Quinine Research Articles

Analysis of Immunobiochemical Parameters in Overweight People in Assessing the Risk of Cardiovascular Diseases

A comparative analysis of specific immunobiochemical parameters, including natural antibodies (NAb) to endogenous regulators of the cardiovascular system, adrenal and gastrointestinal hormones, was performed in students aged 18-22 years with normal and increased body weight (the body mass index from 18.5 to 24.9 kg/m2 and from 25 to 29.9 kg/m2, respectively). The serum content of NAb and hormones was determined by ELISA. The level of the studied indicators depended on the body mass index value. In overweight subjects, the main immune indicators of the biogenic amine system, renin-angiotensin system, and kinin system exceeded the normal. The cortisol level was higher than in subjects with normal body weight. Aldosterone secretion was less dependent on the ACTH content and was lower than in students with normal body weight. The content of cholecystokinin and gastrin corresponded to the values for overweight. These trends in hormone contents are a predisposing factor for further weight gain. Practical significance of the combined assessment of disturbances in the immunological and biochemical homeostasis has been established. Analysis of the adrenal and gastrointestinal hormones can predict the risk of weight gain, but at the same time, changes in the level of immunological indicators in subjects with increased body weight characterizes the possibility of developing cardiovascular pathologies.

Mutant plasminogen in hereditary angioedema is bypassing FXII/kallikrein to generate bradykinin.

Hereditary angioedema (HAE) is characterized by recurrent localized edema in various organs, which can be potentially fatal. There are different types of hereditary angioedema, which include genetic deficiency of C1 inhibitor (C1-INH) and hereditary angioedema with normal C1-INH (HAEnCI). In HAEnCI patients mutations have been identified in the F12, PLG, KNG1, ANGPT1, MYOF, and HS3ST6 genes. The release of bradykinin from kininogen via the kallikrein-kinin system (KKS) has been shown to be the main mediator in HAE-FXII, but for HAE-PLG there are only first indications how the PLG mutations can result in bradykinin release. Here we identified in a multi-generation HAE-PLG family an additional F12 mutation, resulting in the loss of one F12 allele. There were no differences in the clinical presentation between HAE-PLG patients with and without the additional F12 mutation, thus we concluded that the kallikrein-kinin system is bypassed in HAE-PLG. Structural modeling and in vitro assays using purified proteins confirmed the PLG mutation c.988A>G; p.K330E to be a gain of function mutation resulting in an increased bradykinin release by direct cleavage of high molecular weight kininogen (HMWK). Thus, we can provide clinical and experimental evidence that mutant plasminogen in HAE-PLG is bypassing FXII/kallikrein to generate bradykinin.

Fixed-Dose Combination (FDC) Formulation of Quinine Sulphate-Doxycycline (Qidox) for Malaria Therapy

Background: One of the deadliest parasite infections is malaria. A combination of quinine sulphate and doxycycline is another therapeutic option for malaria that is resistant to chloroquine and is anticipated to be able to both combat the issue of anti-malarial medication resistance as well as the compliance to malaria therapy that is still raging in certain locations of Indonesia. Aim: This study will focus on evaluating the possibility of interaction between quinine sulphate and doxycycline followed by formulating the fixed-dose combination of both active pharmaceutical ingredients. Method: The study was designed as a laboratory experiment and applied some examinations. The examination from the organoleptic test of active pharmaceutical ingredients powder, crystallography analysis, and physical analysis of fixed-dose tablet including hardness, friability, and disintegration time testing. Result: The crystallography study reported there was no physical interaction found between quinine sulphate and doxycycline. The formula found excellent tablet printability with a composition of Quinine sulphate and doxycycline (Qidox). Conclusion: quinine sulphate with doxycycline can be combined into one tablet as Fixed-Dose Combination (FDC).

Palatability Profile In Spontaneously Hypertensive Rats.

