Lidocaine, an amide-type regional anesthetic, has been an important medication in the field of anesthesia since its clinical approval. Recently, lidocaine has emerged as a powerful immunomodulatory agent beyond its classical anesthetic properties. This review has summarized the recent basic and clinical studies with sufficient evidence on the multifaceted effects of lidocaine on both innate and adaptive immune cells, including macrophages, neutrophils, eosinophils, basophils, natural killer (NK) cells, mast cells, dendritic cells (DCs), monocytes, and T lymphocytes. We have also detailed how lidocaine affects critical cellular processes, such as cellular polarization, cytokine production, phagocytosis, and apoptosis, through multiple signaling pathways, including NF-κB, TLR4/p38 MAPK, voltage-sensitive sodium channels, HIF1α, TGF-β/Smad3, AMPK-SOCS3, TBK1-IRF7, and G protein-coupled receptors. These immunoregulatory effects of lidocaine are dependent on its concentration, duration of action, and the microenvironment. The immunomodulatory actions of lidocaine may contribute to its potential therapeutic value in various settings of diseases, such as cancer, sepsis, acute lung injury, asthma, organ transplantation, ischemia–reperfusion injury (IRI), and diabetes. We propose that lidocaine can be repurposed as an immunomodulator for treating immune-mediated inflammatory diseases. However, future research should define optimal dosing strategies, validate its mechanisms of action in clinical trials, and explore its novel clinical applications as a complementary immunotherapy.

Acute kidney injury (AKI) remains a common clinical syndrome associated with high morbidity and mortality. However, effective diagnostic biomarkers and specific therapeutic interventions are still lacking. Secretory leukocyte protease inhibitor (SLPI), a serine protease inhibitor with pleiotropic functions, has emerged as an early diagnostic and prognostic biomarker for AKI. Clinical studies reveal significant elevation of serum SLPI in AKI patients compared to non-AKI patients at the acute phase following post-cardiovascular surgery, supporting its diagnostic potential. Furthermore, evidence also suggests that SLPI showed prognostic value for kidney transplantation and chronic kidney disease progression associated with diverse etiology, including diabetes. In addition, current evidence highlights the biological functions of SLPI in inhibiting NF-κB activities, suppressing neutrophil extracellular trap formation, modulating phagocytosis, regulating cell apoptosis, proliferation, differentiation, and potentially fibrosis across various disease contexts. Preclinical studies demonstrate that administration of recombinant SLPI ameliorates renal dysfunction in multiple AKI models, including ischemia-reperfusion injury and nephrotoxic models induced by gentamicin or cisplatin. Furthermore, the antifibrotic properties of SLPI underscore its therapeutic potential in halting AKI progression to chronic kidney disease. By integrating available evidence, this review aims to elucidate that, as an early acute-phase response molecule, SLPI serves dual roles as not only an early diagnostic and prognostic biomarker for AKI, but also a renoprotective molecule countering kidney injury.

The pregnane X receptor (PXR) is a ligand-activated transcription factor and a member of the nuclear receptor superfamily. PXR is constitutively expressed in the hypothalamus and kidney, with its physiological function incompletely understood. In this study, we found that treatment with pregnenolone-16α-carbonitrile (PCN), an endogenous PXR ligand, significantly reduced urine volume and increased urine osmolarity in C57BL/6 mice. In contrast, PXR gene knockout (PXR-/-) mice exhibited impaired urine-concentrating ability, leading to a polyuria phenotype. In addition, treatment of mice with PCN significantly upregulated, whereas PXR gene deficiency substantially reduced, arginine vasopressin (AVP) expression in the hypothalamus. Bioinformatic analysis showed that the mouse AVP gene promoter contains a putative PXR response element (PXRE). The luciferase reporter, ChIP, and electrophoretic mobility shift assays further revealed that PXR can bind to the PXRE, resulting in a significant increase in AVP gene transcription. Collectively, the present study demonstrates that hypothalamic PXR plays a critical role in regulating urine volume, and its activation enhances urine-concentrating capacity primarily by upregulating the expression of AVP in the hypothalamus.NEW & NOTEWORTHY Activation of PXR enhances urine concentration, whereas PXR deficiency diminishes this capacity. PXR is coexpressed with AVP in the hypothalamus, where it upregulates AVP transcription to promote renal water reabsorption. These findings reveal a novel role for PXR in regulating urinary concentration and propose its potential as a therapeutic target for water metabolism disorders, such as diabetes insipidus.

