, Wenwei Yin, Jingjing Cong, Jing Li, Xuefu Wang.

  The inflammasome has been linked to diverse inflammatory and metabolic diseases, and tight control of inflammasome activation is necessary to avoid excessive inflammation. Kynurenic acid (KA) is a tryptophan metabolite in the kynurenine pathway. However, the roles and mechanisms of the regulation of inflammasome activation by KA have not yet been fully elucidated. Here, we found that KA suppressed caspase-1 activation and IL-1β production in macrophages by specifically inhibiting canonical and noncanonical activation of the NLRP3 inflammasome. Mechanistically, KA reduced calcium mobilization through G-protein receptor 35 (GPR35), resulting in reduced mitochondrial damage and decreased mtROS production, thus blocking NLRP3 inflammasome assembly and activation. Importantly, KA prevented lipopolysaccharide-induced systemic inflammation, monosodium urate-induced peritoneal inflammation, and high-fat diet-induced metabolic disorder. Thus, KA ameliorated inflammation and metabolic disorders by blocking calcium mobilization-mediated NLRP3 inflammasome activation via GPR35. Our data reveal a novel mechanism for KA in the modulation of inflammasome activation and suggest that GPR35 might be a promising target for improving NLRP3 inflammasome-associated diseases by regulating calcium mobilization.

Keywords:  GPR35; NLRP3 inflammasome; kynurenic acid; metabolic disorder; systemic inflammation

DOI:  https://doi.org/10.3389/fimmu.2022.1019365
Ann Hepatol. 2022 Oct 26. pii: S1665-2681(22)00122-3. [Epub ahead of print] 100780

Activation of the NLRP3 inflammasome by CCl4 exacerbates hepatopathogenic diet-induced experimental NASH.

Eduardo E Vargas-Pozada, Erika Ramos-Tovar, Juan D Rodriguez-Callejas, Irina Cardoso-Lezama, Silvia Galindo-Gómez, Karla Gil-Becerril, Verónica Rocío Vásquez-Garzón, Jaime Arellanes-Robledo, Víctor Tsutsumi, Saúl Villa-Treviño, Pablo Muriel.

   INTRODUCTION AND OBJECTIVES: Administration of carbon tetrachloride (CCl4), along with an hepatopathogenic diet, is widely employed as a chemical inducer to replicate human nonalcoholic steatohepatitis (NASH) in rodents; however, the role of the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome in this model remains unclear. We aimed to determine the relevance of NLRP3 inflammasome activation in the development of NASH induced by CCl4 along with an hepatopathogenic diet in male Wistar rats.
MATERIALS AND METHODS: Animals were fed either a high fat, sucrose, and cholesterol diet (HFSCD) or a HFSCD plus intraperitoneal injections of low doses of CCl4 (400 mg/kg) once a week for 15 weeks. Liver steatosis, inflammation, fibrosis, and NLRP3 inflammasome activation were evaluated using biochemical, histological, ultrastructural, and immunofluorescence analyses, western blotting, and immunohistochemistry.
RESULTS: Our experimental model reproduced several aspects of the human NASH pathophysiology. NLRP3 inflammasome activation was induced by the combined effect of HFSCD plus CCl4 and significantly increased levels of both proinflammatory and profibrogenic cytokines and collagen deposition in the liver; thus, NASH severity was higher in the HFSCD+CCl4 group than that in the HFSCD group, to which CCl4 was not administered. Hepatic stellate cells, the most profibrogenic cells, were activated by HFSCD plus CCl4, as indicated by elevated levels of α-smooth muscle actin. Thus, activation of the NLRP3 inflammasome, triggered by low doses of CCl4, exacerbates the severity of NASH.
CONCLUSIONS: Our results indicate that NLRP3 inflammasome activation plays a key role and may be an important therapeutic target for NASH treatment.

