Regeneration of Thyroid Glands in the Spleen Restores Homeostasis in Thyroidectomy Mice.

Surgical removal of the thyroid gland (TG) for treating thyroid disorders leaves the patients on lifelong hormone replacement that partially compensates the physiological needs, but regenerating TG is challenging. Here, an approach is reported to regenerate TG within the spleen for fully restoring the thyroid's functions in mice, by transplanting thyroid tissue blocks to the spleen. Within 48 h, the transplanted tissue efficiently revascularizes, forming thyroid follicles similar to the native gland after 4 weeks. Structurally, the ectopically generated thyroid integrates with the surrounding splenic tissue while maintaining its integrity, separate from the lymphatic tissue. Functionally, it fully restores the native functions of the TG in hormone regulation in response to physiological stimuli, outperforming the established method of oral levothyroxine therapy in maintaining systemic homeostasis. The study demonstrates the full restoration of thyroid functions post-thyroidectomy by intrasplenic TG regeneration, providing fresh insights for designing novel therapies for thyroid-related disorders.

Risk factors and predictive models of poor prognosis and delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage complicated with hydrocephalus.

Objective: To evaluate the correlation of serum biological markers and related scales to the occurrence of delayed cerebral ischemia and clinical prognosis in patients with aneurysmal subarachnoid hemorrhage (aSAH) complicated with acute hydrocephalus before admission. Methods: The clinical data of 227 patients with pre-admission aSAH complicated with acute hydrocephalus admitted to Henan Provincial People's Hospital from April 2017 to December 2020 were retrospectively analyzed. Patients were grouped according to the presence or absence of delayed cerebral ischemia (DCI) after surgery and the prognosis at 6 months after discharge. Univariate and multivariable logistic regression analysis were performed to analyze the relationship between serum biological indicators combined with aneurysm related clinical score scale and the occurrence and prognosis of delayed cerebral ischemia. ROC curves and nomogram were drawn. Results: Multivariable Logistic regression analysis showed that high Hunt-Hess grade and surgical clipping were independent risk factors for postoperative DCI (P < 0.05). Older age, higher Hunt-Hess grade, higher CRP and neutrophil levels were independent risk factors for poor prognosis at 6 months after surgery (P < 0.05). ROC curve analysis showed that the area under the curve (AUC) of Hunt-Hess grade and surgical method for predicting DCI in patients with aSAH combined with hydrocephalus after surgery were 0.665 and 0.593. The combined AUC of Hunt-Hess grade and surgical method was 0.685, the sensitivity was 64.9%, and the specificity was 64.7%. The AUC of CRP, neutrophil, age and Hunt-Hess grade for predicting poor prognosis in patients with aSAH combined with hydrocephalus at 6 months after surgery were 0.804, 0.735, 0.596, 0.757, respectively. The combined AUC of CRP, neutrophil, age, Hunt-Hess grade was 0.879, the sensitivity was 79%, and the specificity was 84.5%. According to the correction curve, the predicted probability of the nomogram is basically consistent with the actual probability. Conclusion: Hunt-Hess grade and surgical method are independent predictors of postoperative DCI in patients with aSAH complicated with hydrocephalus. "CRP," "neutrophil," "age" and "Hunt-Hess grade" at admission are independent predictors of clinical prognosis in patients with aSAH complicated with hydrocephalus. The combination of the above indicators has high predictive value.

Link between sterile inflammation and cardiovascular diseases: Focus on cGAS-STING pathway in the pathogenesis and therapeutic prospect.

Sterile inflammation characterized by unresolved chronic inflammation is well established to promote the progression of multiple autoimmune diseases, metabolic disorders, neurodegenerative diseases, and cardiovascular diseases, collectively termed as sterile inflammatory diseases. In recent years, substantial evidence has revealed that the inflammatory response is closely related to cardiovascular diseases. Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway which is activated by cytoplasmic DNA promotes the activation of interferon regulatory factor 3 (IRF3) or nuclear factor-κB (NF-κB), thus leading to upregulation of the levels of inflammatory factors and interferons (IFNs). Therefore, studying the role of inflammation caused by cGAS-STING pathway in cardiovascular diseases could provide a new therapeutic target for cardiovascular diseases. This review focuses on that cGAS-STING-mediated inflammatory response in the progression of cardiovascular diseases and the prospects of cGAS or STING inhibitors for treatment of cardiovascular diseases.

Association of Healthy Diet and Physical Activity With Breast Cancer: Lifestyle Interventions and Oncology Education.