Scoparone (SCO), also known as 6,7-Dimethoxycoumarin, is a naturally occurring bioactive ingredient originally derived from Chinese herb Artemisiae Scopariae Herba (Yin-Chen-Hao). Previous studies have shown that it is effective in treating some of the liver diseases. Beyond its hepatoprotective effects, an expanding body of research has underscored the immunoregulatory properties of SCO, indicating its potential therapeutic benefits for autoimmune and other inflammatory diseases. Over the past decade, significant advances have been made in understanding the mechanistic insights into its effects on immune-mediated diseases as well as liver diseases. SCO has an impact on various immune cells, including mast cells, monocytes, macrophages, neutrophils and T cells, and affects a broad range of intracellular signaling pathways, including TLR4/Myd88/NFκB, TGFβR/Smad3 and JNK/Sab/SHP-1 etc. Therefore, this review not only summarizes the immunomodulatory and therapeutic effects of SCO on immune-based inflammatory diseases (IMIDs), such as inflammatory bowel disease, osteoarthritis, allergic rhinitis, acute lung injury, type 1 diabetes and neuroinflammatory diseases etc., but also provides a comprehensive summary of its therapeutic effects on hepatic diseases, including non-alcoholic steatohepatitis, fulminant hepatic failure and hepatic fibrosis. In this review, we also include the broad impacts of SCO on intracellular signaling pathways, such as TLR4/Myd88/NFκB, TGFβR/Smad3, Nrf2/P38, JAK2/STAT3 and JNK/Sab/SHP-1 etc. Further researches on SCO may help understand its in-depth mechanisms of action and pave the way for the development of novel drugs to prevent and treat various immune-mediated inflammatory disorders as well as hepatic diseases, thereby significantly advancing its innovations and pharmaceutical applications.

Acute kidney injury (AKI) is a critical clinical condition, with high morbidity and mortality globally, and also often worsening or progresses to chronic kidney disease (CKD). Despite advances in supportive and replacement therapy, specific interventions remain limited, in term of targeting a molecule (s) involved in the mechanism underlying AKI and its chronic progression. Recent developments in the technology of RNA interference (RNAi), particularly small interfering RNA (siRNA), offer promising avenues for the specific modulation of genes involved in AKI. This review highlights the potential of siRNA-mediated gene therapy to mitigate AKI and prevent its worsening. Here, the properties and advantages of siRNA agents were addressed. More importantly, the existing research on siRNA chemical modifications and delivery systems enabled specific and precise treatments for AKI, while some extensively studied therapeutic approaches were addressed. Furthermore, the challenges and future prospects of siRNA-based drug development for AKI were discussed, with aims to nourish re-searchers and clinicians alike, and promote establishing efficient organ/cell targeted delivery systems and accelerate potential clinical applications.

The early secreted antigenic target of 6 kDa (ESAT-6), a main effector molecule of the ESX-1 secretion system, is identified as a virulence determinant and immunoregulatory protein of Mycobacterium tuberculosis (Mtb), affecting the interaction between host immune cells and pathogens. ESAT-6 facilitates the survival of mycobacteria and their cell-to-cell spreading through membrane-permeabilizing activity and the regulation of host immune cell functions. In this review, we first summarize the recent knowledge of the roles of ESAT-6 in the survival of bacteria, phagosomal escape, and pathogenicity during Mtb infection. Then, we focused on its complex immunomodulatory effects on different immune cells, such as macrophages, dendritic cells, neutrophils, and T cells, accentuating its capability to either facilitate or inhibit immune responses through different signaling pathways. While our review has summarized its main roles in immunopathology in the context of tuberculosis, we additionally search for emerging evidence indicating that ESAT-6 has anti-inflammatory and immunosuppressive properties. Particularly, we discuss recent preclinical studies showing its capability to suppress transplant rejection and alloimmunity, probably via the induction of regulatory T cells. Nevertheless, the potential clinical use of ESAT-6 remains uncertain and needs further verification by comprehensive preclinical and clinical studies. Thus, we propose that ESAT-6 may be exploited to ameliorate immunopathology in TB infection and to suppress immune-mediated inflammation or transplant rejection as well.

