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Obesity is a constantly growing health problem which reduces quality of life and life expectancy. Bariatric surgery (BS) for obesity is considered when all other conservative treatment modalities have failed. Comparison of the multidisciplinary programs with BS regarding to the weight loss showed that substantial and durable weight reduction have been achieved only with bariatric surgical treatments. Although laparoscopic sleeve gastrectomy is the most popular BS, it has high long-term failure rates, and it is claimed that one of every three patients will undergo another bariatric procedure within a 10-year period. Although BS provides weight loss and improvement of metabolic comorbidities, in long-term follow-up, weight gain is observed in half of the patients, while decrease in bone mass and nutritional deficiencies occur in up to 90%. Moreover, despite significant weight loss, several psychological aspects of patients are worsened in comparison to preoperative levels. Nearly one-fifth of postoperative patients with "Loss-of-eating control" meet food addiction criteria. Therefore, the benefits of weight loss following bariatric procedures alone are still debated in terms of the proinflammatory and metabolic profile of obesity.

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BACKGROUNDS: Fat infiltration of skeletal muscle has been recognized as a common feature of many degenerative muscle disorders. Retinol binding protein 4 (RBP4) is an adipokine that has been demonstrated to be correlated with the presence and severity of sarcopenia in the elderly. However, the exact role and the underlying mechanism of RBP4 in muscle atrophy remains unclear. METHODS: Denervation-induced muscle atrophy model was constructed in wild-type and RBP4 knockout mice. To modify the expression of RBP4, mice were received intramuscular injection of retinol-free RBP4 (apo-RBP4), retinol-bound RBP4 (holo-RBP4) or oral gavage of RBP4 inhibitor A1120. Holo-RBP4-stimulated C2C12 myotubes were treated with siRNAs or specific inhibitors targeting signalling receptor and transporter of retinol 6 (STRA6)/Janus kinase 2 (JAK2)/Signal transducer and activator of transcription 3 (STAT3) pathway. Fat accumulation, myofibre cross-sectional area, myotube diameter and the expression of muscle atrophy markers and myogenesis markers were analysed. RESULTS: The expression levels of RBP4 in skeletal muscles were significantly up-regulated more than 2-fold from 7 days and sustained for 28 days after denervation. Immunofluorescence analysis indicated that increased RBP4 was localized in the infiltrated fatty region in denervated skeletal muscles. Knockout of RBP4 alleviated denervation-induced fatty infiltration and muscle atrophy together with decreased expression of atrophy marker Atrogin-1 and MuRF1 as well as increased expression of myogenesis regulators MyoD and MyoG. By contrast, injection of retinol-bound holo-RBP4 aggregated denervation-induced ectopic fat accumulation and muscle atrophy. Consistently, holo-RBP4 stimulation also had a dose-dependent effect on the reduction of C2C12 myotube diameter and myofibre cross-sectional area, as well as on the increase of Atrogin-1and MuRF1 expression and decrease of MyoD and MyoG expression. Mechanistically, holo-RBP4 treatment increased the expression of its membrane receptor STRA6 (>3-fold) and promoted the phosphorylation of downstream JAK2 and STAT3. Inhibition of STRA6/JAK2/STAT3 pathway either by specific siRNAs or inhibitors could decrease the expression of Atrogin-1 and MuRF1 (>50%) and decrease the expression of MyoD and MyoG (>3-fold) in holo-RBP4-treated C2C12 myotube. RBP4 specific pharmacological antagonist A1120 significantly inhibited the activation of STRA6/JAK2/STAT3 pathway, ameliorated ectopic fat infiltration and protected against denervation-induced muscle atrophy (30% increased myofibre cross-sectional area) in mice. CONCLUSIONS: In conclusion, our data reveal that RBP4 promotes fat infiltration and muscle atrophy through a STRA6-dependent and JAK2/STAT3 pathway-mediated mechanism in denervated skeletal muscle. Our results suggest that lowering RBP4 levels might serve as a promising therapeutic approach for prevention and treatment of muscle atrophy.