Global cancer statistics suggest that breast cancer (BC) is the most diagnosed cancer in women, with an estimated 2. 3 million new cases reported in 2020. Observational evidence shows a clear link between prevention and development of invasive BC and lifestyle-based interventions such as a healthy diet and physical activity. The recent findings reveal that even minimal amounts of daily exercise and a healthy diet reduced the risk of BC, mitigated the side effects of cancer treatment, and stopped the recurrence of cancer in the survivors. Despite the myriad benefits, the implementation of these lifestyle interventions in at-risk and survivor populations has been limited to date. Given the need to disseminate information about the role of physical activity and nutrition in BC reduction, the review aimed to present the recent scientific outreach and update on associations between the lifestyle interventions and BC outcomes to narrow the gap and strengthen the understanding more clearly. This review covers more direct, detailed, and updated scientific literature to respond to frequently asked questions related to the daily lifestyle-based interventions and their impact on BC risk and survivors. This review also highlights the importance of the oncology provider's job and how oncology education can reduce the BC burden.

Reprogramming the spleen into a functioning 'liver' in vivo.

OBJECTIVE: Liver regeneration remains one of the biggest clinical challenges. Here, we aim to transform the spleen into a liver-like organ via directly reprogramming the splenic fibroblasts into hepatocytes in vivo. DESIGN: In the mouse spleen, the number of fibroblasts was through silica particles (SiO2) stimulation, the expanded fibroblasts were converted to hepatocytes (iHeps) by lentiviral transfection of three key transcriptional factors (Foxa3, Gata4 and Hnf1a), and the iHeps were further expanded with tumour necrosis factor-α (TNF-α) and lentivirus-mediated expression of epidermal growth factor (EGF) and hepatocyte growth factor (HGF). RESULTS: SiO2 stimulation tripled the number of activated fibroblasts. Foxa3, Gata4 and Hnf1a converted SiO2-remodelled spleen fibroblasts into 2×106 functional iHeps in one spleen. TNF-α protein and lentivirus-mediated expression of EGF and HGF further enabled the total hepatocytes to expand to 8×106 per spleen. iHeps possessed hepatic functions-such as glycogen storage, lipid accumulation and drug metabolism-and performed fundamental liver functions to improve the survival rate of mice with 90% hepatectomy. CONCLUSION: Direct conversion of the spleen into a liver-like organ, without cell or tissue transplantation, establishes fundamental hepatic functions in mice, suggesting its potential value for the treatment of end-stage liver diseases.

Inhibiting STAT5 significantly attenuated Ang II-induced cardiac dysfunction and inflammation.

Cardiac hypertrophy is a compensatory response to chronic pressure overload. Excessive angiotensin II is an important inducer of cardiac hypertrophy. Signal transducers and activators of transcription 5(STAT5), a member of STATs family which can mediate the transcription of interferon (IFN) genes and immune response has recently been reported to have a close link with non-tumor diseases. However, much remains unknown about how STAT5 might be involved in the progression of hypertrophy. Herein, STAT5-IN-1, a STAT5 inhibitor, was orally administered to Ang II-induced mice. Ang II-stimulated H9c2s cells were used as cell models for the in vitro experiment. Efforts were made to investigate the effects of STAT5-IN-1 in Ang II-induced mice, along with potential mechanism that might account for these effects, which involved treatment with STAT5 inhibitor and the use of siRNA-induced gene silencing. The findings demonstrated that STAT5 inhibitor resulted in a substantial decrease in cardiac hypertrophy in Ang II-induced mice and that this effect is mediated by decreasing inflammation, thus identifying one mechanism of Ang II-induced STAT5 activation. Based on these findings, it can be argued that targeting STAT5 mighted be considered as a potential therapeutic strategy for reducing hypertrophy.

Activation of STING Pathway Contributed to Cisplatin-Induced Cardiac Dysfunction via Promoting the Activation of TNF-α-AP-1 Signal Pathway.

Cardiovascular complications are a well-documented limitation of conventional cancer chemotherapy. As a notable side effect of cisplatin, cardiotoxicity represents a major obstacle to the treatment of cancer. Recently, it has been reported that cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) signaling pathway was associated with the occurrence and development of cardiovascular diseases. However, the effect of STING on cardiac damage caused by cisplatin remains unclear. In this study, cisplatin was shown to activate the cGAS-STING signaling pathway, and deficiency of STING attenuated cisplatin-induced cardiotoxicity in vivo and in vitro. Mechanistically, the STING-TNF-α-AP-1 axis contributed to cisplatin-induced cardiotoxicity by triggering cardiomyocyte apoptosis. In conclusion, our results indicated that STING might be a critical regulator of cisplatin-induced cardiotoxicity and be considered as a potential therapeutic target for preventing the progression of chemotherapy-associated cardiovascular complications.