Conventional immunosuppressants that suppress allograft rejection cause various side effects. Although regulatory T cells (Tregs) are essential for allograft survival, the limited efficacy of Treg therapy demands improvement. Thus, it is imperative to seek new approaches to enhancing Treg suppression. Low-intensity electrostimulation (ES) has been shown to exert antiinflammatory effects without causing major adverse reactions. However, it remains unknown whether and how ES regulates alloimmunity. Here, we found that regional ES delayed murine skin allograft rejection and promoted long-term allograft survival induced by an mTOR inhibitor, rapamycin. ES also extended islet allograft survival. Mechanistically, ES enhanced the expression of lymphotoxin α (LTα) on Tregs after transplantation. Blockade of lymphotoxin β receptor-mediated nonclassical NFκB signaling suppressed lymphatic Treg migration and largely reversed the effects of ES on allograft survival. Moreover, ES failed to extend allograft survival when recipients lacked LTα/lymph nodes or if transferred Tregs lacked LTα. Therefore, ES promoted the lymphatic migration of CD4+Foxp3+ Tregs by upregulating their surface expression of LTα. Finally, ES augmented expression of LTα on murine or human Tregs, but not conventional T cells, while promoting their calcium influx in vitro. This ES-mediated upregulation of LTα relied on calcium influx. Thus, our findings have unveiled novel mechanisms underlying ES-mediated immunoregulation.

The secretory leukocyte protease inhibitor (SLPI) is mainly produced by immune cells and various epithelial cells, and is regulated by a variety of cytokines, such as transforming growth factor β1, interleukin 1β and tumor necrosis factor α. In addition to commonly known anti-protease activity, it has been found in recent years that SLPI plays essential roles in anti-apoptosis, regulating cell cycle, cell differentiation and proliferation, and inhibiting inflammatory response. SLPI can also assist the immune system to clear pathogens/damaged cells by enhancing the phagocytic function of phagocytes, so as to ameliorate tissue damage and promote repair. Moreover, recent studies have shown that the change of SLPI level in the serum of patients post cardiovascular surgery has a high diagnostic value in predicting the occurrence of acute kidney injury, suggesting that SLPI is involved in ischemia-reperfusion (IR) induced acute kidney injury. In this review, we summarized the expression, regulation, signaling pathways and associated biological events of SLPI in different organ injury models, and also discussed and evaluated the potential role of SLPI in renoprotection against IR induced acute kidney injury and its potential as a new biomarker.

Sepsis-associated acute kidney injury (AKI) has high morbidity and mortality, but without cause-specific treatment. Erythropoietin derived Helix B surface peptide (HBSP) alleviates AKI, whereas its underlying mechanisms remain to be further explored. Here, the effects of HBSP on pyroptosis, apoptosis, macrophage polarization and repair were investigated in lipopolysaccharide (LPS)-induced AKI mouse model and cultured kidney epithelial cells. Systemic inflammation, compromised renal function and histology were demonstrated in LPS-treated mice, with upregulated pyroptotic and apoptotic key proteins in the kidneys including GSDMD-N, cleaved IL-1β, IL-18 and caspase-3. These proteins were localized in tubular areas and colocalized with aquaporin-1 (AQP1), with increased F4/80 + M1 macrophages. However, HBSP mitigated pyroptosis, apoptosis and inflammation, and promoted macrophage M2 polarization. In addition, HMGB1 and erythropoietin receptor (EPOR) were increased by LPS and decreased by HBSP, both of which were positively correlated with pyroptotic and apoptotic proteins. Moreover, HBSP reduced TNF-α and IL-6 mRNA levels, as well as pyroptosis and apoptosis in LPS-stimulated TCMK-1 cells. In conclusion, HBSP inhibited tubular pyroptosis and apoptosis, EPOR expression, promoted macrophage M2 polarization, and protected against LPS-induced AKI. These findings provide new mechanistic insights into the renoprotection of HBSP, and facilitate its potential for clinical applications and therapeutic strategies in sepsis-associated AKI.

