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Obesity is characterized by the chronic low-grade activation of the innate immune system. In this respect, macrophage-elicited metabolic inflammation and adipocyte-macrophage interaction have primary importance in obesity. Large quantity of macrophages is accumulated by different mechanisms in obese adipose tissue. Hypertrophic adipocyte-derived chemotactic monocyte chemoattractant protein-1 (MCP-1)/C-C chemokine receptor 2 (CCR2) pathway promotes more macrophage accumulation into the obese adipose tissue. However, obesity-induced changes in adipose tissue macrophage density are mainly dependent on increases in the triple-positive cluster of differentiation (CD)11b+ F4/80+ CD11c+ adipose tissue macrophage subpopulation. As epigenetic regulators, microRNAs (miRNAs) are one of the most important mediators of obesity. miRNAs are expressed by adipocytes as well as macrophages and regulate inflammation with the expression of target genes. A paracrine loop involving free fatty acids and tumor necrosis factor-alpha (TNF-α) between adipocytes and macrophages establishes a vicious cycle that aggravates inflammatory changes in the adipose tissue. Adipocyte-specific caspase-1 and production of interleukin-1beta (IL-1ß) by macrophages; both adipocyte and macrophage induction by toll-like receptor-4 (TLR4) through nuclear factor-kappaB (NF-κB) activation; free fatty acid-induced and TLR-mediated activation of c-Jun N-terminal kinase (JNK)-related pro-inflammatory pathways in CD11c+ immune cells; are effective in mutual message transmission between adipocyte and macrophage and in the development of adipose tissue inflammation. Thus, the metabolic status of adipocytes and their released exosomes are important determinants of macrophage inflammatory output. However, old adipocytes are removed by macrophages through trogocytosis or sending an "eat me" signal. As a single miRNA can be able to regulate a variety of target genes and signaling pathways, reciprocal transfer of miRNAs between adipocytes and macrophages via miRNA-loaded exosomes reorganizes the different stages of obesity. Changes in the expression of circulating miRNAs because of obesity progression or anti-obesity treatment indicate that miRNAs could be used as potential biomarkers. Therefore, it is believed that targeting macrophage-associated miRNAs with anti-obesity miRNA-loaded nano-carriers may be successful in the attenuation of both obesity and adipose tissue inflammation in clinical practice. Moreover, miRNA-containing exosomes and transferable mitochondria between the adipocyte and macrophage are investigated as new therapeutic targets for obesity-related metabolic disorders.

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Chronic low-grade inflammation is a central component in the pathogenesis of obesity-related expansion of adipose tissue and complications in other metabolic tissues. Five different signaling pathways are defined as dominant determinants of adipose tissue inflammation: These are increased circulating endotoxin due to dysregulation in the microbiota-gut-brain axis, systemic oxidative stress, macrophage accumulation, and adipocyte death. Finally, the nucleotide-binding and oligomerization domain (NOD) leucine-rich repeat family pyrin domain-containing 3 (NLRP3) inflammasome pathway is noted to be a key regulator of metabolic inflammation. The NLRP3 inflammasome and associated metabolic inflammation play an important role in the relationships among fatty acids and obesity. Several highly active molecules, including primarily leptin, resistin, adiponectin, visfatin, and classical cytokines, are abundantly released from adipocytes. The most important cytokines that are released by inflammatory cells infiltrating obese adipose tissue are tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), monocyte chemoattractant protein 1 (MCP-1) (CCL-2), and IL-1. All these molecules mentioned above act on immune cells, causing local and then general inflammation. Three metabolic pathways are noteworthy in the development of adipose tissue inflammation: toll-like receptor 4 (TLR4)/phosphatidylinositol-3'-kinase (PI3K)/Protein kinase B (Akt) signaling pathway, endoplasmic reticulum (ER) stress-derived unfolded protein response (UPR), and inhibitor of nuclear factor kappa-B kinase beta (IKKß)-nuclear factor kappa B (NF-κB) pathway. In fact, adipose tissue inflammation is an adaptive response that contributes to a visceral depot barrier that effectively filters gut-derived endotoxin. Excessive fatty acid release worsens adipose tissue inflammation and contributes to insulin resistance. However, suppression of adipose inflammation in obesity with anti-inflammatory drugs is not a rational solution and paradoxically promotes insulin resistance, despite beneficial effects on weight gain. Inflammatory pathways in adipocytes are indeed indispensable for maintaining systemic insulin sensitivity. Cannabinoid type 1 receptor (CB1R) is important in obesity-induced pro-inflammatory response; however, blockade of CB1R, contrary to anti-inflammatory drugs, breaks the links between insulin resistance and adipose tissue inflammation. Obesity, however, could be decreased by improving leptin signaling, white adipose tissue browning, gut microbiota interactions, and alleviating inflammation. Furthermore, capsaicin synthesized by chilies is thought to be a new and promising therapeutic option in obesity, as it prevents metabolic endotoxemia and systemic chronic low-grade inflammation caused by high-fat diet.

