NR2F2 Reactivation in Early-life Adipocyte Stem-like Cells Rescues Adipocyte Mitochondrial Oxidation.

In humans, perinatal exposure to an elevated omega-6 (n6) relative to omega-3 (n3) Fatty Acid (FA) ratio is associated with the likelihood of childhood obesity. In mice, we show perinatal exposure to excessive n6-FA programs neonatal Adipocyte Stem-like cells (ASCs) to differentiate into adipocytes with lower mitochondrial nutrient oxidation and a propensity for nutrient storage. Omega-6 FA exposure reduced fatty acid oxidation (FAO) capacity, coinciding with impaired induction of beige adipocyte regulatory factors PPARγ, PGC1α, PRDM16, and UCP1. ASCs from n6-FA exposed pups formed adipocytes with increased lipogenic genes in vitro, consistent with an in vivo accelerated adipocyte hypertrophy, greater triacylglyceride accumulation, and increased % body fat. Conversely, n6-FA exposed pups had impaired whole animal 13C-palmitate oxidation. The metabolic nuclear receptor, NR2F2, was suppressed in ASCs by excess n6-FA intake preceding adipogenesis. ASC deletion of NR2F2, prior to adipogenesis, mimicked the reduced FAO capacity observed in ASCs from n6-FA exposed pups, suggesting that NR2F2 is required in ASCs for robust beige regulator expression and downstream nutrient oxidation in adipocytes. Transiently re-activating NR2F2 with ligand prior to differentiation in ASCs from n6-FA exposed pups, restored their FAO capacity as adipocytes by increasing the PPARγ-PGC1α axis, mitochondrial FA transporter CPT1A, ATP5 family synthases, and NDUF family Complex I proteins. Our findings suggest that excessive n6-FA exposure early in life dampens an NR2F2-mediated induction of beige adipocyte regulators, resulting in metabolic programming that is shifted towards nutrient storage.

Silencing Nrf2 in cisplatin resistant non-small cell lung cancer cells augments sensitivity towards EGFR inhibitor.

Recently, non-small cell lung cancer (NSCLC) has been the prime concern of cancer clinicians due to its high mortality rate worldwide. Cisplatin, a platinum derivative, has been used as a therapeutic option for treating metastatic NSCLC for several years. However, acquired, or intrinsic drug resistance to Cisplatin is the major obstacle to the successful treatment outcome of patients. Dysregulation of Nrf2 (nuclear factor erythroid 2-related factor 2) and EGFR (epidermal growth factor receptor) signaling have been associated with cellular proliferation, cancer initiation, progression and confer drug resistance to several therapeutic agents including Cisplatin in various cancers. To dissect the molecular mechanism of EGFR activation in resistant cells, we developed Cisplatin-resistant (CisR) human NSCLC cell lines (A549 and NCIH460) with increasing doses of Cisplatin treatment over a 3-month period. CisR cells demonstrated increased proliferative capacity, clonogenic survivability and drug efflux activity compared to the untreated parental (PT) cells. These resistant cells also showed higher levels of Nrf2 and EGFR expression. Here, we found that Nrf2 upregulates both basal and inducible expression of EGFR in these CisR cells at the transcriptional level. Moreover, genetic inhibition of Nrf2 with siRNA in CisR cells showed increased sensitivity towards the EGFR tyrosine kinase inhibitor (TKIs), AG1478. Our study, therefore suggests the use of Nrf2 inhibitors in combinatorial therapy with EGFR TKIs for the treatment of resistant NSCLC.

Adipocyte Mitochondria: Deciphering Energetic Functions across Fat Depots in Obesity and Type 2 Diabetes.