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Background: Gastric cancer (GC) is a highly phenotypically heterogeneous disease and is caused by a combination of factors. Retinol binding protein 4 (RBP4) is a member of a family of lipid transport proteins that are involved in the transport of substances between cells and play a crucial role in a variety of cancers. However, the expression and role of RBP4 in GC remain unknown. Methods: In this study, we explored the expression, prognostic significance, immune microenvironment, drug responsiveness and function of associated signaling pathways of RBP4 in GC using web-based bioinformatics tools. Immunohistochemistry and real-time quantitative PCR were utilized to analyze the tissue and cell expression levels of RBP4. CCK-8, colony formation, EDU incorporation, wound healing and transwell assays were applied to demonstrate the effect of RBP4 on GC cell function. Flow cytometric detection of apoptosis after RBP4 knockdown. Nude mice xenograft model elucidates the role of RBP4 for GC in vivo. Related proteins of the RAS signaling pathway were analyzed by employing Western blot assays. Results: RBP4 is highly expressed in GC. RBP4 is closely associated with patient survival and sensitivity to a wide range of antitumor agents. Knockdown of RBP4 promoted apoptosis and inhibited cell proliferation, invasion and migration. RBP4 promotes GC tumorigenesis in vivo. Finally, RBP4 modulates the RAS/RAF/ERK axis. Conclusion: RBP4 may promote gastric carcinogenesis and development through the RAS/RAF/ERK axis and is expected to be a novel target for GC treatment.

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Vitamin A (retinol) is distributed via the blood bound to its specific carrier protein, retinol-binding protein 4 (RBP4). Retinol-loaded RBP4 is secreted into the circulation exclusively from hepatocytes, thereby mobilizing hepatic retinoid stores that represent the major vitamin A reserves in the body. The relevance of extrahepatic retinoid stores for circulating retinol and RBP4 levels that are usually kept within narrow physiological limits is unknown. Here, we show that fasting affects retinoid mobilization in a tissue-specific manner, and that hormone-sensitive lipase (HSL) in adipose tissue is required to maintain serum concentrations of retinol and RBP4 during fasting in mice. We found that extracellular retinol-free apo-RBP4 induces retinol release by adipocytes in an HSL-dependent manner. Consistently, global or adipocyte-specific HSL deficiency leads to an accumulation of retinoids in adipose tissue and a drop of serum retinol and RBP4 during fasting, which affects retinoid-responsive gene expression in eye and kidney and lowers renal retinoid content. These findings establish a novel crosstalk between liver and adipose tissue retinoid stores for the maintenance of systemic vitamin A homeostasis during fasting.

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BACKGROUND: The prognosis of hepatocellular carcinoma (HCC) is universally poor. Early diagnosis plays a pivotal role in determining the outcome of HCC. METHODS: We employed a comparative proteomics approach to identify potential biomarkers and validated the application of retinol-binding protein 4 (RBP4) as a biomarker for HCC. RBP4 protein expression was examined in liver tissues from 80 HCC patients through immunohistochemical analysis. Serum RBP4 concentrations were measured by ELISA in a cohort comprising 290 HCC patients, matched 202 chronic hepatitis B patients and 269 healthy controls. Survival data were collected from HCC patients. The diagnostic and prognostic values of RBP4 were evaluated using receiver operating curve (ROC) analysis. RESULTS: The validation results demonstrated a significant reduction in RBP4 levels in both liver tissues and serum samples from HCC patients. ROC analysis of the diagnostic value of RBP4 revealed an AUC of 0.879 (95 % CI: 0.854∼0.903) for HCC. When combined with AFP, the AUC increased to 0.919, with a sensitivity of 87.9 % and specificity of 80 %. Survival analysis revealed significantly reduced overall survival time in individuals with low-expression of RBP4 compared to those with high-expression. The joint prognostic model exhibited an AUC of 0.926 (95 % CI: 0.888∼0.964), which was significantly higher than that of AFP alone (AUC=0.809; P <0.0001). CONCLUSIONS: RBP4 shows a great potential as a biomarker with appreciable diagnostic value, complementing the AFP in HCC diagnosis. Additionally, it holds promise as a prognostic biomarker that, when integrated into a combined prognostic model, could greatly improve HCC prognosis efficiency.