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The aim of the present study was to determine whether adipokines monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1) can affect the functions of ovarian cells in cats. The addition of either MCP-1 or PAI-1 increased viability; promoted the accumulation of proliferation markers and progesterone and estradiol release; and decreased the accumulation of apoptosis markers in cultured feline granulosa cells. The present observations suggest that MCP-1 or PAI-1 can be physiological stimulators of ovarian granulosa cell functions.

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BACKGROUND: Neuroimmune dysfunction in alcohol use disorder (AUD) is associated with activation of myeloid differentiation primary response 88 (MyD88)-dependent Toll-like receptors (TLR) resulting in overexpression of the chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2). MCP-1 overexpression in the brain is linked to anxiety, higher alcohol intake, neuronal death, and activation of microglia observed in AUD. The neurosteroid [3α,5α][3-hydroxypregnan-20-one (3α,5α-THP) has been reported as an inhibitor of MyD88-dependent TLR activation and MCP-1 overexpression in mouse and human macrophages and the brain of alcohol-preferring (P) rats. METHODS: We investigated how 3α,5α-THP regulates MCP-1 expression at the cellular level in P rat nucleus accumbens (NAc) and central amygdala (CeA). We focused on neurons, microglia, and astrocytes, examining the individual voxel density of MCP-1, neuronal marker NeuN, microglial marker IBA1, astrocytic marker GFAP, and their shared voxel density, defined as intersection. Ethanol-naïve male and female P rats were perfused 1 h after IP injections of 15 mg/kg of 3α,5α-THP, or vehicle. The NAc and CeA were imaged using confocal microscopy following double-immunofluorescence staining for MCP-1 with NeuN, IBA1, and GFAP, respectively. RESULTS: MCP-1 intersected with NeuN predominantly and IBA1/GFAP negligibly. 3α,5α-THP reduced MCP-1 expression in NeuN-labeled cells by 38.27 ± 28.09% in male and 56.11 ± 21.46% in female NAc, also 37.99 ± 19.53% in male and 54.96 ± 30.58% in female CeA. In females, 3α,5α-THP reduced the MCP-1 within IBA1 and GFAP-labeled voxels in the NAc and CeA. Conversely, in males, 3α,5α-THP did not significantly alter the MCP-1 within IBA1 in NAc or with GFAP in the CeA. Furthermore, 3α,5α-THP decreased levels of IBA1 in both regions and sexes with no impact on GFAP or NeuN levels. Secondary analysis performed on data normalized to % control values indicated that no significant sex differences were present. CONCLUSIONS: These data suggest that 3α,5α-THP inhibits neuronal MCP-1 expression and decreases the proliferation of microglia in P rats. These results increase our understanding of potential mechanisms for 3α,5α-THP modulation of ethanol consumption.

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Rationale & Objective: Tubulointerstitial damage is a feature of early chronic kidney disease (CKD), but current clinical tests capture it poorly. Urine biomarkers of tubulointerstitial health may identify risk of CKD. Study Design: Prospective cohort (Atherosclerosis Risk in Communities [ARIC]) and case-cohort (Multi-Ethnic Study of Atherosclerosis [MESA] and Reasons for Geographic and Racial Differences in Stroke [REGARDS]). Setting & Participants: Adults with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 and without diabetes in the ARIC, REGARDS, and MESA studies. Exposures: Baseline urine monocyte chemoattractant protein-1 (MCP-1), alpha-1-microglobulin (α1m), kidney injury molecule-1, epidermal growth factor, and chitinase-3-like protein 1. Outcome: Incident CKD or end-stage kidney disease. Analytical Approach: Multivariable Cox proportional hazards regression for each cohort; meta-analysis of results from all 3 cohorts. Results: 872 ARIC participants (444 cases of incident CKD), 636 MESA participants (158 cases), and 924 REGARDS participants (488 cases) were sampled. Across cohorts, mean age ranged from 60 ± 10 to 63 ± 8 years, and baseline eGFR ranged from 88 ± 13 to 91 ± 14 mL/min/1.73 m2. In ARIC, higher concentrations of urine MCP-1, α1m, and kidney injury molecule-1 were associated with incident CKD. In MESA, higher concentration of urine MCP-1 and lower concentration of epidermal growth factor were each associated with incident CKD. In REGARDS, none of the biomarkers were associated with incident CKD. In meta-analysis of all 3 cohorts, each 2-fold increase α1m concentration was associated with incident CKD (HR, 1.19; 95% CI, 1.08-1.31). Limitations: Observational design susceptible to confounding; competing risks during long follow-up period; meta-analysis limited to 3 cohorts. Conclusions: In 3 combined cohorts of adults without prevalent CKD or diabetes, higher urine α1m concentration was independently associated with incident CKD. 4 biomarkers were associated with incident CKD in at least 1 of the cohorts when analyzed individually. Kidney tubule health markers might inform CKD risk independent of eGFR and albuminuria.

