Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 23, Issue 7, 2023

The devastating global pandemic Coronavirus disease 2019 (COVID 19) isolated in China in January 2020 is responsible for an outbreak of pneumonia and other multisystemic complications. The clinical picture of the infection has extreme variability: it goes from asymptomatic patients or mild forms with fever, cough, fatigue and loss of smell and taste to severe cases ending up in the intensive care unit (ICU). This is due to a possible cytokine storm that may lead to multiorgan failure, septic shock, or thrombosis. Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV -2), which is the virus that causes COVID 19, binds to angiotensin-converting enzyme 2 (ACE2) receptors, which are expressed in key metabolic organs and tissues, including pancreatic beta cells, adipose tissue, the small intestine and the kidneys. Therefore it is possible to state that newly-onset diabetes is triggered by COVID 19 infection. Although many hypotheses have clarified the potential diabetogenic effect of COVID 19, a few observations were reported during this pandemic. Two male patients admitted to us with devastating hyperglycemia symptoms were diagnosed with type 1/autoimmune diabetes mellitus within 3 months following COVID 19 infection. Autoantibodies and decreased C peptide levels were detected in these patients. We speculated that several mechanisms might trigger autoimmune insulitis and pancreatic beta-cell destruction by COVID 19 infection. We aim to raise awareness of the possible link between SARS-CoV-2 and newly onset type 1 diabetes mellitus. Further studies are needed to determine a more definitive link between the two clinical entities.

Herbal medicine and its derived products have been used in the medicine and nutraceutical sectors for the treatment of human disorders and associated secondary complications. Plant-derived products play an important role in our daily life due to their medicinal properties and pharmacological activities. The attention of scientists to natural products has increased due to their significant biological activities. Flavonoids represent one of the most important phytocompounds present in the higher plants, common fruits, vegetables, herbs, wine, juices, and dried fruits. Flavonoids exert potent antioxidant activity by blocking and scavenging free radicals. Cirsilineol, also called 4',5-dihydroxy-3',6,7-trimethoxyflavone, is an active phytochemical of Artemisia vestita, Artemisia monosperma, Artemisia asiatica, and Agrostis gigantea. Medicinal importance and pharmacological activities of cirsilineol have been investigated in the present work with their analytical aspects in order to know the biological importance of cirsilineol in medicine. Literature data on cirsilineol were collected and analyzed in the present work to study its therapeutic potential against various human disorders and associated secondary complications. Scientific data were collected from Google, Google Scholar, PubMed, Science Direct, and Scopus and analyzed in the present work using the term herbal medicine, flavonoid and cirsilineol. Medicinal plants containing a significant amount of cirsilineol have biological applications in medicine due to their pharmacological activities. This present work signifies the biological importance of cirsilineol in medicine as it has antiproliferative, gastroprotective, anti-Helicobacter pylori, anti-diabetic and anti-oxidant activities. Further therapeutic effectiveness of cirsilineol against different types of cancers, including breast carcinoma and lung carcinoma, has been discussed in the present work. The biological importance of cirsilineol against allergic rhinitis, inflammation, coronavirus, immune system, renal cellular membrane and protein glycation has also been discussed in the present work. However, the importance of analytical methods for the isolation and identification of cirsilineol in medicine has also been analyzed. This work aimed to summarize the health-beneficial aspects of cirsilineol in medicine which will be beneficial to explore the further therapeutic effectiveness of cirsilineol for the treatment of various forms of human disorders.