The spontaneously hypertensive rats (SHRs) have enhanced palatability for NaCl taste as measured by the increased number of hedonic versus aversive responses to intraoral infusion (1ml/1min) of 0.3 M NaCl, in a taste reactivity test in euhydrated condition or after 24h of water deprivation + 2h of partial rehydration (WD-PR). SHRs also ingested more sucrose than normotensive rats, without differences in quinine hydrochloride intake. Here, we investigated the palatability of SHRs (n=8-10) and normotensive Holtzman rats (n=8-10) to sucrose and quinine sulphate infused intraorally in the same conditions that NaCl palatability was increased in SHRs. SHRs had similar number of hedonic responses to 2% sucrose in euhydrated condition (95 ± 19) or after WD-PR (142 ± 25), responses increased when compared to normotensive rats in euhydrated condition (13 ± 3) or after WD-PR (21 ± 6). SHRs also showed increased number of aversive responses to 1.4mM quinine sulphate compared to normotensive rats, whether in euhydrated condition (86 ± 6, vs. normotensive: 54 ± 7) or after WD-PR (89 ± 9, vs. normotensive: 40 ± 9). The results suggest that similar to NaCl taste, sweet taste responses are increased in SHRs and resistant to challenges in bodily fluid balance. They also showed a more intense aversive response in SHRs to bitter taste compared to normotensives. This suggests that the enhanced response of SHRs to taste rewards does not correspond to a decreased response to a typical aversive taste.

Quantitative detection of RAS and KKS peptides in COVID-19 patient serum by stable isotope dimethyl labeling LC-MS.

Angiotensin and kinin metabolic pathways are reported to be altered by many diseases, including COVID-19. Monitoring levels of these peptide metabolites is important for understanding mechanisms of disease processes. In this paper, we report dimethyl labeling of amines in peptides by addition of formaldehyde to samples and deutero-formaldehyde to internal standards to generate nearly identical isotopic standards with 4 m/z units larger per amine group than the corresponding analyte. We apply this approach to rapid, multiplexed, absolute LC-MS/MS quantitation of renin angiotensin system (RAS) and kallikrein-kinin system (KKS) peptides in human blood serum. Limits of detection (LODs) were obtained in the low pg mL-1 range with 3 orders of magnitude dynamic ranges, appropriate for determinations of normal and elevated levels of the target peptides in blood serum and plasma. Accuracy is within ±15% at concentrations above the limit of quantitation, as validated by spike-recovery in serum samples. Applicability was demonstrated by measuring RAS and KKS peptides in serum from COVID-19 patients, but is extendable to any class of peptides or other small molecules bearing reactive -NH2 groups.

Solid-state silica gel-catalyzed synthesis of fluorescent polysubstituted 1,4- and 1,2-dihydropyridines.

We present the green, highly atom-economical, solid-state silica gel-catalyzed synthesis of polysubstituted 1,4- and 1,2-dihydropyridines (DHPs) from commercially available materials, amines and ethyl propiolate. The DHP skeleton was assembled by heating the reactants and silica gel in a closed vessel. Aliphatic amines provided 1,4-isomers as the main or only DHP products, but the reactions of aromatic amines yielded a mixture of 1,4- and 1,2-isomers. To the best of our knowledge, this is the first example of the formation of a 1,2-DHP structure by the reaction of an amine with propiolic ester. Addition of 1 mass percent of H2SO4 to silica gel shifted the product distribution to 1,4-DHP as the main or the only isomer obtained. Experimental and theoretical analyses led to the identification of two key intermediates en route to DHPs and the explanation of the observed regioisomeric ratios. 1,2-DHPs show blue-cyan fluorescence in MeOH with the quantum yield Φ = 0.10-0.22 relative to quinine sulfate Φ = 0.58 and 1,4-DHPs show blue-violet fluorescence with Φ = 0.09-0.81.