This study analyzed 3 cohorts (ARIC, MESA, and REGARDS) of adults without diabetes or prevalent chronic kidney disease (CKD) to determine the associations of 5 urinary biomarkers of kidney tubulointerstitial health with incident CKD, independent of traditional measures of kidney health. Meta-analysis of results from all 3 cohorts suggested that higher baseline levels of urine alpha-1-microglobulin were associated with incident CKD at follow-up. Results from individual cohorts suggested that in addition to alpha-1-microglobulin, monocyte chemoattractant protein-1, kidney injury molecule-1, and epidermal growth factor may also be associated with the development of CKD. These findings underscore the importance of kidney tubule interstitial health in defining risk of CKD independent of creatinine and urine albumin.

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The aim of the present study was to examine the influence of monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1) on ovarian cell functions. Rabbit ovarian granulosa cells were cultured with or without MCP-1 or PAI-1 (at 0, 0.1, 1, or 10 ng/ml). Cell viability, proliferation, cytoplasmic apoptosis and release of progesterone and estradiol were measured by Cell Counting Kit-8 (CCK-8), BrdU incorporation, and cell death detection assays and ELISA. The addition of either MCP-1 or PAI-1 increased cell viability and proliferation and decreased apoptosis. MCP-1 promoted, while PAI-1 suppressed, progesterone release. Both MCP-1 and PAI-1 reduced estradiol output. The present results suggest that MCP-1 or PAI-1 can be physiological promoters of rabbit ovarian cell viability and proliferation, inhibitors of apoptosis and regulators of ovarian steroidogenesis.

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Inflammation plays a crucial role in diabetes and obesity through macrophage activation. Macrophage chemoattractant protein-1 (MCP-1), activin-A, and clusterin are chemokines with known roles in diabetes and obesity. The aim of this study is to investigate their possible diagnostic and/or early prognostic values in children and adolescents with obesity and type-1 diabetes mellitus (T1DM). METHODS: We obtained serum samples from children and adolescents with a history of T1DM or obesity, in order to measure and compare MCP-1, activin-A, and clusterin concentrations. RESULTS: Forty-three subjects were included in each of the three groups (controls, T1DM, and obesity). MCP-1 values were positively correlated to BMI z-score. Activin-A was increased in children with obesity compared to the control group. A trend for higher values was detected in children with T1DM. MCP-1 and activin-A levels were positively correlated. Clusterin levels showed a trend towards lower values in children with T1DM or obesity compared to the control group and were negatively correlated to renal function. CONCLUSIONS: The inflammation markers MCP-1, activin-A, and clusterin are not altered in children with T1DM. Conversely, obesity in children is positively correlated to serum MCP-1 values and characterized by higher activin-A levels, which may reflect an already established systematic inflammation with obesity since childhood.