Keywords:  CCl(4); NASH; NLRP3 inflammasome; fibrosis; inflammation; nonalcoholic steatohepatitis

DOI:  https://doi.org/10.1016/j.aohep.2022.100780
Circulation. 2022 Nov;146(18): 1383-1405

Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 Inhibitors and Reaffirmation of the Nutrient Deprivation Signaling/Autophagy Hypothesis.

Milton Packer.

  SGLT2 (sodium-glucose cotransporter 2) inhibitors produce a distinctive pattern of benefits on the evolution and progression of cardiomyopathy and nephropathy, which is characterized by a reduction in oxidative and endoplasmic reticulum stress, restoration of mitochondrial health and enhanced mitochondrial biogenesis, a decrease in proinflammatory and profibrotic pathways, and preservation of cellular and organ integrity and viability. A substantial body of evidence indicates that this characteristic pattern of responses can be explained by the action of SGLT2 inhibitors to promote cellular housekeeping by enhancing autophagic flux, an effect that may be related to the action of these drugs to produce simultaneous upregulation of nutrient deprivation signaling and downregulation of nutrient surplus signaling, as manifested by an increase in the expression and activity of AMPK (adenosine monophosphate-activated protein kinase), SIRT1 (sirtuin 1), SIRT3 (sirtuin 3), SIRT6 (sirtuin 6), and PGC1-α (peroxisome proliferator-activated receptor γ coactivator 1-α) and decreased activation of mTOR (mammalian target of rapamycin). The distinctive pattern of cardioprotective and renoprotective effects of SGLT2 inhibitors is abolished by specific inhibition or knockdown of autophagy, AMPK, and sirtuins. In the clinical setting, the pattern of differentially increased proteins identified in proteomics analyses of blood collected in randomized trials is consistent with these findings. Clinical studies have also shown that SGLT2 inhibitors promote gluconeogenesis, ketogenesis, and erythrocytosis and reduce uricemia, the hallmarks of nutrient deprivation signaling and the principal statistical mediators of the ability of SGLT2 inhibitors to reduce the risk of heart failure and serious renal events. The action of SGLT2 inhibitors to augment autophagic flux is seen in isolated cells and tissues that do not express SGLT2 and are not exposed to changes in environmental glucose or ketones and may be related to an ability of these drugs to bind directly to sirtuins or mTOR. Changes in renal or cardiovascular physiology or metabolism cannot explain the benefits of SGLT2 inhibitors either experimentally or clinically. The direct molecular effects of SGLT2 inhibitors in isolated cells are consistent with the concept that SGLT2 acts as a nutrient surplus sensor, and thus, its inhibition causes enhanced nutrient deprivation signaling and its attendant cytoprotective effects, which can be abolished by specific inhibition or knockdown of AMPK, sirtuins, and autophagic flux.

Keywords:  TOR serine-threonine kinases; autophagy; heart failure; sirtuins; sodium-glucose transporter 2 inhibitors

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.122.061732
Mol Metab. 2022 Nov 01. pii: S2212-8778(22)00192-2. [Epub ahead of print] 101623

ATF5 is a regulator of exercise-induced mitochondrial quality control in skeletal muscle.

Mikhaela B Slavin, Rita Kumari, David A Hood.

   OBJECTIVES: The Mitochondrial Unfolded Protein Response (UPRmt) is a compartment-specific mitochondrial quality control (MQC) mechanism that uses the transcription factor ATF5 to induce the expression of protective enzymes to restore mitochondrial function. Acute exercise is a stressor that has the potential to temporarily disrupt organellar protein homeostasis, however, the roles of ATF5 and the UPRmt in maintaining basal mitochondrial content, function and exercise-induced MQC mechanisms in skeletal muscle are not known.
METHODS: ATF5 KO and WT mice were examined at rest or after a bout of acute endurance exercise. We measured protein content in whole muscle, nuclear, cytosolic and mitochondrial fractions, in addition to mRNA transcript levels in whole muscle. Using isolated mitochondria, we quantified rates of oxygen consumption and ROS emission to observe the effects of the absence of ATF5 on organelle function.
RESULTS: ATF5 KO mice exhibited a larger and less functional muscle mitochondrial pool, most likely a culmination of enhanced biogenesis via increased PGC-1 α expression, and attenuated mitophagy. The absence of ATF5 resulted in a reduction in antioxidant proteins and increases in mitochondrial ROS emission, cytosolic cytochrome c, and the expression of mitochondrial chaperones. KO muscle also displayed enhanced exercise-induced stress kinase signaling, but a blunted mitophagic and UPRmt gene expression response, complemented by significant increases in the basal mRNA abundance and nuclear localization of ATF4. Instead of promoting its nuclear translocation, acute exercise caused the enrichment of ATF5 in mitochondrial fractions. We also identified PGC-1 α as an additional regulator of the basal expression of UPRmt genes.
CONCLUSION: The transcription factor ATF5 retains a critical role in the maintenance of mitochondrial homeostasis and the appropriate response of muscle to acute exercise for the optimization of mitochondrial quality control.