Background: Piper sarmentosum (PS) is a traditional herb used by Southeast Asian communities to treat various illnesses. Recent pharmacological studies have discovered that PS possesses antioxidant and anti-inflammatory activities. Since oxidative stress and inflammation are two important processes driving the pathogenesis of bone loss, PS may have potential therapeutic effects against osteoporosis. Objective: This review systematically summarised the therapeutic effects of PS on preventing osteoporosis and promoting fracture healing. Methods: A systematic literature search was performed in November 2021 using 4 electronic databases and the search string "Piper sarmentosum" AND (bone OR osteoporosis OR osteoblasts OR osteoclasts OR osteocytes). Results: Nine unique articles were identified from the literature. The efficacy of PS has been studied in animal models of osteoporosis induced by ovariectomy and glucocorticoids, as well as bone fracture models. PS prevented deterioration of bone histomorphometric indices, improved fracture healing and restored the biomechanical properties of healed bone in ovariectomised rats. PS also prevented osteoblast/osteocyte apoptosis, increased bone formation and mineralisation and subsequently improved trabecular bone microstructures and strength of rats with osteoporosis induced by glucocorticoids. Apart from its antioxidant and anti-inflammatory activity, PS also suppressed circulating and skeletal expression of corticosterone and skeletal expression of 11β hydroxysteroid dehydrogenase type 1 but increased the enzyme activity in the glucocorticoid osteoporosis model. This review also identified several research gaps about the skeletal effects of PS and suggested future studies to bridge these gaps. Conclusion: PS may be of therapeutic benefit to bone health. However, further research is required to validate this claim.;

The unbearable heat waves that we are experiencing these days around the world are the result of increasing global warming, leading to heat stress and a constant health issue for the existing population. The thermoregulatory dysfunction of the human body due to climatological changes might result in fluid and electrolyte imbalance and transforms the human body from a normal physiological condition to a distorted pathological state. Subsequently, at one point in time, the human body may fail to handle its normal thermoregulatory function in the form of sudden unconsciousness and health defects. There might be associated dehydration that imposes renal damage, even to the extent to cause acute kidney injury (AKI), followed by chronic kidney disease (CKD). Thus, we cannot deny CKD as a major cause of death, mainly in patients having long-standing medical issues such as cardiac dysfunction, hypertension, diabetes, and obesity, heat stress nephropathy (HSN) might therefore become a major health problem. There is always a hopeful way in our hands, fortunately, which is of course prevention, that comes through government policies and human awareness. The present review brings out light on the alarming resultant facts of heat stress, dehydration, its pathology, molecular derangements, and recommendations for the prevention of heat stress nephropathy.

Background: Modern lifestyle increasingly deprives people from sleep to different degrees. Long-term sleep deprivation will facilitate body’s pathological behaviors, such as lethargy, depression, and anorexia. Objective: This study is an investigation into the mechanism of hydrolyzed seawater pearl tablet in treating chronic sleep deprivation mice model. Methods: The chronic sleep deprivation model was established involving C57BL/6mice; the body weight, behavioral characteristics, hippocampal structure, oxidative stress, apoptosis-related protein expression, and intestinal bacteria in mice were assessed to characterise hydrolyzed seawater pearl tablet. Results: Hydrolyzed seawater pearl tablet significantly accelerated body weight, open field test score, and sugar water preference rate (P < 0.05), alleviated the structural damage of hippocampus, reduced the content of MDA (P < 0.05), Bax protein expression, increased the content of GSH (P < 0.05), the activities of SOD, GSH-Px, and Bcl-2 protein expression in the hippocampus, increased the Escherichia coli, Bacteroides, Bifidobacterium and Lactobacillus (P < 0.05), which are beneficial bacteria in the intestine, in chronic sleep deprivation mice, and reduced the amount of Clostridium perfringens (P < 0.05), which are harmful bacteria in the intestine. Conclusion: Hydrolyzed seawater pearl tablet can improve the depression-like mental state of mice caused by chronic sleep deprivation. The mechanism involves improving the antioxidant activity of the hippocampus to eliminate the excessive ROS, which inhibits cell apoptosis and alleviates tissue structure damage. Meanwhile, it may also be involved in adjusting the microbiota level and improving the mental and behavioral activities of chronic sleep deprivation mice through the intestine-brain axis.