Delivering Antisense Oligonucleotides across the Blood-Brain Barrier by Tumor Cell-Derived Small Apoptotic Bodies.

The blood-brain barrier (BBB) is the most restrictive and complicated barrier that keeps most biomolecules and drugs from the brain. An efficient brain delivery strategy is urgently needed for the treatment of brain diseases. Based on the studies of brain-targeting extracellular vesicles (EVs), the potential of using small apoptotic bodies (sABs) from brain metastatic cancer cells for brain-targeting drug delivery is explored. It is found that anti-TNF-α antisense oligonucleotide (ASO) combined with cationic konjac glucomannan (cKGM) can be successfully loaded into sABs via a transfection/apoptosis induction process and that the sABs generated by B16F10 cells have an extraordinarily high brain delivery efficiency. Further studies suggest that ASO-loaded sABs (sCABs) are transcytosed by b. End3 (brain microvascular endothelial cells, BMECs) to penetrate the BBB, which is mediated by CD44v6, and eventually taken up by microglial cells in the brain. In a Parkinson's disease (PD) mouse model, sCABs dramatically ameliorate PD symptoms via the anti-inflammatory effect of ASO. This study suggests that sABs from brain metastatic cancer cells are excellent carriers for brain-targeted delivery, as they have not only an extraordinary delivery efficiency but also a much higher scale-up production potential than other EVs.

Smectite promotes probiotic biofilm formation in the gut for cancer immunotherapy.

Administration of probiotics to regulate the immune system is a potential anti-tumor strategy. However, oral administration of probiotics is ineffective because of the poor inhabitation of exogenous bacteria in host intestines. Here we report that smectite, a type of mineral clay and established anti-diarrhea drug, promotes expansion of probiotics (especially Lactobacillus) in the murine gut and subsequently elicits anti-tumor immune responses. The ion-exchangeable microstructure of smectite preferentially promotes lactic acid bacteria (LABs) to form biofilms on smectite in vitro and in vivo. In mouse models, smectite laden with LAB biofilms (Lactobacillus and Bifidobacterium) inhibits tumor growth (when used alone) and enhances the efficacy of chemotherapy or immunotherapy (when used in combination with either of them) by activating dendritic cells (DCs) via Toll-like receptor 2 (TLR2) signaling. Our findings suggest oral administration of smectite as a promising strategy to enrich probiotics in vivo for cancer immunotherapy.

Biological effect of ribosomal protein L32 on human breast cancer cell behavior.

Breast cancer (BC) is the most common malignancy among women worldwide. However, identifying effective biomarkers for the diagnosis and treatment of BC is challenging. Based on our previously developed 'humanized' mouse model of BC, microarray expression analysis was performed and multiple differentially expressed genes, including ribosomal protein (RP) L32, were screened. Recent reports have revealed that RPs are relevant to the development and progression of cancer. However, the expression and function of RPL32 in BC remains unknown. Therefore, in the present study, the role of RPL32 in the development of BC was explored. Immunohistochemical staining and reverse transcription­quantitative PCR were used, and it was found that RPL32 was upregulated in human BC tissues and cells. Cell Counting Kit­8, cell invasion and migration assays were performed, which demonstrated that RPL32 knockdown using lentivirus­delivered small interfering RNA inhibited the migration and invasion of BC cells in vitro and in vivo (nude mouse model). Moreover, western blotting showed that RPL32 knockdown decreased the expression levels of matrix metalloproteinase (MMP)­2 and MMP­9. Thus, the present findings indicated a potential oncogenic role of RPL32, suggesting that it may be a novel target for molecular targeted therapy in patients with BC.

Transforming the spleen into a liver-like organ in vivo.

Regenerating human organs remains an unmet medical challenge. Suitable transplants are scarce, while engineered tissues have a long way to go toward clinical use. Here, we demonstrate a different strategy that successfully transformed an existing, functionally dispensable organ to regenerate another functionally vital one in the body. Specifically, we injected a tumor extract into the mouse spleen to remodel its tissue structure into an immunosuppressive and proregenerative microenvironment. We implanted autologous, allogeneic, or xenogeneic liver cells (either primary or immortalized), which survived and proliferated in the remodeled spleen, without exerting adverse responses. Notably, the allografted primary liver cells exerted typical hepatic functions to rescue the host mice from severe liver damages including 90% hepatectomy. Our approach shows its competence in overcoming the key challenges in tissue regeneration, including insufficient transplants, immune rejection, and poor vascularization. It may be ready for translation into new therapies to regenerate large, complex human tissue/organs.