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OBJECTIVES: To observe the clinical efficacy of acupoint application in treating postherpetic neuralgia(PHN) with qi stagnation and blood stasis, and its effects on serum inflammatory factors and 5-hydroxytryptamine (5-HT) in patients. METHODS: A total of 136 PHN patients were randomly divided into an observation group (68 cases, 6 case dropped out) and a control group (68 cases, 5 cases dropped out). In the observation group, the combination of swelling-reducing and pain-relieving patches and acupoint application with herbal powder was used at bilateral Sanyinjiao (SP 6), Shenque (CV 8) and ashi points. Sanyinjiao (SP 6) was applied for 30 min per session, once every 7 days; and Shenque (CV 8) and ashi points were applied for 6-8 h per session, once every 1 day. In the control group, mecobalamin injection was administered at Jiaji (EX-B 2) corresponding to the neural segments governing the painful area, 1 mL per injection, once a day. Each treatment course consisted of 7 days, 4 treatment courses were required in both groups. The visual analog scale (VAS) score for pain, 36-item short form health survey (SF-36) score, traditional Chinese medicine syndrome score, and the serum levels of inflammatory factors (monocyte chemoattractant protein-1 [MCP-1], interleukin-6 [IL-6], tumor necrosis factor-alpha [TNF-α]) and 5-HT were compared in the patients of the two groups before and after treatment, and the clinical efficacy was evaluated. RESULTS: After treatment, the VAS scores, traditional Chinese medicine syndrome scores, serum MCP-1, IL-6, TNF-α, and 5-HT levels were decreased compared with those before treatment in both groups (P<0.05), and the results in the observation group were lower than those in the control group (P<0.05). The SF-36 scores were increased compared with those before treatment in the two groups (P<0.05), and the result in the observation group was higher than that in the control group (P<0.05). The total effective rate of the observation group was 74.2% (46/62), which was higher than 52.4% (33/63, P<0.05) of the control group. CONCLUSIONS: The combination of swelling-reducing and pain-relieving patches and acupoint application with herbal powder has shown better efficacy in treating PHN with qi stagnation and blood stasis, which can significantly alleviate patients symptoms, improve their quality of life, and reduce serum levels of MCP-1, IL-6, TNF-α, and 5-HT.

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ObjectiveTo investigate the application value of Qingre Huashi Sanjie enema prescription in the treatment of the patients with sequelae of pelvic inflammatory disease （syndrome of combined dampness，heat，and stasis） and the effects of this prescription on inflammatory mediators and T lymphocyte subsets. MethodThe patients with sequelae of pelvic inflammatory disease （syndrome of combined dampness，heat，and stasis） treated from May 2022 to August 2023 were included in this study and randomized into two groups （79 cases）. The control group was treated with conventional Western medicine，and the observation group was treated with Qingre Huashi Sanjie enema prescription on the basis of the therapy in the control group. Both groups were treated for 12 weeks. The serum levels of monocyte chemoattractant protein-1 （MCP-1），transforming growth factor-β1 （TGF-β1），and interleukin-6 （IL-6） were measured by enzyme linked immunoserbent assay （ELISA） before and after treatment in both groups. The erythrocyte sedimentation rate （ESR） and fibrinogen （FIB） were measured by an automatic blood rheology analyzer before and after treatment in both groups. The serum levels of CD4+，CD4+/CD8+ before and after treatment in both groups were measured by flow cytometry. The traditional Chinese medicine （TCM） symptom score and the 36-item short form survey （SF-36） score were assessed before and after treatment. The uterine artery resistance index （RI），uterine artery pulsatility index （PI），and uterine artery peak systolic velocity （PSV） were measured by Doppler before and after treatment. The clinical efficacy and the occurrence of adverse reactions were compared between the two groups. ResultAfter treatment，the levels of MCP-1，TGF-β1，IL-6，ESR，and FIB decreased in both groups （P<0.01），and the decreases were larger in the observation group than in the control group （P<0.05，P<0.01）. After treatment，the serum levels of CD4+ and CD4+/CD8+ elevated in both groups （P<0.01） and the observation group had higher levels of CD4+ and CD4+/CD8+ than the control group （P<0.05，P<0.01）. The treatment in both groups decreased the TCM symptom score and TCM sign score and increased the SF-36 score （P<0.01），and the changes were more significant in the observation group than in the control group （P<0.05，P<0.01）. In addition，the treatment lowered RI and PI and elevated PSV （P<0.01），and the changes in these indicators were more significant in the observation group than in the control group （P<0.01）. The total response rate in the observation group was 93.67% （74/79），which was higher than that （79.75%，63/79） in the control group （χ2=6.645，P<0.05）. There was no significant difference in the occurrence of adverse reactions between the two groups. ConclusionFor the patients with sequelae of pelvic inflammatory disease （syndrome of combined dampness，heat，and stasis），Qingre Huashi Sanjie enema prescription can reduce inflammation，attenuate hypercoagulability，improve hemodynamics，and regulate the immune function，demonstrating a definite therapeutic effect.