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AIM: To explore the link between the RBP4 rs3758539 genotype and metabolic syndrome risk factors and whether the impact of this genetic variation displays any potential race discrepancy. MATERIALS AND METHODS: This meta-analysis followed the PRISMA guidelines and was registered with PROSPERO (registration no. CRD42023407999). PubMed, Web of Science, Embase, Cochrane Library, Google Scholar, Airiti Library and CINAHL databases were used for the study search until October 2023. We evaluated the methodological quality using the Joanna Briggs Institute checklist and determined the correlation using a random-effects meta-analysis. RESULTS: The results indicated that individuals with the rs3758539 GA/AA genotype had a higher risk profile, including lower high-density lipoprotein levels [correlation: -0.045, 95% confidence interval (CI): -0.080 to -0.009, p = .015, I2 = 46.9%] and higher body mass index (correlation: 0.117, 95% CI: 0.036-0.197, p = .005, I2 = 82.0%), body fat (correlation: 0.098, 95% CI: 0.004-0.191, p = .041, I2 = 64.0%), and low-density lipoprotein levels (correlation: 0.074, 95% CI: 0.010-0.139, p = .024, I2 = 0%), of developing metabolic syndrome than those with the GG genotype. The subgroup analysis maintained a significantly positive correlation between the rs3758539 GA/AA genotype and body mass index (correlation: 0.163, 95% CI: 0.031-0.289, p = .016, I2 = 88.9%) but a negative correlation with high-density lipoprotein levels (correlation: -0.047, 95% CI: -0.087 to -0.006, p = .025, I2 = 65.7%) in the Asian group only. CONCLUSION: The current meta-analysis supports a significant link between the RBP4 rs3758539 GA/AA genotype and the metabolic syndrome.

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In this review, we outline our current understanding of the mechanisms involved in the absorption, storage, and transport of dietary vitamin A to the eye, and the trafficking of rhodopsin protein to the photoreceptor outer segments, which encompasses the logistical backbone required for photoreceptor cell function. Two key mechanisms of this process are emphasized in this manuscript: ocular and systemic vitamin A membrane transporters, and rhodopsin transporters. Understanding the complementary mechanisms responsible for the generation and proper transport of the retinylidene protein to the photoreceptor outer segment will eventually shed light on the importance of genes encoded by these proteins, and their relationship on normal visual function and in the pathophysiology of retinal degenerative diseases.

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The lipocalin proteins are a large family of small extracellular proteins that demonstrate significant heterogeneity in sequence similarity and have highly conserved crystal structures. They have a variety of functions, including acting as carrier proteins, transporting retinol, participating in olfaction, and synthesizing prostaglandins. Importantly, they also play a critical role in human diseases, including cancer. Additionally, they are involved in regulating cellular homeostasis and immune response and dispensing various compounds. This comprehensive review provides information on the lipocalin family, including their structure, functions, and implications in various diseases. It focuses on selective important human lipocalin proteins, such as lipocalin 2 (LCN2), retinol binding protein 4 (RBP4), prostaglandin D2 synthase (PTGDS), and α1-microglobulin (A1M).

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BACKGROUND: Adverse childhood experiences (ACE) elevate the risk of both major depressive disorder (MDD) and metabolic diseases. The underlying pathophysiology might include alterations of adipokine levels as a consequence of ACE. In this study, we used a full-factorial design to investigate the levels of select adipokines in women with ACE-only (n = 23), MDD-only (n = 27), ACE+MDD (n = 25) and healthy controls (HC, n = 29) to identify metabolic makers associated with vulnerability and resilience of developing MDD after ACE exposure. METHODS: Serum levels of adiponectin, leptin, adiponectin-to-leptin (A/L) ratio, and retinol binding protein 4 (RBP4) were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: Adiponectin levels did not differ between groups. Individuals with vs. without MDD showed higher leptin serum concentrations. As predicted, A/L ratio indicated lower values in individuals with vs. without ACE. RBP4 showed a more nuanced pattern with reduced levels in the ACE-only and MDD-only groups compared to HC. Furthermore, the ACE-only group showed lower RBP4 concentrations compared to ACE+MDD. These results were not accounted by BMI or medication status. CONCLUSION: Our results do not support the utility of adiponectin and leptin as predictors of vulnerability or resilience of developing MDD after ACE. In contrast, RBP4 might play a role in resilience towards the development of MDD following ACE. Further research on this more recently discovered adipokine seems warranted.