Aims: This study aims to examine the association between non-insulin-based insulin resistance indices and periodontitis severity in young males. Background: Periodontitis has been reported with an association with insulin resistance in middle- and old-aged adults. Objective: The association between insulin resistance and localized periodontitis in young adults is unclear. Methods: A total of non-diabetic 1,111 military males in Taiwan were included in this study. Localized periodontitis was classified as healthy (N =665), stage I (N =130), stage II (N =161), and stage III (N =155) based on the world workshop in 2017. Insulin resistance was assessed by serum triglycerides concentrations, the triglycerides glucose (TyG) index, the product of serum triglycerides and fasting glucose, and the ratio of serum triglycerides to high-density lipoprotein cholesterol (TG/HDL-C). Multiple logistic regression analysis with adjustment for age, tobacco smoking, alcohol intake, abdominal obesity, and hypertension was used to determine the associations. Results: Serum TG concentrations, TyG index, and TG/HDL-C ratio were dose-dependently associated with a greater risk of localized periodontitis severity (from stage I to stage III) [odds ratios and 95% confidence intervals: 1.001 (0.999-1.004), 1.003 (1.001-1.004) and 1.003 (1.002- 1.005) for TG; 1.45 (1.03-2.03), 1.65 (1.22-2.22) and 1.66 (1.22-2.26) for TyG index; 1.06 (0.99- 1.14), 1.09 (1.03-1.15) and 1.10 (1.04-1.16) for TG/HDL-C ratio]. However, the association was only found in obese individuals and those free of impaired fasting glucose. Conclusion: The present study confirmed that periodontitis may lead to insulin resistance in young male adults, particularly for those with obesity and without hyperglycemia. The TyG index is suggestive as the strongest indicator for the association between insulin resistance and periodontitis in young adults.

Background: Studies have indicated that Ban-Xia Xie-Xin Decoction (BXXXD) has therapeutic effects on type 2 diabetes mellitus (T2DM). However, due to the complexity of components and diversity of targets, the mechanisms are still not fully elucidated. Objective: In this research, we systematically analysed the targets of BXXXD through the method of network pharmacology and further validated them through experiments. Methods: The active components and therapeutic targets were identified, and these targets were analysed by the methods of gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) analysis. Then, based on these network pharmacology analyses, we validated the main targets through animal experiments. Results: A total of 169 active components and 159 targets were identified. KEGG analysis showed that the mitogen-activated protein kinase (MAPK) signalling pathway, tumour necrosis factor (TNF) signalling pathway, the phosphatidylinositol 3' -kinase (PI3K), Akt signalling pathway, and other pathways were related to the treatment of T2DM by BXXXD. PPI network analysis showed that the key genes included signal transducers and activators of transcription 3 (STAT3), JUN, TNF, Recombinant V-Rel Reticuloendotheliosis Viral Oncogene Homolog A (RELA), Akt/PKB- 1 (Protein kinase B), TP53, mitogen-activated protein kinase-1 (MAPK-1), mitogen-activated protein kinase-3 (MAPK-3), interleukin- 6 (IL6), and mitogen-activated protein kinase-14 (MAPK- 14), respectively. Animal experiments showed that BXXXD could reduce blood glucose and improve insulin resistance, which may be related to the mechanisms of inhibiting TNF, interleukin-1 (IL-1), IL-6, and interleukin-17 (IL-17) and promoting Akt phosphorylation. Conclusion: Our research revealed the mechanisms of BXXXD in the treatment of diabetes, which laid a solid foundation for further studies on the molecular mechanisms of BXXXD in the treatment of T2DM.