Adipose tissue, a central player in energy balance, exhibits significant metabolic flexibility that is often compromised in obesity and type 2 diabetes (T2D). Mitochondrial dysfunction within adipocytes leads to inefficient lipid handling and increased oxidative stress, which together promote systemic metabolic disruptions central to obesity and its complications. This review explores the pivotal role that mitochondria play in altering the metabolic functions of the primary adipocyte types, white, brown, and beige, within the context of obesity and T2D. Specifically, in white adipocytes, these dysfunctions contribute to impaired lipid processing and an increased burden of oxidative stress, worsening metabolic disturbances. Conversely, compromised mitochondrial function undermines their thermogenic capabilities, reducing the capacity for optimal energy expenditure in brown adipocytes. Beige adipocytes uniquely combine the functional properties of white and brown adipocytes, maintaining morphological similarities to white adipocytes while possessing the capability to transform into mitochondria-rich, energy-burning cells under appropriate stimuli. Each type of adipocyte displays unique metabolic characteristics, governed by the mitochondrial dynamics specific to each cell type. These distinct mitochondrial metabolic phenotypes are regulated by specialized networks comprising transcription factors, co-activators, and enzymes, which together ensure the precise control of cellular energy processes. Strong evidence has shown impaired adipocyte mitochondrial metabolism and faulty upstream regulators in a causal relationship with obesity-induced T2D. Targeted interventions aimed at improving mitochondrial function in adipocytes offer a promising therapeutic avenue for enhancing systemic macronutrient oxidation, thereby potentially mitigating obesity. Advances in understanding mitochondrial function within adipocytes underscore a pivotal shift in approach to combating obesity and associated comorbidities. Reigniting the burning of calories in adipose tissues, and other important metabolic organs such as the muscle and liver, is crucial given the extensive role of adipose tissue in energy storage and release.

Nrf2 inhibition regulates intracellular lipid accumulation in mouse insulinoma cells and improves insulin secretory function.

High amount of fat in the pancreas is linked to poor functioning of ß-cells and raises the risk of type 2 diabetes. Here we report the putative role of a circulatory glycoprotein Fetuin-A, a known obesity marker, in promoting lipid accumulation in ß-cells and its association with Fatty acid translocase/CD36 for lipid storage culminate in ß-cell dysfunction. Additionally, this work reveals regulation of CD36 via Nrf2, a key regulator of oxidative stress, and reduction of lipid accumulation by suppression of Nrf2 that restores ß-cell function. Palmitate (0.50 mM) and Fetuin-A (100 µg/mL) exposure showed high levels of intracellular lipid in MIN6 (mouse insulinoma cells) with a concomitant decrease in insulin secretion. This also increased the expression of important lipogenic factors, like CD36, PGC1α, PPARγ, and SREBP1. Flow cytometry analysis of CD36 membrane localization has been corroborated with an increased accumulation of lipids as indicated by Oil-Red-O staining. Immunoblotting and immunofluorescence of Nrf2 indicated its high expression in palmitate-fetuin-A incubation and translocation in the nucleus. Suppression of Nrf2 by siRNA showed a reduced expression of lipogenic genes, ablation of lipid droplets, decrease in the number of apoptotic cells, and restoration of insulin secretion with a corresponding increase of Pdx1, BETA2, and Ins1 gene expression. Our study thus suggested an important aspect of lipid accumulation in the pancreatic ß-cells contributing to ß-cell dysfunction and demonstrated the role of Fetuin-A in CD36 expression, with a possible way of restoring ß-cell function by targeting Nrf2.

Spontaneous Rectus Sheath Hematoma.

Rectus sheath hematoma (RSH) is one of the surgical emergencies that mimics peritonitis or other causes of acute abdominal pain. It is usually seen in old age, post-trauma, anticoagulation therapy pregnancy, chronic cough, and liver disease. Nevertheless, RSHs can be spontaneous without any underlying predisposing factors. Here, we present a 51-year-old female with sudden onset abdominal pain, abdominal distention, hypotension, and severe pallor. After initial resuscitation, the patient underwent radiological imaging. This suggested an RSH with active bleeding from the inferior epigastric artery or profunda femoris artery. The patient underwent digital subtraction angiography and angioembolization of the profunda femoris branch. After a few days, the patient continued deteriorating and succumbed to acute respiratory distress syndrome (ARDS).

