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Mitochondria form a complex, interconnected reticulum that is maintained through coordination among biogenesis, dynamic fission, and fusion and mitophagy, which are initiated in response to various cues to maintain energetic homeostasis. These cellular events, which make up mitochondrial quality control, act with remarkable spatial precision, but what governs such spatial specificity is poorly understood. Herein, we demonstrate that specific isoforms of the cellular bioenergetic sensor, 5′ AMP-activated protein kinase (AMPKα1/α2/β2/γ1), are localized on the outer mitochondrial membrane, referred to as mitoAMPK, in various tissues in mice and humans. Activation of mitoAMPK varies across the reticulum in response to energetic stress, and inhibition of mitoAMPK activity attenuates exercise-induced mitophagy in skeletal muscle in vivo. Discovery of a mitochondrial pool of AMPK and its local importance for mitochondrial quality control underscores the complexity of sensing cellular energetics in vivo that has implications for targeting mitochondrial energetics for disease treatment.

Acute and chronic tissue injury results in the generation of a myriad of environmental cues that macrophages respond to by changing their phenotype and function. This phenotypic regulation is critical for controlling tissue inflammation and resolution. Here, we have identified the adaptor protein disabled homolog 2 (DAB2) as a regulator of phenotypic switching in macrophages. Dab2 expression was upregulated in M2 macrophages and suppressed in M1 macrophages isolated from both mice and humans, and genetic deletion of Dab2 predisposed macrophages to adopt a proinflammatory M1 phenotype. In mice with myeloid cell-specific deletion of Dab2 (Dab2fl/fl Lysm-Cre), treatment with sublethal doses of LPS resulted in increased proinflammatory gene expression and macrophage activation. Moreover, chronic high-fat feeding exacerbated adipose tissue inflammation, M1 polarization of adipose tissue macrophages, and the development of insulin resistance in DAB2-deficient animals compared with controls. Mutational analyses revealed that DAB2 interacts with TNF receptor-associated factor 6 (TRAF6) and attenuates IκB kinase β-dependent (IKKβ-dependent) phosphorylation of Ser536 in the transactivation domain of NF-κB p65. Together, these findings reveal that DAB2 is critical for controlling inflammatory signaling during phenotypic polarization of macrophages and suggest that manipulation of DAB2 expression and function may hold therapeutic potential for the treatment of acute and chronic inflammatory disorders.

Obesity-linked (type 2) diabetic nephropathy (T2DN) has become the largest contributor to morbidity and mortality in the modern world. Recent evidences suggest that inflammation may contribute to the pathogenesis of T2DN and T-regulatory cells (Treg) are protective. We developed a novel cytokine (named IL233) bearing IL-2 and IL-33 activities in a single molecule and demonstrated that IL233 promotes Treg and T-helper (Th) 2 immune responses to protect mice from inflammatory acute kidney injury. Here, we investigated whether through a similar enhancement of Treg and inhibition of inflammation, IL233 protects from T2DN in a genetically obese mouse model, when administered either early or late after the onset of diabetes. In the older mice with obesity and microalbuminuria, IL233 treatment reduced hyperglycemia, plasma glycated proteins, and albuminuria. Interestingly, IL233 administered before the onset of microalbuminuria not only strongly inhibited the progression of T2DN and reversed diabetes as indicated by lowering of blood glucose, normalization of glucose tolerance and insulin levels in islets, but surprisingly, also attenuated weight gain and adipogenicity despite comparable food intake. Histological examination of kidneys showed that saline control mice had severe inflammation, glomerular hypertrophy, and mesangial expansion, which were all attenuated in the IL233 treated mice. The protection correlated with greater accumulation of Tregs, group 2 innate lymphoid cells (ILC2), alternately activated macrophages and eosinophils in the adipose tissue, along with a skewing toward T-helper 2 responses. Thus, the novel IL233 cytokine bears therapeutic potential as it protects genetically obese mice from T2DN by regulating multiple contributors to pathogenesis. A novel bifunctional cytokine IL233, bearing IL-2 and IL-33 activities reverses inflammation and protects from type-2 diabetic nephropathy through promoting T-regulatory cells and type 2 immune response.