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BACKGROUND AND AIMS: Ustekinumab has been proven to be effective for treatment of patients with Crohn's disease; however, 30-40% of patients have been reported to lose clinical response within 2 years. We aimed to evaluate the efficacy of ustekinumab and identify predictors of short-term and long-term efficacy in Crohn's disease. METHODS: Patients with Crohn's disease receiving their first ustekinumab infusion in our hospital between June 2017 and September 2020 were prospectively enrolled. Concentrations of serum cytokines and chemokines were measured using a multiplex bead array assay. RESULTS: Fifty-nine Crohn's disease patients were enrolled in this study. Among 34 clinically active patients, 38.2% achieved a clinical response at week 8. None of the assayed factors were associated with short-term clinical response. Cumulative persistence rates of ustekinumab were 77.6% at 1 year and 58.9% at 2 years. Univariate Cox regression analysis revealed that Harvey-Bradshaw Index scores at baseline, concomitant immunomodulator treatment, and concentrations of interferon gamma-induced protein-10, monocyte chemoattractant protein-1 (MCP-1), and interleukin (IL)-1RA, IL-4, IL-6, and IL-8 were significantly associated with loss of efficacy. Multivariate Cox regression analysis found that biologic naïve status (hazard ratio [HR]: 0.1191, 95% confidence interval [CI]: 0.02458-0.5774) and MCP-1 concentrations (HR: 1.038, 95% CI: 1.015-1.062) were significantly and associated with loss of sustained efficacy for ustekinumab treatment. CONCLUSIONS: Our findings suggest that pretreatment serum MCP-1 analysis, combined with a history of biologic use, could be a novel biomarker for predicting the long-term efficacy of ustekinumab in patients with Crohn's disease.

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OBJECTIVES: The decision to surgically intervene in a hydronephrotic kidney in children is based on many debatable guidelines, some requiring repeated ultrasounds or renal scans. Urinary proteins have the potential to reflect renal disorders and hence can be the alternatives to such scans. Here, we aim to assess the role of urinary Neutrophil Gelatinase-Associated Lipocalin, Monocyte Chemoattractant Protein-1, and Interleukin-6 (IL-6) in such patients. METHODS: Seventeen children had obstructive hydronephrosis requiring pyeloplasty (UPJO), while seven were kept on conservative management in view of non-obstructive dilation (NOD). Urine samples were measured for the three urinary proteins at the time of presentation and following pyeloplasty using commercially available ELISA kits. RESULTS: The levels of all three urinary proteins were significantly higher in patients with UPJO children compared to the NOD group. Cut-off values to differentiate obstructive from non-obstructive hydronephrosis were obtained. A significant fall in the post-operative value of urinary IL-6 was also observed. CONCLUSION: This study highlights the potentiality of urinary proteins as biomarkers in identifying children with hydronephrosis and picking out the ones with obstructive hydronephrosis who will require pyeloplasty. The drop in levels after pyeloplasty can be employed to evaluate the effectiveness of pyeloplasty when sent serially.

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Background: At present, the incidence of obesity is increasing. Several studies have shown that obesity can reduce male fertility by affecting spermatogenesis and semen quality. Traditional Chinese medicine (TCM) has fewer side effects and stable efficacy in the treatment of related diseases. This study aimed to investigate the effect of Huaji Jianpi Decoction on the semen quality of high-fat diet-induced obese mice. Methods: The obese male mice model was constructed by using high-fat diet and the Huaji Jianpi Decoction was processed into an aqueous extract. Mice were allocated in the normal group (n=30) and five different treatment groups (n=50). Huaji Jianpi Decoction was applied in low-, medium- and high-dose [17.52 g/(kg·d), 35.04 g/(kg·d) and 70.07 g/(kg·d), respectively]. The body weight, body fat, testis wet weight, testis coefficient, and routine sperm parameters were detected and analyzed. Meanwhile, transmission electron microscope (TEM) was used to observe testis ultrastructure. reverse-transcription quantitative PCR (RT-qPCR) was used to measure the expression of tumour necrosis factor α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1). Results: Compared with normal mice (ND), the testis wet weight and testis coefficient of mice in the blank group were significantly decreased, while the number of mitochondria was observed to be decreased on testis ultrastructure examination, and apoptotic cells and germ cells in the spermatogenic tubules were shed. After Huaji Jianpi Decoction administration, the body fat and blood lipid levels of obese mice were decreased, the testis wet weight and testis coefficient were increased, and semen parameters were increased. Different doses of Huaji Jianpi Decoction could improve testicular weight, sperm density, sperm motility, forward motility, and total sperm motility. Huaji Jianpi Decoction could also downregulate TNF-α and MCP-1 expression and inhibit germ cell apoptosis to improve semen quality. Conclusions: Huaji Jianpi Decoction can improve the semen quality of high-fat diet-induced obese mice by reducing weight and lipid levels.