Review of Suprachoroidal Delivery and its Application in Small Molecule Therapy

Therapies for retinal diseases have witnessed remarkable progress, particularly in the domain of drug delivery routes. Intravitreal injections have especially revolutionized the treatment landscape for various proliferative retinopathies. The emergence of suprachoroidal space as a novel drug delivery site is poised to overcome challenges seen in optimizing drug penetration, targeting, and bioavailability. This approach holds promise for delivering various agents, including steroids, anti-vascular endothelial growth factor molecules, gene vectors, and small molecules, with multiple clinical trials demonstrating this delivery method's potential to reduce treatment burdens and optimize visual outcomes. Particularly, small molecule therapy for retinal diseases finds ease of application through the suprachoroidal route in that small molecule agents have a wide range of targets in disease pathway, greater tissue penetration, and cost-effectiveness in production. The suprachoroidal administration of axitinib, a tyrosine kinase inhibitor, has shown promise in the OASIS trial for treating neovascular age-related macular degeneration. Integrin antagonists and plasma Kallikrein-kinin system inhibitors, also delivered suprachoroidally, exhibit targeted distribution and potential for long-acting therapy.

Formulation and Evaluation of Quinine sulfate Dispersible Tablets with Emphasis on Taste Masking using Cyclodextrin

Dispersible tablets (DTs), also termed quick dissolving, fast melting, fast dissolving, fast disintegrating and rapid dissolving tablets, are uncoated or film-coated tablets intended to be dispersed in water before administration giving a homogeneous dispersion. Conventional quinine tablets have bitter taste when broken or dispersed to allow administration for children. Cyclodextrins (CDs) are cyclic oligosaccharides whose structural feature gives a hydrophobic interior and a hydrophilic exterior are widely used to increase the solubility of poorly soluble drugs. Recent studies showed that CDs masked taste of bitter drugs. The main objective of the present study was to formulate Quinine Sulphate as dispersible tablets via direct compression using different ratios of super-disintegrants. Three formulae were prepared (F1: Crosspovidone 5%, F2: Crosscarmellose 5% and F3: combination of crosspovidone 2.5% + crosscarmellose 2.5%). Further formulation development was done for taste improvement; four formulae were prepared based on the ratio of Quinine: Hydroxy propyl β - Cyclodextrin (HP- βCD) and the method of preparation. The prepared dispersible tablets were then evaluated for various parameters like thickness, hardness, friability, weight variation, assay of content and dispersion time. In vitro drug release profile was also determined. F3 was selected as optimized formula since it showed good dispersion time (58 sec.), acceptable limits of quality control tests and highest percentage of drug released at the end of 10 minutes. Acceptable taste for F3 was achieved when Quinine was complex at the ratio of 1:2 Quinine HP- βCD and the complex dried from water as solvent. More studies using other concentrations and/or complication methods for Cyclodextrin or other approaches are recommended for better taste masking.

Physiological and pathological role of factor XII

Introduction. The most widely accepted notion of the function of blood clotting factor XII (FXII, Hageman factor) is its involvement in the internal blood clotting pathway. However, the biological role of FXII is diverse.Aim – to review the diverse biological functions of FXII.Main findings. FXII is a serine protease. The structure of FXII has a high degree of homology with plasminogen, tissue plasminogen activator and urokinase plasminogen activator. Activated FXII (FXIIa) has five substrates: high-molecular kininogen, precallikrein, FXI, plasminogen, complement proteins (C1s, C1r). FXII provides hemostatic balance by participating in the processes of blood clotting and fibrinolysis. FXII regulates inflammatory and allergic reactions by interacting with the kallikreinkinin system and the complement system. FXII has biological activity in various cells in vivo: endotheliocytes, platelets, monocytes, neutrophils, fi broblasts, dendritic cells, which determines its diverse role in physiological and pathological processes.