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This study aimed to analyze changes in retinol-binding protein 4 (RBP4) levels before and after bariatric surgery in obese individuals. Bariatric surgery is a safe and effective treatment for morbid obesity, impacting molecules like RBP4. A systematic review and meta-analysis of 12 relevant studies were conducted, utilizing databases such as PubMed, Cochrane Central, Web of Science, and Scopus. Significant differences in RBP4, glucose, and BMI levels pre- and post-surgery were observed. Meta-regression analysis explored associations with age, pre-BMI, triglycerides, glucose, and post-insulin levels. Findings suggest RBP4 may improve insulin sensitivity after bariatric surgery, warranting further investigation as a potential pharmacotherapeutic target. These results highlight the importance of understanding RBP4's role in the context of bariatric surgery and its implications for improving metabolic health in obese individuals.

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Background: Gestational diabetes mellitus (GDM) is a prevalent condition where diabetes is diagnosed during pregnancy, affecting both maternal and fetal outcomes. Retinol-binding protein 4 (RBP4) is a circulating adipokine which belongs to the lipocalin family and acts as a specific carrier protein that delivers retinol (vitamin A) from the liver to the peripheral tissues. Growing data indicate that circulating RBP4 levels may positively correlate with GDM. Thus, this systematic review and meta-analysis aimed to investigate the potential relationship between circulating RBP4 levels and GDM when measured at various stages of pregnancy. Methods: MEDLINE, CINAHL, EMCARE, EMBASE, Scopus, and Web of Science databases were searched to identify studies comparing pregnant women with and without GDM, whose circulating RBP4 levels were measured in at least one pregnancy trimester. Findings were reported using standardized mean difference (SMD) and random-effects models were used to account for variability among studies. Furthermore, the risk of bias was assessed using the RoBANS tool. Results: Out of the 34 studies identified, 32 were included in the meta-analysis (seven with circulating RBP4 levels measured in the first trimester, 19 at 24-28 weeks, and 14 at >28 weeks of pregnancy). RBP4 levels were statistically higher in the GDM group than in controls when measured during all these pregnancy stages, with the noted RBP4 SMD being 0.322 in the first trimester (95% CI: 0.126-0.517; p < 0.001; 946 GDM cases vs. 1701 non-GDM controls); 0.628 at 24-28 weeks of gestation (95% CI: 0.290-0.966; p < 0.001; 1776 GDM cases vs. 1942 controls); and 0.875 at >28 weeks of gestation (95% CI: 0.252-1.498; p = 0.006; 870 GDM cases vs. 1942 non-GDM controls). Significant study heterogeneity was noted for all three pregnancy timepoints. Conclusion: The present findings indicate consistently higher circulating RBP4 levels in GDM cases compared to non-GDM controls, suggesting the potential relevance of RBP4 as a biomarker for GDM. However, the documented substantial study heterogeneity, alongside imprecision in effect estimates, underscores the need for further research and standardization of measurement methods to elucidate whether RBP4 can be utilized in clinical practice as a potential GDM biomarker. Systematic review registration: PROSPERO (CRD42022340097: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022340097).

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Here, we present the results of our the electrochemical aptasensing strategy for retinol binding protein-4 (RBP-4) detection based on a thiolated aptamer against RBP-4 and 6-mercaptohexanol (MCH) directly immobilized on a gold electrode surface. The most important parameters affecting the magnitude of the analytical signal generated were optimized: (i) the presence of magnesium ions in the immobilization and measurement buffer, (ii) the concentration of aptamer in the immobilization solution and (iii) its folding procedure. In this work, a systematic assessment of the electrochemical parameters related to the optimization of the sensing layer of the aptasensor was carried out (electron transfer coefficients (α), electron transfer rate constants (k0) and surface coverage of the thiolated aptamer probe (ΓApt)). Then, under the optimized conditions, the analytical response towards RBP-4 protein, in the presence of an Fe(CN)63-/4- redox couple in the supporting solution was assessed. The proposed electrochemical strategy allowed for RBP-4 detection in the concentration range between 100 and 1000 ng/mL with a limit of detection equal to 44 ng/mL based on electrochemical impedance spectroscopy (EIS). The specificity studies against other diabetes biomarkers, including vaspin and adiponectin, proved the selectivity of the proposed platform. These preliminary results will be used in the next step to miniaturize and test the sensor in real samples.