Keywords:  Exercise; Mitochondria; Mitochondrial Quality Control; Mitochondrial Unfolded Protein Response (UPR(mt)); Protein Homeostasis; Skeletal Muscle

DOI:  https://doi.org/10.1016/j.molmet.2022.101623
Front Oncol. 2022 ;12 1029491

Coffee reduces the risk of hepatocellular carcinoma probably through inhibition of NLRP3 inflammasome activation by caffeine.

Frank S Fan.



Keywords:  NLRP3 inflammasome; caffeine; coffee; hepatocellular carcinoma; pyroptosis

DOI:  https://doi.org/10.3389/fonc.2022.1029491
Angew Chem Int Ed Engl. 2022 Nov 01.

Selective Cross-Ketonization of Carboxylic Acids Enabled by Metallaphotoredox Catalysis.

Andrew Whyte, Tehshik Peter Yoon.

  Carboxylic acids are attractive building blocks for synthetic chemistry because they are chemically stable, abundant, and commercially available with substantial structural diversity. The process of combining two carboxylic acids to furnish a ketone is termed ketonization. This is a potentially valuable transformation that has been underutilized in organic synthesis due to the harsh reaction conditions generally required and the lack of selectivity obtained when coupling two distinct carboxylic acids. We report herein a metallaphotoredox strategy that selectively generates unsymmetrical ketones via cross-ketonization of two structurally dissimilar carboxylic acids. Cross-selectivity is achieved by exploiting diverging reactivity of differentially substituted acids towards critical one- and two-electron processes in the proposed coupling mechanism. This method is broadly applicable to a variety of functionalized carboxylic acids. It can also be applied to acids of similar steric profile by exploiting differences in their relative rates of decarboxylation.

Keywords:  Photocatalysis; carboxylic acids; cross-coupling; ketonization; radical reactions

DOI:  https://doi.org/10.1002/anie.202213739
Front Oral Health. 2022 ;3 1017543

Inhibition of NLRP3 inflammasome activation by caffeine might be a potential mechanism to reduce the risk of squamous cell carcinoma of the oral cavity and oropharynx with coffee drinking.

Frank S Fan.



Keywords:  NLRP3 inflammasome; caffeine; coffee; oral cavity; oropharynx; squamous cell carcinoma

DOI:  https://doi.org/10.3389/froh.2022.1017543
Cureus. 2022 Sep;14(9): e29537

A Rare Case of Severe Diabetic Ketoacidosis in a Patient With Metastatic Renal Cell Carcinoma Being Treated With Nivolumab.

Talal Bazzi, Eisha Gupta, Ayman Mohamed, Megha Vashi.

  Immune checkpoint inhibitors are becoming of more use as clinicians are prescribing them for patients with different malignancies. As their use continues to increase, clinicians must be aware of the side effects, which are autoimmune in nature. Autoimmune diabetes has been described in the past while patients were being treated with programmed cell death protein 1 (PD-1) inhibitors, but it usually occurs after the patient's fourth or fifth cycle. In this case presentation, we describe a patient with no history of type 1 or 2 diabetes presenting to the emergency department with severe diabetic ketoacidosis. At the time of presentation, he was on his 22nd cycle of nivolumab for metastatic renal cell carcinoma. The patient was eventually treated successfully, but upon discharge, he was prescribed a large dose of insulin regimen to control his blood sugar levels at home. We attributed his new diagnosis of insulin-dependent diabetes to the PD-1 inhibitor nivolumab.