Aortoesophageal Fistula Occurring Due to Aortic Aneurysm.

Upper gastrointestinal bleeding is a rare presentation of the aortoesophageal fistula (AEF) and is usually caused by thoracic aortic aneurysms. We present the case of a 61-year-old male who presented with chest pain and hematemesis. A chest X-ray showed a widened mediastinum. The patient underwent computed tomography angiography (CTA), which showed the presence of a large aneurysm in the aorta, which caused compression of the trachea, esophagus, and left pulmonary artery. Additionally, there was evidence of an AEF. It was decided to perform an emergency surgical intervention on the patient. However, the patient had multiple episodes of hematemesis and expired.

A Rare Phenomenon of Stercoral Ileal Perforation in a Pregnant Woman.

Perforation peritonitis is one of the most common emergency presentations in Indian hospitals. Stercoral perforations are rare due to increased intraluminal pressure on the gut wall from impacted feces. This is associated with transmural necrosis. We present a 31-year-old pregnant woman who reported abdominal pain and vomiting at 34 weeks of gestation. The diagnosis was unclear from examination and imaging studies, and a provisional diagnosis of acute appendicitis was made. The patient underwent laparotomy and was found to have fecal contamination and multiple stercoral ileal perforations. The bowel segment was resected and exteriorized as a stoma.

Duodeno-duodenal intussusception presenting as upper gastrointestinal bleed.

Duodeno-duodenal intussusception (DDI) is the type of intestinal intussusception in which a segment of the duodenum invaginates into the next part of the duodenum. We present a case of a male patient in his 50s presenting with right upper abdominal pain with multiple episodes of vomiting and a history of melena for 1 month. Imaging studies showed the presence of DDI without apparent growth. The patient underwent upper gastrointestinal endoscopy, which showed a doubtful growth in the duodenum, and the biopsy, was suggestive of adenocarcinoma. The patient underwent Whipple's procedure, and postoperative histology was diagnostic of Brunner's gland adenoma. The patient improved well without any complications.

Cardiac Arrest Due to Anaphylactic Shock Following Vecuronium Injection.

Anaphylaxis under anesthesia is a rare but potentially severe disease. Although anaphylaxis is rare, it can be lethal if not diagnosed and treated appropriately. We present the case of a 43-year-old male with no prior allergy history who experienced a severe anaphylactic reaction that resulted in cardiac arrest after the intravenous injection of vecuronium. His surgery was postponed, and the patient required intensive care with ventilator support and other supportive measures. Post-reaction dermal sensitivity tests revealed a clear allergic reaction to vecuronium which confirmed the diagnosis retrospectively. Eventually, the patient made a full recovery and was rescheduled for surgery at a later date.

Metabolic benefits of 17α-estradiol in liver are partially mediated by ERß in male mice.

Metabolic dysfunction underlies several chronic diseases. Dietary interventions can reverse metabolic declines and slow aging but remaining compliant is difficult. 17α-estradiol (17α-E2) treatment improves metabolic parameters and slows aging in male mice without inducing significant feminization. We recently reported that estrogen receptor α is required for the majority of 17α-E2-mediated benefits in male mice, but that 17α-E2 also attenuates fibrogenesis in liver, which is regulated by estrogen receptor ß (ERß)-expressing hepatic stellate cells (HSC). The current studies sought to determine if 17α-E2-mediated benefits on systemic and hepatic metabolism are ERß-dependent. We found that 17α-E2 treatment reversed obesity and related systemic metabolic sequela in both male and female mice, but this was partially blocked in female, but not male, ERßKO mice. ERß ablation in male mice attenuated 17α-E2-mediated benefits on hepatic stearoyl-coenyzme A desaturase 1 (SCD1) and transforming growth factor ß1 (TGF-ß1) production, which play critical roles in HSC activation and liver fibrosis. We also found that 17α-E2 treatment suppresses SCD1 production in cultured hepatocytes and hepatic stellate cells, indicating that 17α-E2 directly signals in both cell-types to suppress drivers of steatosis and fibrosis. We conclude that ERß partially controls 17α-E2-mediated benefits on systemic metabolic regulation in female, but not male, mice, and that 17α-E2 likely signals through ERß in HSCs to attenuate pro-fibrotic mechanisms.