Glycated albumin modulates the contact system with implications for the kallikrein-kinin and intrinsic coagulation systems

BackgroundHuman serum albumin (HSA) is the most abundant plasma protein and is sensitive to glycation in vivo. The chronic hyperglycemic conditions in patients with diabetes mellitus (DM) induce a nonenzymatic Maillard reaction that denatures plasma proteins and forms advanced glycation end products (AGEs). HSA-AGE is a prevalent misfolded protein in patients with DM and is associated with factor XII activation and downstream proinflammatory kallikrein-kinin system activity without any associated procoagulant activity of the intrinsic pathway. ObjectivesThis study aimed to determine the relevance of HSA-AGE toward diabetic pathophysiology. MethodsThe plasma obtained from patients with DM and euglycemic volunteers was probed for activation of FXII, prekallikrein (PK), and cleaved high-molecular-weight kininogen by immunoblotting. Constitutive plasma kallikrein activity was determined via chromogenic assay. Activation and kinetic modulation of FXII, PK, FXI, FIX, and FX via in vitro–generated HSA-AGE were explored using chromogenic assays, plasma-clotting assays, and an in vitro flow model using whole blood. ResultsPlasma obtained from patients with DM contained increased plasma AGEs, activated FXIIa, and resultant cleaved cleaved high-molecular-weight kininogen. Elevated constitutive plasma kallikrein enzymatic activity was identified, which positively correlated with glycated hemoglobin levels, representing the first evidence of this phenomenon. HSA-AGE, generated in vitro, triggered FXIIa-dependent PK activation but limited the intrinsic coagulation pathway activation by inhibiting FXIa and FIXa-dependent FX activation in plasma. ConclusionThese data indicate a proinflammatory role of HSA-AGEs in the pathophysiology of DM via FXII and kallikrein-kinin system activation. A procoagulant effect of FXII activation was lost through the inhibition of FXIa and FIXa-dependent FX activation by HSA-AGEs.

The COVID-19 explorer-An integrated, whole patient knowledge model of COVID-19 disease.

Since early 2020 the COVID-19 pandemic has paralyzed the world, resulting in more than half a billion infections and over 6 million deaths within a 28-month period. Knowledge about the disease remains largely disjointed, especially when considering the molecular mechanisms driving the diversity of clinical manifestations and symptoms. Despite the recent availability of vaccines, there remains an urgent need to develop effective treatments for cases of severe disease, especially in the face of novel virus variants. The complexity of the situation is exacerbated by the emergence of COVID-19 as a complex and multifaceted systemic disease affecting independent tissues and organs throughout the body. The development of effective treatment strategies is therefore predicated on an integrated understanding of the underlying disease mechanisms and their potentially causative link to the diversity of observed clinical phenotypes. To address this need, we utilized a computational technology (the Dataome platform) to build an integrated clinico-molecular view on the most important COVID-19 clinical phenotypes. Our results provide the first integrated, whole-patient model of COVID-19 symptomatology that connects the molecular lifecycle of SARS-CoV-2 with microvesicle-mediated intercellular communication and the contact activation and kallikrein-kinin systems. The model not only explains the clinical pleiotropy of COVID-19, but also provides an evidence-driven framework for drug development/repurposing and the identification of critical risk factors. The associated knowledge is provided in the form of the open source COVID-19 Explorer (https://covid19.molecularhealth.com), enabling the global community to explore and analyze the key molecular features of systemic COVID-19 and associated implications for research priorities and therapeutic strategies. Our work suggests that knowledge modeling solutions may offer important utility in expediting the global response to future health emergencies.

The des-Arg9-bradykinin/B1R axis: Hepatic damage in COVID-19.

Patients infected by the SARS-CoV-2 virus are commonly diagnosed with threatening liver conditions associated with drug-induced therapies and systemic viral action. RNA-Seq data from cells in bronchoalveolar lavage fluid from COVID-19 patients have pointed out dysregulation of kallikrein-kinin and renin-angiotensin systems as a possible mechanism that triggers multi-organ damage away from the leading site of virus infection. Therefore, we measured the plasma concentration of biologically active peptides from the kallikrein-kinin system, bradykinin and des-Arg9-bradykinin, and liver expression of its proinflammatory axis, bradykinin 1 receptor (B1R). We measured the plasma concentration of bradykinin and des-Arg9-bradykinin of 20 virologically confirmed COVID-19 patients using a liquid chromatography-tandem mass spectrometry-based methodology. The expression of B1R was evaluated by immunohistochemistry from post-mortem liver specimens of 27 COVID-19 individuals. We found a significantly higher blood level of des-Arg9-bradykinin and a lower bradykinin concentration in patients with COVID-19 compared to a healthy, uninfected control group. We also observed increased B1R expression levels in hepatic tissues of patients with COVID-19 under all hepatic injuries analyzed (liver congestion, portal vein dilation, steatosis, and ischemic necrosis). Our data indicate that des-Arg9-bradykinin/B1R is associated with the acute hepatic dysfunction induced by the SARS-CoV-2 virus infection in the pathogenesis of COVID-19.