Keywords:  autoimmune diabetes; cancer treatment; cancer treatment side effects; diabetic ketoacidosis; metastatic renal cell carcinoma; nivolumab; nivolumab-related adverse events

DOI:  https://doi.org/10.7759/cureus.29537
Front Endocrinol (Lausanne). 2022 ;13 971745

Interleukin-18 in metabolism: From mice physiology to human diseases.

Emmanuel Somm, François R Jornayvaz.

  Interleukin-18 (IL-18) is a classical member of the IL-1 superfamily of cytokines. As IL-1β, IL-18 precursor is processed by inflammasome/caspase-1 into a mature and biologically active form. IL-18 binds to its specific receptor composed of two chains (IL-18Rα and IL-18Rβ) to trigger a similar intracellular signaling pathway as IL-1, ultimately leading to activation of NF-κB and inflammatory processes. Independently of this IL-1-like signaling, IL-18 also specifically induces IFN-γ production, driving the Th1 immune response. In circulation, IL-18 binds to the IL-18 binding protein (IL-18BP) with high affinity, letting only a small fraction of free IL-18 able to trigger receptor-mediated signaling. In contrast to other IL-1 family members, IL-18 is produced constitutively by different cell types, suggesting implications in normal physiology. If the roles of IL-18 in inflammatory processes and infectious diseases are well described, recent experimental studies in mice have highlighted the action of IL-18 signaling in the control of energy homeostasis, pancreatic islet immunity and liver integrity during nutritional stress. At the same time, clinical observations implicate IL-18 in various metabolic diseases including obesity, type 1 and 2 diabetes and nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). In the present review, we summarize and discuss both the physiological actions of IL-18 in metabolism and its potential roles in pathophysiological mechanisms leading to the most common human metabolic disorders, such as obesity, diabetes and NAFLD/NASH.

Keywords:  NAFLD; NASH; diabetes mellitus; gut microbiota; inflammation; interleukin-18; obesity

DOI:  https://doi.org/10.3389/fendo.2022.971745
Sci Afr. 2022 Nov;18 e01407

Common NLRP3 inflammasome inhibitors and Covid-19: Divide and conquer.

Gaber El-Saber Batiha, Ali I Al-Gareeb, Damilare Rotimi, Oluyomi Stephen Adeyemi, Hayder M Al-Kuraishy.

  Severe SARS-CoV-2 infection causes systemic inflammation, cytokine storm, and hypercytokinemia due to activation of the release of pro-inflammatory cytokines that have been associated with case-fatality rate. The immune overreaction and cytokine storm in the infection caused by SARS-CoV-2 may be linked to NLRP3 inflammasome activation which has supreme importance in human innate immune response mainly against viral infections. In SARS-CoV-2 infection, NLRP3 inflammasome activation results in the stimulation and synthesis of natural killer cells (NKs), NFκB, and interferon-gamma (INF-γ), while inhibiting IL-33 expression. Various efforts have identified selective inhibitors of NLRP3 inflammasome. To achieve this, studies are exploring the screening of natural compounds and/or repurposing of clinical drugs to identify potential NLRP3 inhibitors. NLRP3 inflammasome inhibitors are expected to suppress exaggerated immune reaction and cytokine storm-induced-organ damage in SARS-CoV-2 infection. Therefore, NLRP3 inflammasome inhibitors could mitigate the immune-overreaction and hypercytokinemia in Covid-19 infection.

Keywords:  Covid-19; NLRP3 inflammasomes; SARS-CoV-2; Therapeutic inhibitors

DOI:  https://doi.org/10.1016/j.sciaf.2022.e01407