An "all-in-one" scaffold targeting macrophages to direct endogenous bone repair in situ.

Scaffolds for tissue repair are designed in an increasingly complicated manner to meet multi-facet biological needs during the healing process. However, overly sophisticated design, especially the use of multiple components and delivery of exogenous cells, hampers the bench-to-bedside translation. Here, a multi-functional - yet mono-compositional - bioactive scaffold is devised to mediate the full-range, endogenous bone repair. Based on immunoactivity screening, a chemically-modified glucomannan polysaccharide is selected and processed into an anisotropic porous scaffold, which accurately stimulates macrophages to produce pro-regenerative cytokines. These cytokines effectively enhance the recruitment ("R") and induced osteogenesis ("IO") of the bone progenitor cells in situ. Meanwhile, the anisotropic porosity and carbohydrate signal of the scaffold facilitate differential adhesion ("A") and distribution ("D") of the macrophages and bone progenitor cells - enabling the former's accumulation at the surface while encouraging the latter's infiltration into the scaffold. Implanted in a rat calvarial defect model, this "RADIO" system effectively promotes healing over 12 weeks, with the obvious formation of hard callus through the scaffold. In summary, RADIO integrates multiple functions into one single scalable system ("all-in-one") to govern the dynamic bone-repair process, by harnessing the power of host macrophages. RADIO represents an open platform to solving the long-lasting complexity-versus-simplicity dilemma in biomaterials design. STATEMENT OF SIGNIFICANCE: Biomaterials as versatile tools for tissue repair are becoming increasingly complicated, yet overly sophisticated design - especially the use of multiple components, exogenous cells, and overdosed growth factors - hampers their clinical application. The pre-requisite for designing a successful integrative scaffold is to identify an inherent biological target responding to biomaterial signals, thereby efficiently and safely promoting tissue repair via the endogenous healing capability instead of extra multifarious biochemical components. For bone regeneration, the pivotal regulator is macrophages. Through activating host macrophages, our single-component scaffold system coordinates the entire bone regenerative cascade in situ and induces successful bone regeneration in a calvarial defect model. This scaffold represents a scalable and multi-functional approach to effectively simplify the sophisticated design in regenerative medicine.

Synthesis and Evaluation of Camptothecin Antibody-Drug Conjugates.

Antibody-drug conjugates (ADCs) that incorporate the exatecan derivative DXd in their payload are showing promising clinical results in solid tumor indications. The payload has an F-ring that also contains a second chiral center, both of which complicate its synthesis and derivatization. Here we report on new camptothecin-ADCs that do not have an F-ring in their payloads yet behave similarly to DXd-bearing conjugates in vitro and in vivo. This simplification allows easier derivatization of camptothecin A and B rings for structure-activity relationship studies and payload optimization. ADCs having different degrees of bystander killing and the ability to release hydroxyl or thiol-bearing metabolites following peptide linker cleavage were investigated.

A Case Study Comparing Heterogeneous Lysine- and Site-Specific Cysteine-Conjugated Maytansinoid Antibody-Drug Conjugates (ADCs) Illustrates the Benefits of Lysine Conjugation.

Antibody-drug conjugates are an emerging class of cancer therapeutics constructed from monoclonal antibodies conjugated with small molecule effectors. First-generation molecules of this class often employed heterogeneous conjugation chemistry, but many site-specifically conjugated ADCs have been described recently. Here, we undertake a systematic comparison of ADCs made with the same antibody and the same macrocyclic maytansinoid effector but conjugated either heterogeneously at lysine residues or site-specifically at cysteine residues. Characterization of these ADCs in vitro reveals generally similar properties, including a similar catabolite profile, a key element in making a meaningful comparison of conjugation chemistries. In a mouse model of cervical cancer, the lysine-conjugated ADC affords greater efficacy on a molar payload basis. Rather than making general conclusions about ADCs conjugated by a particular chemistry, we interpret these results as highlighting the complexity of ADCs and the interplay between payload class, linker chemistry, target antigen, and other variables that determine efficacy in a given setting.

Growing Trans-Species Islets in Tumor Extract-Remodeled Testicles.