Background: The immunomodulatory effects of plants have been utilised to enhance the immunity of humans against infections. However, evidence of such effects of agarwood leaves is very limited despite the long tradition of consuming the leaves as tea. Objective: This study aimed to investigate the immuno-modulatory effects of agarwood leaf extract (ALE) derived from Aquilaria malaccensis using RAW264.7 murine macrophages. Methods: In this study, RAW264.7 macrophages were incubated with ALE alone for 26 hours or ALE for 2 hours, followed by bacterial lipopolysaccharide for 24 hours. The nitrite and cytokine production (tumour necrosis factor-alpha (TNFα), interleukin (IL)-1β, IL-6, and IL-10), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX2) expression in the macrophages were assayed. Results: The study showed that ALE alone was immunostimulatory on the macrophages by increasing the nitrite, TNFα, and IL-6 production and COX2 expression (p<0.05 vs. untreated unstimulated cells). Pre-treatment of ALE suppressed nitrite level and iNOS expression but enhanced TNFα and IL-6 production and COX2 expression (p<0.05 vs. untreated lipopolysaccharides (LPS)-stimulated cells). ALE also increased IL-10 production regardless of LPS stimulation (p<0.05 vs. untreated cells). Conclusion: ALE was able to promote the immune response of macrophages by upregulating pro-inflammatory cytokine levels and COX2 expression. It also regulated the extent of the inflammation by reducing iNOS expression and increasing IL-10 levels. Thus, ALE may have a role in enhancing the innate immune system against infection; however, its validation from in vivo studies is still pending.

Background: Both low-grade systemic and hepatic inflammation could result in increased left ventricular mass (LVM) in the general population. However, the associations, which might be modified by exercise, have not been clarified in physically active young adults. Methods: The study included 2,004 military males aged 18–43 years in eastern Taiwan. Systemic and hepatic inflammation was defined by the upper tertiles of blood white blood cell (WBC) counts (7.51-11.00 x 103/μL) and serum alanine aminotransferase (ALT: 30-120 U/L), respectively. LVM indexed for the body height ≥49 g/m².7 was defined as left ventricular hypertrophy (LVH) based on echocardiography. Multiple logistic regression analysis adjusting for age, smoking, alcohol intake, physical fitness, and metabolic syndrome was utilized to determine the associations. Results: As compared to the lower WBC/lower ALT group, there tended to have an increased risk of LVH with the higher WBC/lower ALT group, the lower WBC/higher ALT group, and the higher WBC/higher ALT group [odds ratios: 0.89 (95% confidence intervals (CI): 0.41-1.94), 1.90 (95% CI: 0.86-4.22) and 2.48 (95% CI: 1.04-5.92); p-value for trend = 0.01]. Conclusion: Our study suggested that in physically active males, those with hepatic inflammation rather than low-grade systemic inflammation had a higher risk of LVH. Hepatic injury might be relevant to LVH as an early sign of end-organ damage regardless of physical fitness in young adults.

Background: Pancreatic neuroendocrine neoplasms (pNENs) are rare primary tumors of the pancreas. Although these tumors are heterogeneous and can be classified as functional or non-functional according to pancreatic endocrine biomarkers, the more prevalent type is non-functional pNENs with endocrine differentiation but with non-specific symptoms and often late diagnoses. The treatment option for patients often involves surgical management, but the reported outcomes, especially on insulin secretion change and the trend of diabetes in these patients, varied to date. Hence, the purpose of this clinical report is to study the functional change of pancreatic β- cell corresponding to the mass of tumorectomy of pNEN in a diabetic patient. Case Presentation: We reported that a 39-year-old man with diabetes was found complicated with neuroendocrine neoplasm. He was admitted to the General Surgery of our hospital for further examination and therapy. The patient received a pancreatectomy + splenectomy + lymphadenectomy on the pancreatic body and tail. We analyzed the pancreatic mass change and performed Oral Glucose Tolerance Test (OGTT) before and after the surgery to evaluate the function of the pancreas. Conclusion: This case may provide us a reference to predict the extent of islet function loss before the pancreatectomy, and apply personalized hypoglycemic therapy after surgery in these patients.