Ultrasound is a promising medical imaging modality benefiting from low-cost and real-time acquisition. Accurate tracking of an anatomical landmark has been of high interest for various clinical workflows such as minimally invasive surgery and ultrasound-guided radiation therapy. However, tracking an anatomical landmark accurately in ultrasound video is very challenging, due to landmark deformation, visual ambiguity and partial observation. In this paper, we propose a long-short diffeomorphism memory network (LSDM), which is a multi-task framework with an auxiliary learnable deformation prior to supporting accurate landmark tracking. Specifically, we design a novel diffeomorphic representation, which contains both long and short temporal information stored in separate memory banks for delineating motion margins and reducing cumulative errors. We further propose an expectation maximization memory alignment (EMMA) algorithm to iteratively optimize both the long and short deformation memory, updating the memory queue for mitigating local anatomical ambiguity. The proposed multi-task system can be trained in a weakly-supervised manner, which only requires few landmark annotations for tracking and zero annotation for deformation learning. We conduct extensive experiments on both public and private ultrasound landmark tracking datasets. Experimental results show that LSDM can achieve better or competitive landmark tracking performance with a strong generalization capability across different scanner types and different ultrasound modalities, compared with other state-of-the-art methods.

The progression of renal fibrosis to end-stage renal disease (ESRD) is significantly influenced by transforming growth factor-beta (TGF-beta) signal pathway. This study aimed to develop nanoparticles (PMVs@PLGA complexes) with platelet membrane camouflage, which can transport interfering RNA to target and regulate the TGF-β1 pathway in damaged renal tissues. The aim is to reduce the severity of acute kidney injury and to reduce fibrosis in chronic kidney disease. Hence, we formulated PMVs@TGF-β1-siRNA NP complexes and employed them for both in vitro and in vivo therapy. From the experimental findings we know that the PMVs@siRNA NPs could effectively target the kidneys in unilateral ureteral obstruction (UUO) mice and ischemia/reperfusion injury (I/R) mice. In animal models of treatment, PMVs@siRNA NP complexes effectively decreased the expression of TGF-β1 and mitigated inflammation and fibrosis in the kidneys by blocking the TGF-β1/Smad3 pathway. Therefore, these PMVs@siRNA NP complexes can serve as a promising biological delivery system for treating kidney diseases.

Psoriasis is a chronic, recurrent, and inflammatory skin disease. Topical agents, which can avoid the adverse effects of systemic treatment, are the first-choice therapy for patients with mild-to-moderate psoriasis. Hederacoside C (HSC) with anti-inflammatory properties has been used to treat some inflammatory diseases. We speculated that HSC might also be effective for psoriasis treatment. However, topical application of HSC for psoriasis treatment is challenging because of its low water solubility and poor skin permeability. Therefore, it is important to effectively deliver HSC percutaneously using certain biomaterials. Here we constructed a hydroxypropyl-β-cyclodextrin-coated liposome gel formulation for the loading and percutaneously delivering of HSC, referred to as HSC-Lipo@gel. The characterization, stability, release properties, and mechanical or transdermal features of the HSC-Lipo@gel were evaluated. Its therapeutic potential was also demonstrated using mouse models of IMQ-induced psoriasis. We found that HSC-Lipo@gel effectively improved the skin permeability of HSC with the property of good stability and sustained release. Importantly, HSC-Lipo@gel showed higher efficacy than HSC@gel without liposomes in alleviating psoriatic skin lesions. It attenuated epidermal hyperplasia and suppressed expression of IL-17A, TNF-α, IL-6, and IL-23 in lesional skin. Interestingly, HSC-Lipo@gel reduced the expression of CC chemokine ligand 17 (CCL17), but not CCL22, in the skin. Especially, HSC-Lipo@gel inhibited CCL17 expression by skin dendritic cells while increasing regulatory T cells (Tregs) in both skin and draining lymph nodes of psoriatic mice. Administration of CCL17 resulted in severe skin lesions and reduced CD4+FoxP3+ Tregs in psoriatic mice previously treated with HSC-Lipo@gel. Finally, HSC or HSC-Lipo also suppressed the CCL17 production by dendritic cells in vitro. Therefore, HSC-Lipo@gel alleviated psoriasiform skin inflammation by increasing cutaneous Tregs via downregulation of the expression of CCL17, but not CCL22. Thus, HSC-Lipo@gel may be a stable, highly permeable, and effective system for topical treatment of psoriasis.