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BACKGROUND: Depression is a common illness with no definite treatment. METHODS: The study involved 2 experimental periods; 45-day (P1) followed by 30-day (P2). 40 adult albino rats were randomly divided into 4 groups. Grp 1 received saline orally while Grp 2 reserpine inraperitoneally (ip) during P1 and P2. Grps 3 and 4 received reserpine during P1, followed by reserpine plus B. monnieri, and reserpine plus citalopram ip during P2, respectively. Forced swimming test (FST) was performed at beginning and end of P1 and P2. Animals were sacrificed by end of P2 and brain taken for histopathological examination and ELISA estimation of serotonin, dopamine, norepinephrine, BDNF, MCP-1, FAS, and Bcl-2. RESULTS: During P1, reserpine prolonged immobility time (IT) in FST in Grps 2, 3, and 4. IT was subsequently lowered in Grps 3 and 4 but remained elevated in Grp 2 by end of P2. Serotonin, dopamine and norepinephrine were lowered in Grps 2, 3, and 4, but in Grps 3 and 4, levels were comparable to Grp1. BDNF and Bc1-2 were reduced in Grps 2, 3, and 4, with higher levels in Grps 3 and 4 than Grp 2. MCP-1 and FAS were elevated in Grps 2, 3, and 4, but levels were lower in Grps 3 and 4 than in Grp 2. Histopathology showed congested cerebral cortex in Grp 2 and normal cortex in other groups. LIMITATIONS: Only adult male rats were involved and effects of co-administration of B. monnieri and citalopram were not characterized. CONCLUSION: B. monnieri improves depression comparable to citalopram in reserpine-induced depression.

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RATIONALE & OBJECTIVE: Acute kidney injury (AKI) is common in patients with coronavirus disease 2019 (COVID-19) and associated with poor outcomes. Urinary biomarkers have been associated with adverse kidney outcomes in other settings and may provide additional prognostic information in patients with COVID-19. We investigated the association between urinary biomarkers and adverse kidney outcomes among patients hospitalized with COVID-19. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Patients hospitalized with COVID-19 (n=153) at 2 academic medical centers between April and June 2020. EXPOSURE: 19 urinary biomarkers of injury, inflammation, and repair. OUTCOME: Composite of KDIGO (Kidney Disease: Improving Global Outcomes) stage 3 AKI, requirement for dialysis, or death within 60 days of hospital admission. We also compared various kidney biomarker levels in the setting of COVID-19 versus other common AKI settings. ANALYTICAL APPROACH: Time-varying Cox proportional hazards regression to associate biomarker level with composite outcome. RESULTS: Out of 153 patients, 24 (15.7%) experienced the primary outcome. Twofold higher levels of neutrophil gelatinase-associated lipocalin (NGAL) (HR, 1.34 [95% CI, 1.14-1.57]), monocyte chemoattractant protein (MCP-1) (HR, 1.42 [95% CI, 1.09-1.84]), and kidney injury molecule 1 (KIM-1) (HR, 2.03 [95% CI, 1.38-2.99]) were associated with highest risk of sustaining primary composite outcome. Higher epidermal growth factor (EGF) levels were associated with a lower risk of the primary outcome (HR, 0.61 [95% CI, 0.47-0.79]). Individual biomarkers provided moderate discrimination and biomarker combinations improved discrimination for the primary outcome. The degree of kidney injury by biomarker level in COVID-19 was comparable to other settings of clinical AKI. There was evidence of subclinical AKI in COVID-19 patients based on elevated injury biomarker level in patients without clinical AKI defined by serum creatinine. LIMITATIONS: Small sample size with low number of composite outcome events. CONCLUSIONS: Urinary biomarkers are associated with adverse kidney outcomes in patients hospitalized with COVID-19 and may provide valuable information to monitor kidney disease progression and recovery.