Small Cell Carcinoma of the Gallbladder.

Primary neuroendocrine carcinoma of the gallbladder (GB) is a rare, highly dismal lethal disease with a fatal prognosis. A 45-year-old female presented with right upper abdomen pain and multiple vomiting episodes. Imaging studies showed diffuse thickening of the wall of the GB with locoregional invasion into the nearby structures with extensive abdominal lymph node metastasis and arteriovenous encasements. Ultrasound-guided fine-needle aspiration was done, which was diagnostic of small cell carcinoma of the GB. The patient was planned for palliative chemotherapy. A small cell variant of neuroendocrine carcinoma of the GB is a rare entity with a moribund lethality associated with it. Patients are diagnosed in advanced stages with not many treatment modalities to offer. Usually, patients are treated with palliative chemotherapy.

Tension Pneumoperitoneum as a Result of Diastatic Perforation.

Tension pneumoperitoneum is a vapid presentation of pneumoperitoneum, which generally refers to free air in the abdomen and can mimic abdominal compartment syndrome. A diastatic perforation in the abdomen refers to a perforation of the cecum due to a distal obstruction in the colon, manifesting as a closed-loop syndrome. We present a 46-year-old male diagnosed with obstructed left inguinal hernia who underwent hernioplasty. Postoperatively, the patient had progressive abdominal distention and abdominal pain. An abdominal x-ray and computed tomography of the abdomen showed massive air in the abdomen. The patient was diagnosed to have tension pneumoperitoneum. Needle decompression of the abdomen was done, and the patient underwent an emergency laparotomy. Intraoperatively, we found a large cecal perforation and a large amount of pneumoperitoneum. The patient underwent limited resection and ileostomy and ascending mucus fistula. Postoperatively, the patient had an uneventful course and was discharged.

Metabolic benefits of 17α-estradiol in liver are partially mediated by ERß in male mice.

Metabolic dysfunction underlies several chronic diseases. Dietary interventions can reverse metabolic declines and slow aging but remaining compliant is difficult. 17α-estradiol (17α-E2) treatment improves metabolic parameters and slows aging in male mice without inducing significant feminization. We recently reported that estrogen receptor α is required for the majority of 17α-E2-mediated benefits in male mice, but that 17α-E2 also attenuates fibrogenesis in liver, which is regulated by estrogen receptor ß (ERß)-expressing hepatic stellate cells (HSC). The current studies sought to determine if 17α-E2-mediated benefits on systemic and hepatic metabolism are ERß-dependent. We found that 17α-E2 treatment reversed obesity and related systemic metabolic sequela in both male and female mice, but this was partially blocked in female, but not male, ERßKO mice. ERß ablation in male mice attenuated 17α-E2-mediated benefits on hepatic stearoyl-coenyzme A desaturase 1 (SCD1) and transforming growth factor ß1 (TGF-ß1) production, which play critical roles in HSC activation and liver fibrosis. We also found that 17α-E2 treatment suppresses SCD1 production in cultured hepatocytes and hepatic stellate cells, indicating that 17α-E2 directly signals in both cell-types to suppress drivers of steatosis and fibrosis. We conclude that ERß partially controls 17α-E2-mediated benefits on systemic metabolic regulation in female, but not male, mice, and that 17α-E2 likely signals through ERß in HSCs to attenuate pro-fibrotic mechanisms.

Paraneoplastic leukemoid syndrome in squamous cell carcinoma of the forearm.