Although pancreatic islet transplantation holds promise for the treatment of type I diabetes, its application has been significantly hampered by transplant rejection. Here, an approach is demonstrated to support trans-species islet beta cells from a rat to grow and function in the body of a mouse host while overcoming graft rejection. This approach, which builds on remodeling of the mouse testicle by local injection of a tumor homogenate, establishes an immunosuppressive and proregenerative niche in the testicle. This remodeling proves necessary and effective in shaping the testicle into a unique site to accommodate xenograft cells. Rat pancreatic beta cells-from both the insulinoma (cancer cells) and pancreatic islet (normal tissue)-survive, grow, and form a desirable morphology in the remodeled mouse testicle. Notably, when hyperglycemia is induced in the host body, these xenografts secrete insulin to regulate the blood glucose level in mice for as long as 72 days. Furthermore, no graft rejection, acute inflammation, or safety risks are observed throughout the study. In summary, it is demonstrated that the growth of xenogeneic insulinoma cells in a mouse testicle might serve as an alternative approach for islet transplantation.

Producing anti-inflammatory macrophages by nanoparticle-triggered clustering of mannose receptors.

Macrophages are highly plastic cells that can either mediate or suppress inflammation, depending on their cellular phenotype and cytokine secretion. Inducing macrophages from an inflammatory ('M1') to anti-inflammatory ('M2') phenotype has significant implications for the treatment of inflammatory diseases and regeneration of injured tissues. Although certain cytokines, such as interleukin-4 and -13, are known to induce this phenotypic switch, their therapeutic use in vivo has both safety and efficacy concerns. Here, we demonstrate an alternative approach to change macrophage phenotype from M1 to M2, through inducing the clustering of mannose receptors (MR) on the cell surface, by using carbohydrate-presenting substrates. We prepared and screened glucomannan-decorated silicon oxide of different sizes ranging from 10 to 1000 nm, and identified one type (KSiNP30) that could potently induce MR clustering on macrophages and thereby stimulated the cells into an M2 phenotype - as an unexpected consequence of MR activation. Further administration of KSiNP30 in a murine model of inflammatory bowel disease efficiently alleviated the colitis symptoms, indicating the translational potential of our finding for therapeutic applications. In summary, we report for the first time an approach to modulate cellular immune responses by manipulating the assembly of cell-surface receptors, without the aid of cytokines. Our approach may provide insights for the development of new anti-inflammatory therapies.

Long Noncoding RNA Meg3 Regulates Mafa Expression in Mouse Beta Cells by Inactivating Rad21, Smc3 or Sin3α.

BACKGROUND/AIMS: The main pathogenic mechanism of diabetes is a decrease in the number of islet beta cells or a decline in their function. Recent studies have shown that pancreatic long noncoding RNAs (lncRNAs) have a high degree of tissue specificity and may be involved in the maintenance of islet cells function and the development of diabetes. The aim of this study was to investigate the molecular regulatory mechanism of mouse maternal expressed gene 3 (Meg3) in insulin biosynthesis in pancreatic islets. METHODS: Chromatin immunoprecipitation-quantitative polymerase chain reaction (qPCR) and RNA immunoprecipitation-qPCR were used to investigate the molecular mechanism of lncRNA Meg3 in insulin biosynthesis by regulating v-Maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MafA), a mature beta cell marker in the MIN6 beta cell line. Further, the expression levels of Meg3, Ezh2, MafA, Rad21, Smc3, and Sin3α were analyzed in vivo and in vitro by RT-PCR and western blotting. RESULTS: Intranuclear lncRNA Meg3 can bind EZH2, a methyltransferase belonging to the Polycomb repressive complex-2, in pancreatic islet cells. In addition, knockdown of Ezh2 can also inhibit the expression of MafA and Ins2, while expression levels of Rad21, Smc3, and Sin3α are upregulated, by interfering with Ezh2 or Meg3 in pancreatic beta cells. Knockdown of Meg3 resulted in the loss of EZH2 binding and H3K27 trimethylation occupancy of Rad21, Smc3, and Sin3α promoter regions. The inhibition of Rad21, Smc3, or Sin3α, which directly act on the MafA promoter, leads to upregulated expression of MafA in both MIN6 cells and mouse islets. Moreover, the synthesis and secretion of insulin were increased by inhibition of these transcription factors. CONCLUSIONS: Pancreatic lncRNA Meg3 can epigenetically regulate the expression of Rad21, Smc3, and Sin3α via EZH2-driven H3K27 methylation. By inhibiting the expression of Rad21, Smc3, or Sin3α, Meg3 promotes the expression of MafA and affects the production of insulin.