Acute kidney injury (AKI) is a risk factor of chronic kidney disease, without specific treatment. This study investigated the effect of co-treatment using erythropoietin-derived helix B surface peptide (HBSP) and caspase-3 small interfering RNA (CASP3siRNA) on preventing fibrosis post AKI in order to achieve better efficacy by different action mechanisms. Ischemia-reperfusion (IR) in mice was induced by clamping bilateral renal pedicles for 30 min followed by 2-week reperfusion, with HBSP and/or CASP3siRNA administered at the onset of IR. Serum creatinine, apoptosis, active caspase-3 and high mobility group protein B1 (HMGB1) in kidneys were decreased by HBSP, CASP3siRNA or both, with increased PCNA. α-SMA expression and collagen I deposition were also reduced by CASP3siRNA and both. Most interestingly, the co-treatment further reduced tubulointerstitial damage and fibrosis, but raised PCNA compared to CASP3siRNA. EPOR/βcR was reduced by HBSP, and positively correlated with Sirius red staining, whereas EPOR was unchanged. In TCMK-1 cells, H2O2 raised apoptosis and α-SMA were reduced by HBSP, while the same was occurred to HMGB1. However, HMGB1 was further increased by EPOR siRNA under H2O2 stimulation with/without HBSP treatment. In conclusion, this study demonstrated synergistic long-term renoprotection post IR-AKI by HBSP and CASP3siRNA, which may be due to co-inhibiting inflammation and stimulating repair at early stage, and subsequently preventing fibrosis.

Zhen-Wu-Tang (ZWT), a conventional herbal mixture, has been recommended for treating lupus nephritis (LN) in clinic. However, its mechanisms of action remain unknown. Here we aimed to define the immunological mechanisms underlying the effects of ZWT on LN and to determine whether it affects renal tissue-resident memory T (TRM) cells. Murine LN was induced by a single injection of pristane, while in vitro TRM cells differentiated with IL-15/TGF-β. We found that ZWT or mycophenolate mofetil treatment significantly ameliorated kidney injury in LN mice by decreasing 24-h urine protein, Scr and anti-dsDNA Ab. ZWT also improved renal pathology and decreased IgG and C3 depositions. In addition, ZWT down-regulated renal Desmin expression. Moreover, it lowered the numbers of CD8+ TRM cells in kidney of mice with LN while decreasing their expression of TNF-α and IFN-γ. Consistent with in vivo results, ZWT-containing serum inhibited TRM cell differentiation induced by IL-15/TGF-β in vitro. Mechanistically, it suppressed phosphorylation of STAT3 and CD122 （IL2/IL-15Rβ）expression in CD8+ TRM cells. Importantly, ZWT reduced the number of total F4/80+CD11b+ and CD86+, but not CD206+, macrophages in the kidney of LN mice. Interestingly, ZWT suppressed IL-15 protein expression in macrophages in vivo and in vitro. Thus, we have provided the first evidence that ZWT decoction can be used to improve the outcome of LN by reducing CD8+ TRM cells via inhibition of IL-15/IL-15R /STAT3 signaling.