The paraneoplastic leukemoid reaction is a rare haematological paraneoplastic syndrome, which is typically seen with solid tumours and squamous cell carcinomas. As an indication of bone marrow infiltration and malignancy involvement, it indicates a poor outcome and a grave prognosis. We report a woman in her 50s, who presented with an ulcer over the right forearm. Biopsy revealed squamous cell carcinoma. The patient underwent radiological investigations, which showed the presence of metastatic squamous cell carcinoma. Incidentally, the patient was found to have leucocytosis, which was attributed to a paraneoplastic leukemoid reaction, after ruling out all other causes of leukemoid reaction. Due to metastatic disease, the patient was planned for palliative radiotherapy and the best supportive care.

Adipose tissue macrophages and their role in obesity-associated insulin resistance: an overview of the complex dynamics at play.

Obesity, a major global health concern, is characterized by serious imbalance between energy intake and expenditure leading to excess accumulation of fat in adipose tissue (AT). A state of chronic low-grade AT inflammation is prevalent during obesity. The adipose tissue macrophages (ATM) with astounding heterogeneity and complex regulation play a decisive role in mediating obesity-induced insulin resistance. Adipose-derived macrophages were broadly classified as proinflammatory M1 and anti-inflammatory M2 subtypes but recent reports have proclaimed several novel and intermediate profiles, which are crucial in understanding the dynamics of macrophage phenotypes during development of obesity. Lipid-laden hypertrophic adipocytes release various chemotactic signals that aggravate macrophage infiltration into AT skewing toward mostly proinflammatory status. The ratio of M1-like to M2-like macrophages is increased substantially resulting in copious secretion of proinflammatory mediators such as TNFα, IL-6, IL-1ß, MCP-1, fetuin-A (FetA), etc. further worsening insulin resistance. Several AT-derived factors could influence ATM content and activation. Apart from being detrimental, ATM exerts beneficial effects during obesity. Recent studies have highlighted the prime role of AT-resident macrophage subpopulations in not only effective clearance of excess fat and dying adipocytes but also in controlling vascular integrity, adipocyte secretions, and fibrosis within obese AT. The role of ATM subpopulations as friend or foe is determined by an intricate interplay of such factors arising within hyperlipidemic microenvironment of obese AT. The present review article highlights some of the key research advances in ATM function and regulation, and appreciates the complex dynamics of ATM in the pathophysiologic scenario of obesity-associated insulin resistance.

Neonatal intake of Omega-3 fatty acids enhances lipid oxidation in adipocyte precursors.

Establishing metabolic programming begins during fetal and postnatal development, and early-life lipid exposures play a critical role during neonatal adipogenesis. We define how neonatal consumption of a low omega-6 to -3 fatty acid ratio (n6/n3 FA ratio) establishes FA oxidation in adipocyte precursor cells (APCs) before they become adipocytes. In vivo, APCs isolated from mouse pups exposed to the low n6/n3 FA ratio had superior FA oxidation capacity, elevated beige adipocyte mRNAs Ppargc1α, Ucp2, and Runx1, and increased nuclear receptor NR2F2 protein. In vitro, APC treatment with NR2F2 ligand-induced beige adipocyte mRNAs and increased mitochondrial potential but not mass. Single-cell RNA-sequencing analysis revealed low n6/n3 FA ratio yielded more mitochondrial-high APCs and linked APC NR2F2 levels with beige adipocyte signatures and FA oxidation. Establishing beige adipogenesis is of clinical relevance, because fat depots with energetically active, smaller, and more numerous adipocytes improve metabolism and delay metabolic dysfunction.

Spontaneous Evisceration of Small Bowel in Incisional Hernia.

Spontaneous rupture of an incisional hernia leading to the evisceration of the intra-abdominal organs is one of the malefic complications seen in these patients. In addition to its rarity, it gets accompanied by possible lethality in the form of incarceration, sequential strangulation, necrosis, and eventual gangrene. If not treated aptly, the clinical scenario could lead to a life-threatening condition with a delay in timely intervention. With less than 20 documented cases, herein, we report a 48-year-old female with a previous history of a midline laparotomy who presented to us with an acute spontaneous evisceration of the small bowel. The patient was immediately decided on surgical management with exploratory laparotomy, adhesiolysis, and primary repair of the abdominal wall defect. Postoperatively, the patient improved without any complications.