Downregulation of Long Noncoding RNA Gas5 Affects Cell Cycle and Insulin Secretion in Mouse Pancreatic ß Cells.

BACKGROUND: Evidence shows that long non-coding RNAs (lncRNAs) are involved in individual development, cell differentiation, cell cycle processes and other important life processes and are closely related to major human diseases, including diabetes. Recent studies have reported that lncRNAs are involved in ß cell functions and that lncRNA Gas5 levels decreased in T2DM patients' serum. The purpose of this study was to clarify the role of lncRNA Gas5 in mouse ß cell functions in vitro and in vivo. METHODS: lncRNA Gas5 expression in T2DM and normal mouse tissues was analyzed using qRT-PCR. RNAi, qRT-PCR, Annexin V-FITC assays, western blot, GSIS and RIA were performed to detect the effects of lncRNA Gas5 on insulin synthesis and secretion in vitro and in vivo. RESULTS: The lncRNA Gas5 level was significantly decreased in db/db mice. However, lncRNA Gas5 expression was relatively high in the pancreas of normal mice. Knockdown of lncRNA Gas5 expression led to cell cycle G1 arrest and impaired insulin synthesis and secretion in Min6 cells. Further, knockdown of lncRNA Gas5 expression in primary isolated islets resulted in decreased expression of insulin gene and transcription factors, Pdx1 and MafA. These results indicate that lncRNA Gas5 might perform as a new regulator, maintaining ß cell identity and function by affecting insulin synthesis and secretion.

Intraorgan Targeting of Gold Conjugates for Precise Liver Cancer Treatment.

Intraorgan targeting of chemical drugs at tumor tissues is essential in the treatment of solid tumors that express the same target receptor as normal tissues. Here, asialoglycoprotein receptor (ASGP-R)-targeting paclitaxel-conjugated gold nanoparticles (Gal/PTX-GNPs) are fabricated as a demonstration to realize the precise treatment of liver cancer. The enhanced biological specificity and therapeutic performance of drugs loaded on nanoparticles not only rely on the ligands on carriers for receptor recognition but are also determined by the performance of gold conjugates with designed structure. The tumor cell selectivity of the designed conjugates in liver tumor (HepG2) cells is close to six times of that incubated with control conjugates without galactose modification in liver normal (L02) cells. The drug level in tumor versus liver of Gal/PTX-GNPs is 121.0% at 8 h post injection, a 15.7-fold increase in the tumor specificity compared to that of GNPs conjugated with PTX only. This intraorgan-targeting strategy results in a considerable improvement of performance in treating both Heps heterotopic and orthotopic xenograft tumor models, which is expected to be used for the enhanced antitumor efficacy and reduced hepatotoxicity in liver cancer treatment.

Blockade of myeloid differentiation protein 2 prevents obesity-induced inflammation and nephropathy.

Obesity is a major and independent risk factor of kidney diseases. The pathogenic mechanisms of obesity-associated renal injury are recognized to at least involve a lipid-rich and pro-inflammatory state of the renal tissues, but specific mechanisms establishing causal relation remain unknown. Saturated fatty acids are elevated in obesity, and known to induce chronic inflammation in kidneys. Myeloid differentiation protein 2 (MD2) is an important protein in lipopolysaccharide-induced innate immunity response and inflammation. We suggested that obesity-associated renal injury is regulated by MD2 thereby driving an inflammatory renal injury. The used three mouse models for in vivo study: MD2 knockout mice (KO) maintained on high fat diet (HFD), wild-type mice on HFD plus L6H21, a specific MD2 inhibitor and KO mice given palmitic acid (PA) by IV injection. The in vitro studies were carried out in cultured renal tubular epithelial cells, mouse mesangial cells and primary macrophages, respectively. The HFD mice presented with increased hyperlipidemia, serum creatinine and proteinuria. Renal tissue from HFD mice had increased fibrosis, inflammatory cytokines, macrophage infiltration, and activation of NF-κB and MAPKs. This HFD-induced renal injury profile was not observed in KO mice or L6H21-treated mice. Mice given PA mimmicked the HFD-induced renal injury profiles, which were prevented by MD2 knockout. The in vitro data further confirmed MD2 mediates PA-induced inflammation. MD2 is causally related with obesity-associated renal inflammatory injury. We believe that MD2 is an attractive target for future therapeutic strategies in obesity-associated kidney diseases.