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Retinol-binding protein 4 (RBP4) was controversially associated with type 2 diabetes mellitus (T2DM). This meta-analysis aimed at evaluating the association between RBP4 level and T2DM risk. MEDLINE and EMBASE were searched to identify relevant studies up to 3 December 2022. Random effects model was used to pool multivariate-adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Publication bias was estimated by Funnel plot and Egger's test, it was considered to be significant when P < 0.05. Eight studies including 8087 participants were finally included. Compared to those with the lowest level, subjects with the highest level of RBP4 have a higher risk of T2DM (OR = 1.47, 95% CI: 1.16-1.78, P < 0.001, I2 = 86.9%). No publication bias among the included studies was found (t = 0.94, P = 0.377). This meta-analysis indicated that high RBP4 level was associated with increasing risk of T2DM.

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INTRODUCTION: Several studies showed the correlation of retinol-binding protein 4 (RBP4) with increased cardiovascular risk - including higher values of carotid intima-media thickness (cIMT) - particularly in individuals with obesity. OBJECTIVES: Our study aimed to investigate the impact of rs10882273; rs3758538; rs3758539, and rs7094671 RBP4 gene variants on RBP4 serum concentrations as well as cIMT values (a marker of subclinical atherosclerosis) among female patients with obesity. PATIENTS AND METHODS: We recruited 74 women with obesity and 24 women without obesity as a study and control group, respectively. The genotypic and allelic frequencies of RBP4 gene variants were evaluated for associations with serum RBP4 and cIMT. RESULTS: The median serum RBP4 concentrations were 20.30 µg/mL and 19.80 µg/mL in the patients and control group, respectively (p = 0.740). No significant differences were seen in cIMT values between the two studied groups (0.60 [0.50-1.00] vs. 0.60 ± 0.10 in the patient and control group, respectively); however, the results were close to reaching significance (p = 0.071), similar as in observed association of the minor haplotype AA for rs7084671 and rs375839 with female obesity (p = 0.0559). The correlation analysis showed no significant differences between RBP4 gene variants with serum RBP4 and cIMT. CONCLUSIONS: According to our knowledge, this is the first study investigating the association between RBP4 gene variants and serum RBP4 and cIMT among Polish female patients with obesity. However, our results show that genetic variants rs10882273, rs3758538, rs3758539, and rs7094671 of the RBP4 gene are not associated with RBP4 serum concentrations or cIMT values among women with obesity.

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There is a significant comorbidity between obesity and periodontitis, while adipokines are pivotal in the immunoinflammatory process, which may play a role in this special relationship. We aimed to assess the effect of adipokines as mediators in the progression of periodontitis in obese Sprague Dawley rats. Rats were divided into four groups: normal body weight with and without periodontitis and obesity with and without periodontitis. Experimental obesity and periodontitis were induced by a high-fat diet or ligaturing, and the effect was measured using metabolic and micro-computed tomography analysis and histological staining. Compared with the other three groups, the group of periodontitis with obesity (OP) had the heaviest alveolar bone absorption, the largest increase in osteoclasts, the utmost inflammatory cell infiltration and the highest expressions of pro-inflammatory cytokines and nuclear factor-kappa B ligand (RANKL); meanwhile, its expression of the osteogenesis-related gene was the lowest among the four groups. The expressions of leptin, visfatin, resistin, retinol-binding protein 4 (RBP4) and asprosin were upregulated, while adiponectin was decreased significantly in OP. The strong positive associations between the periodontal or circulating levels of RBP4 (or asprosin) and the degree of alveolar resorption in experimental periodontitis and obese rats were revealed. The upregulated expression of inflammation biomarkers, the corresponding degradation in connective tissue and the generation of osteoclasts in periodontitis were activated and exacerbated in obesity. The elevated level of RBP4/asprosin may contribute to a more severe periodontal inflammatory state in obese rats.