Phagocytosis plays vital roles in injury and repair, while its regulation by properdin and innate repair receptor, a heterodimer receptor of erythropoietin receptor (EPOR)/β common receptor (βcR), in renal ischaemia-reperfusion (IR) remains unclear. Properdin, a pattern recognition molecule, facilitates phagocytosis by opsonizing damaged cells. Our previous study showed that the phagocytic function of tubular epithelial cells isolated from properdin knockout (PKO) mouse kidneys was compromised, with upregulated EPOR in IR kidneys that was further raised by PKO at repair phase. Here, helix B surface peptide (HBSP), derived from EPO only recognizing EPOR/βcR, ameliorated IR-induced functional and structural damage in both PKO and wild-type (WT) mice. In particular, HBSP treatment led to less cell apoptosis and F4/80+ macrophage infiltration in the interstitium of PKO IR kidneys compared to the WT control. In addition, the expression of EPOR/βcR was increased by IR in WT kidneys, and furthered increased in IR PKO kidneys, but greatly reduced by HBSP in the IR kidneys of PKO mice. HBSP also increased PCNA expression in IR kidneys of both genotypes. Moreover, iridium-labelled HBSP (HBSP-Ir) was localized mainly in the tubular epithelia after 17-h renal IR in WT mice. HBSP-Ir also anchored to mouse kidney epithelial (TCMK-1) cells treated by H2O2. Both EPOR and EPOR/βcR were significantly increased by H2O2 treatment, while further increased EPOR was showed in cells transfected with small interfering RNA (siRNA) targeting properdin, but a lower level of EPOR was seen in EPOR siRNA and HBSP-treated cells. The number of early apoptotic cells was increased by EPOR siRNA in H2O2-treated TCMK-1, but markedly reversed by HBSP. The phagocytic function of TCMK-1 cells assessed by uptake fluorescence-labelled E.coli was enhanced by HBSP dose-dependently. Our data demonstrate for the first time that HBSP improves the phagocytic function of tubular epithelial cells and kidney repair post IR injury, via upregulated EPOR/βcR triggered by both IR and properdin deficiency.

Acute kidney injury (AKI) is a common critical disease clinically with high morbility and mortality and some survival patients also progress to chronic kidney disease. Renal ischemia-reperfusion (IR) is one of the main causes of AKI, in which, its repair and potential fibrosis, apoptosis, inflammation and phagocytosis play important roles. During the progression of IR-induced AKI, the expression of erythropoietin homodimer receptor (EPOR)2 and EPOR and β common receptor formed heterodimer receptor (EPOR/βcR) is changed dynamically. Moreover, (EPOR)2 and EPOR/βcR may synergistically participate in renoprotection at the stage of AKI and early repair, whereas at the late stage of AKI, the (EPOR)2 induces renal fibrosis and the EPOR/βcR facilitates repair and remodelling. The underlying mechanism, signaling pathways and the different effect turning point of (EPOR)2 and EPOR/βcR have not been well defined. It has been reported that EPO, according to its 3D structure, derived helix B surface peptide (HBSP) and cyclic HBSP (CHBP) only bind to EPOR/βcR. Synthesized HBSP, therefore, provides an effective tool to distinguish the different roles and mechanisms of both receptors, with the (EPOR)2 promoting fibrosis or the EPOR/βcR leading to repair/remodelling at the late stage of AKI. This review discusses the similarities and differences of (EPOR)2 and EPOR/βcR in their impacts on apoptosis, inflammation and phagocytosis in AKI, repair and fibrosis post IR, associated mechanisms, signaling pathways and outcomes.

Accurate tracking of an anatomical landmark over time has been of high interests for disease assessment such as minimally invasive surgery and tumor radiation therapy. Ultrasound imaging is a promising modality benefiting from low-cost and real-time acquisition. However, generating a precise landmark tracklet is very challenging, as attempts can be easily distorted by different interference such as landmark deformation, visual ambiguity and partial observation. In this paper, we propose a long-short diffeomorphic motion network, which is a multi-task framework with a learnable deformation prior to search for the plausible deformation of landmark. Specifically, we design a novel diffeomorphism representation in both long and short temporal domains for delineating motion margins and reducing long-term cumulative tracking errors. To further mitigate local anatomical ambiguity, we propose an expectation maximisation motion alignment module to iteratively optimize both long and short deformation, aligning to the same directional and spatial representation. The proposed multi-task system can be trained in a weakly-supervised manner, which only requires few landmark annotations for tracking and zero annotation for long-short deformation learning. We conduct extensive experiments on two ultrasound landmark tracking datasets. Experimental results show that our proposed method can achieve better or competitive landmark tracking performance compared with other state-of-the-art tracking methods, with a strong generalization capability across different scanner types and different ultrasound modalities.