Background/Objectives: The micronutrient iron is closely connected to inflammation and is among the complex factors contributing to beta-cell failure in diabetes. High levels of dietary iron increase the risk of developing type 2 diabetes, and excessive iron uptake by beta-cells can cause oxidative stress and inhibit function. Elevated levels of proinflammatory cytokines in obese individuals, such as interleukin (IL)-1beta and IL-6, increase the risk of developing type 2 diabetes, and there is evidence that these low levels of circulating cytokines can lead to islet dysfunction. Methods: In this study, gene microarray and other data were analyzed for expression differences in islets treated for 48 h with 10 pg/mL IL-1beta + 20 pg/mL IL-6 as a model of low-grade inflammation versus untreated. Results: Three iron-associated genes were among the most cytokine-sensitive in the mouse genome: Hamp, Steap4, and Lcn2. These proteins are all involved with increasing/retaining cellular iron. We hypothesized that increased cellular iron would lead to increased susceptibility to ferroptosis. Surprisingly, 24 h pre-exposure to low-grade inflammation, which upregulates this iron-gene network, prevented subsequent erastin-induced ferroptosis. We also found that Steap4 overexpression reduced islet dysfunction caused by high-dose proinflammatory cytokines (10× low-dose), suggesting an overall protective effect. Steap4 overexpression also upregulated Hamp and Lcn2, suggesting Steap4 regulates these cytokine-sensitive iron genes.; in contrast, ferritin and ferroportin gene expression, which are not sensitive to cytokines, were unchanged. Conclusions: These data suggest an inflammation-induced network of genes involved in cellular iron uptake and retention plays a protective role in islets against oxidative stress and ferroptosis.

Abstract Microneedle patch device has been widely utilized for transdermal drug delivery in pain management, but is challenged by accurate control of drug release and subsequent diffusion to human body. The recent emerging wearable electronics that could be integrated with microneedle devices offers a facile approach to address such a challenge. Here a 3D printed microheater integrated drug-encapsulated microneedle patch system for drug delivery is presented. The ink solution comprised of polydimethylsiloxane (PDMS) and multiwalled carbon nanotubes (MWCNTs) with mass concentration of up to 45% is prepared and used to print crack-free stretchable microheaters on substrates with a broad range of materials and geometric curves. The adhesion strength of printed microheater on microneedle patch in elevated temperatures are measured to evaluate their integration performance. Assessments of encapsulated drug release into rat’s skin are confirmed by examining degradation of microneedles, skin morphologies, and released fluorescent signals. Results and demonstrations established here creates a new opportunity for developing sensor controlled smart microneedle patch systems by integrating with wearable electronics, potentially useful in clinic and biomedical research.

Background Rajasthan state of India is exhibiting diverse malaria transmission patterns shaped by its varied ecological landscapes. This study explores five decades (1975–2023) of malaria patterns in different ecogeographical regions of Rajasthan. Methods The four ecogeographical regions of Rajasthan, namely Desert, Aravalli, Gangetic plain, and Hadoti Plateau, were taken into consideration to identify spatio-temporal malaria trend, Anopheles species diversity, and insecticide susceptibility status of malaria vectors with public health insecticides. Additionally, correlation analysis between malaria incidence (API) and average annual rainfall was conducted to understand the climatic influence on transmission dynamics. Results Over five decades, Malaria peaked in 1976 and 1996, followed by a sharp decline post-2000. Median API ranged from 1 (Gangetic plain) to 1.93 (Hadoti Plateau), with frequent outbreaks in the Gangetic plain and Hadoti Plateau regions. Rainfall was positively correlated with API in Desert region (r = 0.39; p = 0.006) and Gangetic Plain (r = 0.35; p = 0.014) regions. Hadoti Plateau region showed a weak negative correlation with rains (r = −0.08; p = 0.58). Anopheles stephensi and Anopheles culicifacies were predominant vectors, resistant to organochlorides and organophosphates, but susceptible to synthetic pyrethroids. Aravalli showed the highest Plasmodium falciparum prevalence among all regions. Discussion The study highlights the need for region-specific vector control, real-time surveillance, and adaptive policies to tackle malaria challenges. High-risk areas like Aravalli and Hadoti Plateau require focused interventions combining community awareness, improved healthcare access, and climate-responsive strategies. Integrating ecological insights with innovative tools such as GIS mapping and interactive dashboards can enhance monitoring, guide targeted actions, and reduce vector density. These efforts are crucial to sustain progress and accelerate malaria elimination across the diverse ecological zones of Rajasthan.