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Prior studies demonstrated an equivocal conclusion about the association between the level of retinol-binding protein 4 (RBP4)/visfatin and periodontitis patients with obesity. The aim of our study (Prospero ID: CRD42023469058) was to systematically review the available articles linking the biofluid levels of RBP4/visfatin to the comorbidity of periodontitis and obesity. Clinical trials were screened in accordance with specific inclusion criteria from seven databases up to November 2023. A quality assessment was performed with the Newcastle-Ottawa Scale and ROBINS-I tools for observational and interventional trials, respectively. The standard mean difference (SMD) with a 95% confidence interval (CI) related to the RBP4 level was recorded; the other indicators related to the visfatin level were measured via the mean difference (MD) with the corresponding 95% CI, and Fisher's Z transformation was measured to reveal the association using Review Manager 5.4. The current evidence was based on five observational studies and two interventional studies. All of them were included in the systematic review, and six of them were in the meta-analysis. Statistical analysis indicated that there was no significant difference in the circulating levels of RBP4 in the periodontitis patients with obesity or without, who were labeled as OP or NP, respectively (155 OP-107 NP: SMD = 1.38; 95% CI: -0.18-2.94, p = 0.08), as well as the periodontal healthy patients with a normal weight, who were labelled as NnP (116 OP-79 NnP: SMD = 6.76; 95% CI: -5.34-18.87, p = 0.27). Meanwhile, a significant higher level of serum visfatin was found in the OP patients than that of the NP (86 OP-45 NP: MD = 4.21; 95% CI: 2.65-5.77, p < 0.00001)/NnP (164 OP-88 NnP: MD = 13.02; 95% CI: 7.34-18.70, p < 0.00001) group. In addition, a positive association was observed between the serum RBP4 and body mass index/clinical attachment loss (CAL). And, then, there was a positive association between the serum visfatin and periodontal parameters, including the probing depth, CAL, and plaque index, as well as metabolic parameters, including the total cholesterol, triglycerides, fasting blood glucose, and low-density lipoprotein cholesterol. Here, the circulating RBP4 level was not independently related to the comorbidity of periodontitis and obesity, while serum visfatin was significantly associated with periodontitis and obesity. Notably, the positive association between circulating RBP4/visfatin and the periodontal parameters/metabolic parameters firmly suggested that the higher severity of the obese or periodontal status was associated with an elevated level of serum visfatin or RBP4 in the OP group. With more rigorous longitudinal research, the exact causations between RBP4/visfatin and the patients affected by obesity and periodontitis could be disentangled. RBP4 and visfatin might be novel, enlightening prospective bio-indexes for the targeted treatment of comorbidities.

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Background: Common neuropathologies associated with dementia include Alzheimer's disease neuropathologic change (ADNC) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Biofluid proteomics provides a window into the pathobiology of dementia and the information from biofluid tests may help guide clinical management. Methods: Participants were recruited from a longitudinal cohort of older adults at the University of Kentucky AD Research Center. A convenience sample of clinically obtained lumbar puncture cerebrospinal fluid (CSF) samples was analyzed from 29 older adults that had autopsy confirmation of the presence or absence of LATE-NC. Nine of the participants had autopsy-confirmed LATE-NC. Antemortem CSF specimens were analyzed in two separate processes: From one group, aliquots were depleted of highly abundant proteins using affinity spin columns. Tryptic digests of sample proteins were subjected to liquid chromatographic separation and mass spectrometry using an Eksigent Ekspert nanoLC 400 system in line with a Sciex 6600+ mass spectrometer. Protein identification was performed using Protein Pilot (Sciex, ver. 5) software, and relative quantification was performed using the SWATH processing microApp in PeakView and MarkerView software (Sciex), respectively. Following data analyses, additional studies were performed using western blots. Results: A total of 830 proteins were identified in the samples depleted of abundant proteins, and 730 proteins were identified in the non-depleted samples. Whereas some dementia-related proteins were detected (Aß peptide and α-synuclein protein), others were not (TDP-43, TMEM106B, and tau proteins). When the Bonferroni correction was applied to correct for multiple comparisons, only 4 proteins showed differential expression (LATE-NC vs non-LATE-NC) in the nondepleted samples (RBP4, MIF, IGHG3 and ITM2B), whereas none showed statistically different changes in the depleted samples. Post-hoc western blots confirmed that RBP4 expression was higher in the LATE-NC cases at the group level, but there was overlap between the levels of RBP4 in LATE-NC and non-LATE-NC cases. Conclusions: An exploratory assessment of CSF proteomes of autopsy-confirmed LATE-NC and non-LATE-NC cases from a community-based cohort failed to demonstrate a clear-cut proteomic fingerprint that distinguished the two groups. There was intriguing increase in RBP4 protein levels in CSF from LATE-NC cases. This may provide clues about pathogenetic mechanisms in LATE-NC.