Behavior of the renal kallikrein in spontaneously hypertensive rats: Influence of sexual hormones and aldosterone-sensitive distal nephron ion channels

The renal kallikrein-kinin system (RKKS) has been related to blood pressure control and sodium and water balance. We have previously shown that female spontaneously hypertensive rats (SHR) have high urinary kallikrein activity (UKa) and lower blood pressure (BP) than males whereas ovariectomy stimulates UKa and diminishes BP. We also showed that high K+ intake and prepuberal gonadectomy (Gx) diminish BP with a concomitant increase in UKa and plasma aldosterone levels. Since kallikrein co-localize in the same distal nephron segments of aldosterone effectors, we explored the effect of pharmacological blockage of aldosterone receptor, epithelial Na+ (ENaC) and the rectifying outer medulla K+ (ROMK) channels in different gonad contexts on the gene expression, renal tissue content and urine release of kallikrein. Klk1 gene expression was determined by real-time PCR and enzymatic activity of kallikrein by the amidolytic method. We found that the inhibition of the aldosterone receptor by spironolactone increases kallikrein renal tissue storage and decreases its urinary activity, especially in Gx rats. Moreover, ENaC blockade by benzamil increases the renal content of kallikrein without affecting synthesis or excretion, especially in females and Gx animals, while the inhibition of ROMK by glibenclamide increases the synthesis and renal content of kallikrein only in intact male animals. We concluded that RKKS regulation showed sexual dimorphism and seemed to be modulated by sex hormones throughout a process involving aldosterone and the aldosterone-sensitive ion channels..

Proteolysis and Deficiency of α1-Proteinase Inhibitor in SARS-CoV-2 Infection.

The SARS-CoV-2 pandemic had stimulated the emergence of numerous publications on the α1-proteinase inhibitor (α1-PI, α1-antitrypsin), especially when it was found that the regions of high mortality corresponded to the regions with deficient α1-PI alleles. By analogy with the data obtained in the last century, when the first cause of the genetic deficiency of α1-antitrypsin leading to elastase activation in pulmonary emphysema was proven, it can be supposed that proteolysis hyperactivation in COVID-19 may be associated with the impaired functions of α1-PI. The purpose of this review was to systematize the scientific data and critical directions for translational studies on the role of α1-PI in SARS-CoV-2-induced proteolysis hyperactivation as a diagnostic marker and a therapeutic target. This review describes the proteinase-dependent stages of viral infection: the reception and penetration of the virus into a cell and the imbalance of the plasma aldosterone-angiotensin-renin, kinin, and blood clotting systems. The role of ACE2, TMPRSS, ADAM17, furin, cathepsins, trypsin- and elastase-like serine proteinases in the virus tropism, the activation of proteolytic cascades in blood, and the COVID-19-dependent complications is considered. The scientific reports on α1-PI involvement in the SARS-CoV-2-induced inflammation, the relationship with the severity of infection and comorbidities were analyzed. Particular attention is paid to the acquired α1-PI deficiency in assessing the state of patients with proteolysis overactivation and chronic non-inflammatory diseases, which are accompanied by the risk factors for comorbidity progression and the long-term consequences of COVID-19. Essential data on the search and application of protease inhibitor drugs in the therapy for bronchopulmonary and cardiovascular pathologies were analyzed. The evidence of antiviral, anti-inflammatory, anticoagulant, and anti-apoptotic effects of α1-PI, as well as the prominent data and prospects for its application as a targeted drug in the SARS-CoV-2 acquired pneumonia and related disorders, are presented.