Background: Beta-blockers, mainly propranalol, are usually administered to control heart rate in patients with thyrotoxicosis, especially when congestive heart failure presents. However, when thyrotoxicosis is not controlled, heart rate may be difficult to control even with maximal doses of propranolol. This presentation alerts physicians to the possibility of using ivabradine, a selective inhibitor of the sinoatrial pacemaker, for the control of heart rate. Case Presentation: We present a 37-year-old woman with thyrotoxicosis and congestive heart failure whose heart rate was not controlled with a maximal dose of beta blockers during a thyroid storm. The addition of ivabradine, a selective inhibitor of the sinoatrial pacemaker, controlled her heart rate within 48 hours. Conclusion: Ivabradine should be considered in patients with thyrotoxicosis, including those with heart failure, in whom beta blockers are insufficient to control heart rate.

Background: Immunotherapy-associated hypophysitis is an uncommon adverse event. However, if not handled properly, it could lead to fatal sequelae. Case Presentations: Case 1. A 66-year-old man presented to our hospital with hyponatremia. He had low plasma levels of adrenocorticotropin and cortisol. The patient had a history of non-small cell lung cancer and had undergone 16 cycles of immunotherapy with sintilimab, a monoclonal antibody against programmed cell death protein 1 (PD1). He was diagnosed with adrenal insufficiency secondary to immunotherapy-associated hypophysitis and received a physiological dose of glucocorticoids. Upon discharge, he has prescribed a continued course of hormone replacement therapy combined with immunotherapy. Case 2. The second case profiled here involved a 58- year-old patient diagnosed with gastric antrum cancer. After ten months of immunotherapy with carrelizumab, a human high-affinity immunoglobulin G4 (IgG4) anti-PD-1 monoclonal antibody drug, the patient was referred to the Endocrinology Department at our medical centre for adrenal nodules and intolerance of anorexia. He also suffered from hypophysitis and was prescribed hormone replacement therapy combined with immunotherapy. Conclusion: This article discusses the clinical characteristics, diagnosis, treatment, and subsequent follow-up for immunotherapy-associated hypophysitis in the context of two case reports. Based on our findings and observations, we conclude that patients with immunotherapy should regularly be referred to endocrine-related follow-up during tumour treatment.

; Background: Therapeutic targets in type 2 diabetes mellitus (T2D) are oriented towards nephron- and cardio-protection and the prescription of antihyperglycemic agents with proven renal and cardiovascular benefits are increasing over time. Failure to promptly diagnose insulinopenic diabetes may adversely affect the adequacy of treatment and have harmful consequences, including severe hyperglycemia and diabetic ketoacidosis. Case Presentation: Herein we present the case of a 57-year-old woman referred to our clinic due to poor glycemic control (HbA1c 80 mmol/mol, therapeutic target <53 mmol/mol), class III obesity (BMI 41 kg/m2; normal value <25 kg/m²), and high cardiovascular risk misdiagnosed with T2D several years before. C-peptide measurement (0.3 ng/dL; reference range 1.1 – 4.4 ng/mL) confirmed the diagnosis of an insulinopenic form of diabetes, and the islet autoimmunity was consequently measured (GADA 2,000 UA/mL, reference range <5 UA/mL; IA2 17.1 UA/mL, reference range <7.5 UA/mL) and defined the diagnosis of an autoimmune form of diabetes. Discussion: Deprescribing insulin therapy in T2D patients in favor of other antihyperglycemic medications has become a growing therapeutic opportunity to provide adequate glucose control, promote weight loss, improve insulin sensitivity, and ameliorate cardiovascular and renal outcomes. However, a blunted insulin reserve poses significant restriction on the prescription of non-insulin agents (e.g., diabetic ketoacidosis due to gliflozins). According to our experience, the routine testing of insulin reserve provides detailed information on diabetes pathophysiology with positive implications for the appropriateness of pharmacological prescriptions. Conclusion: As part of our routine evaluation of diabetic patients, C-peptide measurement is a valuable and inexpensive tool to reclassify diabetes types and provide more appropriate disease management.