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The ancient use of herbs for the treatment of various human diseases have been documented, with several scientific literatures supporting the use of medicinal plants. There is however a major concern about the phyto-constituents in the plants that performs the healing function and the mechanism by which it works for different ailments are still a research prospect. Cardiometabolic disease (CMD) is no doubt becoming more frequent globally and this is due to poor approach in therapy, contrary effects linked with intensive control, inept strategies with old drugs, inadequate control of some risk factors and lack of knowledge of the pathophysiological mechanisms that lead to this malaise. Retinol-binding protein 4 (RBP4) are predominantly secreted in the liver and adipose tissues and several researches have observed that elevation in serum levels of RBP4 often observed in obese experimental animals and human subjects causes CMD (obesity, insulin resistance, hyperlipidemia, etc.). RBP4 has gained special attention in the last 20 years in the field of metabolism research. This review aims to show research interaction of some medicinal plants targeting RBP4 in treating CMD and to encourage researchers, who are interested in CMD drug design, to focus on medicinal plants that inhibit the secretion of serum RBP4 in the adipose tissue for therapeutic approach to CMD. It also aims to identify the major bioactive compounds of plants that serves as a better and cheaper drug candidate for CMD and also study the signaling pathway which the plant material uses to regulate the metabolic consequences.

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The auditory cortex exerts a powerful, yet heterogeneous, effect on subcortical targets. Auditory corticofugal projections emanate from layers 5 and 6 and have complementary physiological properties. While several studies suggested that layer 5 corticofugal projections branch widely, others suggested that multiple independent projections exist. Less is known about layer 6; no studies have examined whether the various layer 6 corticofugal projections are independent. Therefore, we examined branching patterns of layers 5 and 6 auditory corticofugal neurons, using the corticocollicular system as an index, using traditional and novel approaches. We confirmed that dual retrograde injections into the mouse inferior colliculus and auditory thalamus co-labeled subpopulations of layers 5 and 6 auditory cortex neurons. We then used an intersectional approach to relabel layer 5 or 6 corticocollicular somata and found that both layers sent extensive branches to multiple subcortical structures. Using a novel approach to separately label layers 5 and 6 axons in individual mice, we found that layers 5 and 6 terminal distributions partially spatially overlapped and that giant terminals were only found in layer 5-derived axons. Overall, the high degree of branching and complementarity in layers 5 and 6 axonal distributions suggest that corticofugal projections should be considered as 2 widespread systems, rather than collections of individual projections.

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The positive correlation between serum levels of retinol binding protein 4 (RBP4) and gestational diabetes (GDM) has been proven in the previous meta-analysis on case-control studies. However, its association with serum levels of leptin is not studied in any meta-analysis. Therefore, we performed an updated systematic review of observational studies evaluating the association between serum RBP4 and leptin with the risk of GDM. A systematic search was performed on four databases, including PubMed, Scopus, Web of Science, and Google Scholar, up to March 2021. After screening and deleting duplicates, nine articles met our inclusion criteria. Studies had case-control and cohort design, and included 5074 participants with a mean age range between 18 and 32.65 years (2359 participants for RBP4 and 2715 participants for leptin). Interestingly, this meta-analysis revealed higher levels of RBP4 (OR=2.04; 95% CI: 1.37, 3.04) and leptin (OR=2.32; 95% CI: 1.39, 3.87) are significantly associated with the increased risk of overall GDM. The subgroup analysis approved the results based on the study design, trimester of pregnancy and serum/plasms to investigate the source of heterogeneity. The present meta-analysis determines serum leptin and RBP4 levels as predictors of GDM occurrence. However, studies included in this meta-analysis showed significant heterogeneity.