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Background: Atherosclerosis is a complex lipid-driven inflammatory disease in which numerous cell types and inflammatory mediators are involved in the progression of hypertension to stroke. Mediators' markers that could predict the progression of hypertension to stroke are of research importance. We assessed the predictive value of individual and combined cytokines and monocyte chemoattractant protein-1 (MCP-1) among hypertensives with or without stroke. Methods: In a case-control study, we enrolled 63 cases with stroke and hypertension (HPT-S), 59 stroke-free hypertensives (HPT), and 53 stroke free normotensives as controls (CS). Sociodemographic data and blood samples were collected for the estimation of Interleukin-10 (IL-10), IL-6, IL-8, IL-1ß and monocyte chemoattractant protein-1 (MCP-1) using commercially available ELISA kits from Biobase Biotech, Shanghai, China. The Receiver Operator Characteristics (ROC) analysis was used to calculate diagnostic accuracy for cytokines in predicting stroke among hypertensives. A combined bioscore model of IL-10 and MCP-1 was generated to predict stroke among hypertensives. The multiple logistic regression analysis was used to assess the chances of IL-10 and MCP-1 in predicting stroke among hypertensives. Statistical analyses were performed using R-language. Results: The HPT-S group had significantly higher levels of MCP-1 and IL-10 compared to the HPT and CS groups (p < 0.05). There was no significant difference in IL-1ß, IL-8 and IL-6 amongst the three study groups. MCP-1 and IL-10 were predictive of stroke occurrence among hypertensives and were used to develop a bioscore model. An elevated MCP-1 and IL-10 with a bioscore 2 had a predictive accuracy of 0.81, a sensitivity of 0.77 and specificity of 0.84. At a bioscore of 1, the sensitivity and specificity for predicting stroke among hypertensives was 97.0% and 61.0% respectively. In a binary logistic regression, having a bioscore of 1 [aOR = 20.43, 95% CI (2.17-192.62), p = 0.008] or 2 [aOR = 26.00, 95% CI (2.92-231.31), p = 0.003] were significantly associated with stroke occurrence among hypertensives. Conclusion: Higher levels of IL-10 with a concomitant level of MCP-1 could serve as a good predictor of stroke among hypertensives. Subsequently, MCP-1 may prove useful as a therapeutic target for atherosclerosis in hypertensives. Combined bioscore of MCP-1 and IL-10 could serve as a good predictor of stroke among hypertensives.

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BACKGROUND: Spinal cord injury (SCI) is a serious condition that can cause physical disability and sensory dysfunction. Cytokines play an extremely important role in the acute phase of SCI. Clarifying the cytokine expression profile is of great importance. METHODS: Cytokine array analysis was used to explore the changes in 67 different proteins at 0 hours, 2 hours, 1 day, 3 days, and 7 days after acute SCI in rats. The differentially expressed cytokines in the various periods were analyzed and compared. The biological processes related to the differentially expressed proteins were examined using Gene Ontology (GO) analysis. RESULTS: Immediately after SCI (0 hours), only ciliary neurotrophic factor (CNTF) was slightly up-regulated, while 23 other proteins were down-regulated. At 2 hours after SCI, there were 3 upregulated and 21 downregulated proteins. At 1 day after SCI, there were 5 upregulated and 6 downregulated proteins. At 3 days after SCI, there were 6 upregulated and 4 downregulated proteins. At 7 days after SCI, there were 4 upregulated and 9 downregulated proteins. Erythropoietin (EPO) and Fms related tyrosine kinase 3 ligand (Flt-3L) were downregulated at all time points. CD48 was decreased at 2 hours to 7 days after SCI. Monocyte chemotactic protein-1 (MCP-1) was the only protein that was upregulated at 2 hours to 7 days. The GO and pathway analyses revealed that the cytokine-related pathways, cell death, and proliferation might play a key role during secondary SCI. CONCLUSIONS: This study identified 3 downregulated proteins during SCI, that being EPO, Flt-3L, and CD48. MCP-1 was the only upregulated protein, and its expression was upregulated till day 7 following SCI. These 4 identified genes may be potential therapeutic targets for the treatment of SCI.

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For over 70 years, serum creatinine has remained the primary index for detection and monitoring of kidney disease. Tubulointerstitial damage and fibrosis are highly prognostic for subsequent kidney failure in biopsy studies, yet this pathology is invisible to the clinician in the absence of a biopsy. Recent discovery of biomarkers that reflect distinct aspects of kidney tubule disease have led to investigations of whether these markers can provide additional information on risk of chronic kidney disease (CKD) progression and associated adverse clinical end points, above and beyond estimated glomerular filtration rate and albuminuria. These biomarkers can be loosely grouped into those that mark tubule cell injury (eg, kidney injury molecule 1, monocyte chemoattractant protein 1) and those that mark tubule cell dysfunction (eg, α1-microglobulin, uromodulin). These kidney tubule biomarkers provide new opportunities to monitor response to therapeutics used to treat CKD patients. In this review, we describe results from some unique contributions in this area and discuss the current challenges and requirements in the field to bring these markers to clinical practice. We advocate for a broader assessment of kidney health that moves beyond a focus on the glomerulus, and we highlight how such tools can improve diagnostic accuracy and earlier assessment of therapeutic efficacy or harm in CKD patients.