Contamination of drinking water with endocrine-disrupting chemicals (EDCs) raises concerns over the security and long-term sustainability of clean water supplies as well as human exposure via daily water intake. In this study, the seasonal disparity and occurrence of six phthalates and bisphenol-A in the drinking water supply system and associated health-risk were examined. The detection frequencies of the ∑6PAEs ranged from 24 to 100% in the winter whereas; in summer it is below the detection limit up to 100%. DEHP was the most prevalent phthalate congener ranging from 1.14 to 8351.85 µg/L (winter) and 0.552 to 410.29 µg/L (summer) surpassing the permissible limit. However, BPA concentrations were found under the permissible limit. The results suggested that PAEs concentration displayed significant seasonal variations with the highest in winter and the lowest in summer. The exposure to PAEs and BPA from drinking water was assessed, indicating a possible health risk to humans with a hazard quotient (HQ) > 1 for DEHP only. The findings necessitate an immediate scrutiny of these EDCs in drinking water supply system and are critical for implementing effective technologies at the WTP scale to ensure the quality and safety of drinking water to ascertain human and environmental health.

Apoptosis: how cells become targets Apoptosis occurs in essentially all tissues as part of normal development and homeostasis. Yet even in tissues with high cellular turnover, apoptotic cells are rarely seen; this has been attributed to the ability of apoptotic cells to advertise their presence via release of 'find-me' signals to recruit phagocytes and initiate prompt clearance. It has been unclear, however, what type of find-me signals are released by apoptotic cells and how these are sensed by phagocytes. In this paper apoptotic cells are shown to release ATP and UTP that act as a 'find me ' signal and chemoattractant for phagocytes expressing the P2Y 2 ATP/UTP receptor. The efficient removal of apoptotic cells in vivo is thought to be due to the release of 'find-me' signals by apoptotic cells that recruit motile phagocytes. Here, the caspase-dependent release of ATP and UTP during the early stages of apoptosis is demonstrated. ATP and UTP are found to act as chemoattractants in a process mediated through the ATP/UTP receptor P2Y 2 , which is present on monocytes and macrophages. Phagocytic removal of apoptotic cells occurs efficiently in vivo such that even in tissues with significant apoptosis, very few apoptotic cells are detectable 1 . This is thought to be due to the release of ‘find-me’ signals by apoptotic cells that recruit motile phagocytes such as monocytes, macrophages and dendritic cells, leading to the prompt clearance of the dying cells 2 . However, the identity and in vivo relevance of such find-me signals are not well understood. Here, through several lines of evidence, we identify extracellular nucleotides as a critical apoptotic cell find-me signal. We demonstrate the caspase-dependent release of ATP and UTP (in equimolar quantities) during the early stages of apoptosis by primary thymocytes and cell lines. Purified nucleotides at these concentrations were sufficient to induce monocyte recruitment comparable to that of apoptotic cell supernatants. Enzymatic removal of ATP and UTP (by apyrase or the expression of ectopic CD39) abrogated the ability of apoptotic cell supernatants to recruit monocytes in vitro and in vivo . We then identified the ATP/UTP receptor P2Y 2 as a critical sensor of nucleotides released by apoptotic cells using RNA interference-mediated depletion studies in monocytes, and macrophages from P2Y 2 -null mice 3 . The relevance of nucleotides in apoptotic cell clearance in vivo was revealed by two approaches. First, in a murine air-pouch model, apoptotic cell supernatants induced a threefold greater recruitment of monocytes and macrophages than supernatants from healthy cells did; this recruitment was abolished by depletion of nucleotides and was significantly decreased in P2Y 2 -/- (also known as P2ry2 -/- ) mice. Second, clearance of apoptotic thymocytes was significantly impaired by either depletion of nucleotides or interference with P2Y receptor function (by pharmacological inhibition or in P2Y 2 -/- mice). These results identify nucleotides as a critical find-me cue released by apoptotic cells to promote P2Y 2 -dependent recruitment of phagocytes, and provide evidence for a clear relationship between a find-me signal and efficient corpse clearance in vivo .