Kallikrein proteoforms and reproductive parameters in stallion are conditioned by climate

Horses are seasonal polyoestrous animals, and the photoperiod is the main factor modulating their reproductive activity. There is no consensus on the andrological and biochemical factors that influence breeding seasonality. To assess the involvement of climate in reproduction, Mangalarga Marchador stallions were monitored over 1 year regarding semen quality and seminal plasma proteome. Here, we show that kallikrein (KLKs) proteoforms in seminal plasma are involved in climate conditioning of reproduction. During the breeding season, greater abundance and different types of KLKs occurred simultaneously to lower sperm motility, greater semen volumes and higher concentrations of glucose and cholesterol. Considering that vasodilation due to activation of the kallikrein-kinin system and the consequent inhibition of the renin-angiotensin system may be associated with lower sperm motility, unravelling the involvement of KLK proteoforms in reproductive seasonality is a priority in horse breeding.

The activity of trypsin in the pancreatic juice and blood of poultry increases simultaneously in the postprandial period.

Modern literature data indicate that the role of trypsin goes far beyond its digestive function. Once in the blood, trypsin is involved as part of the kallikrein-kinin system in the regulation of blood pressure, regulates pancreatic function by activating PAR receptors, and influences inflammation and immunity in the cell. The interaction of trypsin in the intestine and serum in the living healthy organism has been insufficiently studied. On the basis of our own studies and literature data, we concluded that after overnight fasting the increase of trypsin activity in pancreatic juice and blood serum in the postprandial period occurs in parallel, which determines not only digestion of food protein but also the level of metabolism. Consequently, determining the optimal amount of crude protein in the diet during the morning meal is a paramount task for physiologists.

Integrated in silico-in vitro molecular modeling and design of halogenated phenylalanine-containing antihypertensive peptide inhibitors with halogen bonds to target human angiotensin-I-converting enzyme

Angiotensin-I-converting enzyme (ACE) is a key regulator of blood pressure as its critical role in the renin-angiotensin-aldosterone and kallikrein-kinin systems. Although a variety of natural and food peptides have been discovered to possess ACE-inhibitory activity over the past decades, they cannot be directly used as drugs due to their low efficiency and bad bioavailability. In this study, the intermolecular interaction of ACE with a snake venom inhibitor of bradykinin potentiating peptide b (BPPb) was investigated systematically at structural and energetic levels. The C-terminal region of the peptide can tightly pack against the enzyme active site and is primarily responsible for the enzyme inhibition. A tetrapeptide that covers the C-terminal region of BPPb exhibited a satisfactory ACE-inhibitory profile, which was used as start to generate a number of phenylalanine (Phe)-containing antihypertensive peptide inhibitors. The ortho-, meta- and para-positions of peptide Phe−2 phenyl moiety were systematically substituted with halogen atoms. It is revealed that bromine substitution separately at the meta- and para-positions can considerably improve the peptide inhibitory activity by 7.6-fold and 3.7-fold by forming a bifurcated halogen-bonding system with ACE His513 and Val518 residues as well as a binary halogen-bonding system with ACE Glu384 residue, respectively.

In vitro reconstitution of kallikrein-kinin system and progress curve analysis.

Human kallikrein-kinin system (KKS) is a proteolytic cascade with two serine-protease zymogen couples (Factor XII and prekallikrein (PK) and their activated forms, FXIIa, PKa, respectively), releasing bradykinin by cleavage of native high-molecular-weight kininogen (nHK) into cleaved HK. For KKS investigation in human plasma, this cascade is usually triggered on ice eventually by mixing with purified proteins. It has been established that purified FXIIa, PK, and nHK required a fixed order and timing for mixing protein on ice to ensure reproducibility of testing, we investigated the activation kinetics of both enzymes. The activation process of this in vitro minimal reconstitution of KKS was studied by progress curve analysis, in condition of high enzyme/substrate ratio and by using on natural rather than peptide substrates.FXIIa and PKa were found five-times less active on ice than at 37°C: kcat = 0.133 ± 0.034 and 0.0119 ± 0.0027 s−1, KM = 672 ± 150 and 115 ± 24 nM, respectively. The progress curve analysis of our in vitro KKS reconstitutions differed from a Michaelis–Menten mathematical simulation by a faster initial rate and a slower late rate. These two features were also observed ex vivo by using dextran sulfate-activated plasma and could reinforce the hypothesis of a maximal local effect (bradykinin release) and a minimal systemic consequence (PK preservation) in KKS activation process.Analyzing the complete curve of cold KKS activation would provide valuable information for ex vivo investigation of KKS in samples from patients presenting with hereditary angioedema and other inflammatory conditions.