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The eye is regarded as an immune privileged site. Since the presence of a vasculature would impair vision, the vasculature of the eye is located outside of the central light path. As a result, many regions of the eye evolved mechanisms to deliver immune cells to sites of dysgenesis, injury, or in response to the many age-related pathologies. While the purpose of these immune responses is reparative or protective, cytokines released by immune cells compromise visual acuity by inducing inflammation and fibrosis. The response to traumatic or pathological injury is distinct in different regions of the eye. Age-related diseases impact both the anterior and posterior segment and lead to reduced quality of life and blindness. Here we focus attention on the role that inflammation and fibrosis play in the progression of age-related pathologies of the cornea and the lens as well as in glaucoma, the formation of epiretinal membranes, and in proliferative vitreoretinopathy.

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BACKGROUND: Transarterial chemoembolization (TACE) is a widely accepted treatment for unresectable or intermediate-stage hepatocellular carcinoma (HCC). However, response rates to TACE are heterogeneous and it is not fully understood which patients benefit most from TACE therapy in terms of tumor response. To identify the possible predictive roles of the perioperative monocyte chemoattractant protein-1 (MCP-1) levels in patients of HCC treated with TACE. METHODS: Forty patients of HCC receiving TACE were enrolled in a single center prospective observational study. MCP-1 and miR-210 levels were measured in 40 HCC patients at baseline before TACE and compared with 17 healthy controls by immunoassay and reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). Tumor response assessments were taken after TACE treatment 4-6 weeks. Univariate and multivariate analysis were conducted to analyze factors correlated with tumor response in a Logistic regression model. The predictive roles of the involved variables on tumor response in patients with HCC suffering TACE were examined by receiver operating characteristic (ROC) curve analysis. RESULTS: The serum MCP-1 and miR-210 levels were significantly elevated in HCC patients compared to healthy subjects. Patients with the low preintervention MCP-1 and miR-210 levels attained a higher probability of achieving an objective response (OR) (88.5% vs.42.9%, P=0.007; 76.9% vs. 35.7%, P=0.010, respectively). Pre-TACE MCP-1 level (<816.63 pg/mL) was an independent risk factor associated with OR after TACE by univariate and multivariate analysis while Pre-TACE miR-210 level (<4.43 relative expression) was just positive by univariate analysis. ROC curve analysis showed that a combined index based on those two factors exhibited optimal predictive power of tumor response among all the involved variables (area under the curve =0.823, 95% CI: 0.681-0.965). Additionally, high pre-TACE serum MCP-1 level was correlated with cirrhosis, vascular invasion and Barcelona Clinic Liver Cancer (BCLC) stage. Elevated pre-TACE serum miR-210 level was associated with and BCLC stage. CONCLUSIONS: The study demonstrates that the pre-TACE serum MCP-1 level serves as an effective predictor for tumor response. These findings probably help discriminate HCC patients pre-TACE who specially benefit from TACE regarding OR.

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NADPH oxidase (Nox) 4 produces H2O2 by forming a heterodimer with p22phox and is involved in hemangioendothelioma development through monocyte chemoattractant protein-1 (MCP-1) upregulation. Here, we show that Nox4 protein levels were maintained by p22phox in hemangioendothelioma cells and Nox4 protein stability was dependent on p22phox coexpression. Conversely, the degradation of Nox4 monomer was enhanced by p22phox knockdown. Under hypoxic conditions in hemangioendothelioma cells, p22phox was downregulated at the mRNA and protein levels. Downregulation of p22phox protein resulted in the enhanced degradation of Nox4 protein in hypoxia-treated hemangioendothelioma cells. In contrast, Nox2, a Nox isoform, was not altered at the protein level under hypoxic conditions. Nox2 exhibited a higher affinity for p22phox compared with Nox4, suggesting that when coexpressed with Nox4 in the same cells, Nox2 acts as a competitor. Nox2 knockdown restored Nox4 protein levels partially reduced by hypoxic treatment. Thus, Nox4 protein levels were attenuated in hypoxia-treated cells resulting from p22phox depletion. MCP-1 secretion was decreased concurrently with hypoxia-induced Nox4 downregulation compared with that under normoxia.

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