Over the last few years, the microbiome has emerged as a high-priority research area to discover missing links between brain health and gut dysbiosis. Emerging evidence suggests that the commensal gut microbiome is an important regulator of the gut–brain axis and plays a critical role in brain physiology. Engaging microbiome-generated metabolites such as short-chain fatty acids, the immune system, the enteric nervous system, the endocrine system (including the HPA axis), tryptophan metabolism or the vagus nerve plays a crucial role in communication between the gut microbes and the brain. Humans are exposed to a wide range of pollutants in everyday life that impact our intestinal microbiota and manipulate the bidirectional communication between the gut and the brain, resulting in predisposition to psychiatric or neurological disorders. However, the interaction between xenobiotics, microbiota and neurotoxicity has yet to be completely investigated. Although research into the precise processes of the microbiota–gut–brain axis is growing rapidly, comprehending the implications of environmental contaminants remains challenging. In these milieus, we herein discuss how various environmental pollutants such as phthalates, heavy metals, Bisphenol A and particulate matter may alter the intricate microbiota–gut–brain axis thereby impacting our neurological and overall mental health.

IntroductionMost oral cancers in India present in advanced stages and tend to have poor oncological outcomes. Chemotherapy has been associated with improved oncological outcomes in various cancers, but its role in oral cancer is still not well-defined in curative settings beyond radiosensitisation. Despite an excellent response rate, neoadjuvant chemotherapy trials have failed to show an oncological advantage. Earlier studies were limited by their heterogeneous patient population, including all head and neck subsites, and included both inoperable cancer and early-stage operable cases. Due to such patient selection, the intended results were never met. Patients with biologically aggressive diseases (advanced nodal disease) may derive greater benefit from induction chemotherapy (ICT). Therefore, we aim to determine the oncological advantage of adding ICT to oral squamous cell cancer with advanced nodal disease (N2–N3).Methods and analysisThe study is an open-label, multicentre, randomised controlled trial, with an allocation ratio of 1:1, being conducted at seven leading cancer centres in India. The primary objective is to compare survival outcomes with and without ICT before surgery in patients with oral squamous cell carcinoma (OSCC) and advanced nodal disease, specifically focusing on 2-year disease-free survival (DFS). Secondary objectives include assessing overall survival (OS), clinical and pathological response rates, treatment compliance, treatment completion rates, adverse events, treatment-related toxicity (using Common Terminology Criteria for Adverse Events, V.5.0), quality of life (measured with Functional Assessment of Cancer Therapy-General and Functional Assessment of Cancer Therapy-Head and Neck) and postoperative complications (using the modified Clavien-Dindo classification).The study population consists of patients with operable OSCC and advanced nodal disease (N2–N3), adequate organ function, aged 18–65 years and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2. The treatment arms are the standard arm Surgery arm (SURG), which involves surgery followed by adjuvant radiotherapy with or without concurrent chemotherapy, and the experimental arm (ICT), in which patients will receive two cycles of ICT using either cisplatin, docetaxel and 5-fluorouracil or cisplatin, docetaxel and capecitabine, followed by surgery and adjuvant radiotherapy with or without concurrent chemotherapy. The sample size was calculated to detect an HR of 0.67 with 80% power. A total of 184 events are required, and with an accrual rate of 15 patients per month, 300 patients will be recruited. DFS analysis will occur 32 months after the trial begins, and follow-up will continue for 5 years. OS analysis will be conducted when 184 deaths are observed. Taking 10% of the withdrawal of consent, a total of 346 patients need to be included.Ethics and disseminationThis trial aims to establish the potential superiority of ICT or definitively determine its futility in OSCC with advanced nodal disease. A positive outcome could provide practice-changing data, particularly for Indian patients, whereas negative results could halt the use of ICT in this setting, directing research efforts towards more effective treatment strategies.Trial registration numberCTRI/2024/03/064586; NCT06737822; Institutional Ethics Committee (IEC) number: AIIMS/IEC/2023/4622 (lead site).