Kinin B1 receptor modulates mitochondrial activity responsivity in fasting and voluntary exercise

The Kallikrein-Kinin System (KKS) plays an important role in energy metabolism. We have previously described the importance of the kinin B1 receptor (B1R) in metabolism regulation. Considering that the liver manages the different energy demands of different body tissues, we combined two stressful conditions – fasting and voluntary exercise – to address how B1R may affect liver metabolism, focusing on mitochondrial function. AimsTo investigate how the kinin B1 receptor (B1R) modulates mitochondrial activity under stress conditions, focusing on the rate of energy expenditure and shift in metabolism. Main methodsWild-type and B1R-knockout (B1KO) male mice remained in a calorimetric cage with a wheel for 7 days; 48 h before euthanasia, half of the animals from both groups were submitted to fasting conditions. Mitochondrial activity, ketone bodies, and gene expression involving mitochondrial activity were evaluated. Key findingsB1R modulates the mitochondrial activity under fasting and voluntary exercise, reducing the VO2 expenditure and HEAT. B1KO animals who exercised and underwent fasting did not have increased glucose levels, suggesting a preference for lipids as an energy source. Moreover, these animals displayed RER around 0.8, which indicates a β-oxidation increment. Interestingly, the lack of B1R did not induce mitochondrial activity and biogenesis, suggesting interference in metabolism responsivity, a condition modulated by sirtuins under PGC-1α control. SignificanceB1R modulates mitochondrial respiratory control ratios, which suggests metabolic suppression, influencing hepatic metabolism and, consequently, energy homeostasis.

Comparison Levels of Copper, Zinc, and Cu/Zn Ratio of in Pre-eclampsia and Normal Pregnancy

Introduction
 Preeclampsia is a syndrome that occurs in pregnancy, characterized by hypertension, proteinuria and edema. Zinc and copper are micronutrients that play a role in the performance of several important enzymes in the human body, such as CuZnSOD and ACE2 enzymes that play a role in the pathogenesis of severe preeclampsia. Zinc also plays a role in the kallikrein-kinin system in the formation of bradykinin which then acts as a vasodilator. This study plans to compare the level of copper (Cu), Zink (Zn), and Cu/Zn ratio in preeclamtic and normal pregnancy women.
 Method
 The study recruited 30 pregnant women with severe preeclampsia who were treated at Dr. Hasan Sadikin Bandung and 30 normal pregnant women at one of the Independent Practice Midwives in the Cibabat area, which was conducted in the period September 2021 - November 2021. This research was an analytical observational study with a cross sectional study design. Cu and Zn levels were examined using inductively coupleds plasma mass spectrometry (ICP-MS). Chi Square, student’s t test, Mann Whitney and multivariat analysis were used for statistical analysis.
 Results
 The results of this study showed that the average Cu levels were higher in severe preeclampsia (mean: 2.149 vs. 2.116 mol/L, p=0.728). The median Zn level in the subjects with severe preeclampsia was higher than in normal pregnancies (58 vs 49 g/dL, p<0.001). The median Cu/Zn ratio in severe preeclampsia subjects was lower than in normal pregnancies (0.034 vs 0.063 g/dL, p=0.021).
 Conclusion
 Zn levels was significantly increased in the preeclampsia group, Cu levels was not significantly increased in the preeclampsia group and the ratio of Cu/Zn levels was significantly decreased in preeclampsia group compared to normal pregnancies.