Intratumoral injection of mRNA encoding survivin in combination with STAT3 inhibitor stattic enhances antitumor effects.

Intratumoral delivery of mRNA encoding immunostimulatory molecules can initiate a robust, global antitumor response with little side effects by enhancing local antigen presentation in the tumor and the tumor draining lymph node. Neoantigen-based mRNA nanovaccine can inhibit melanoma growth in mice by intratumoral injection. Myeloid-derived suppressor cells (MDSCs) suppress antitumor immune responses by secreting immunosuppressive agents, such as reactive oxygen species (ROS). Suppression of STAT3 activity by stattic may reduce MDSC-mediated immunosuppression in the TME and promote the antitumor immune responses. In this study, in vitro transcribed mRNA encoding tumor antigen survivin was prepared and injected intratumorally in BALB/c mice bearing subcutaneous colon cancer tumors. In vivo studies demonstrated that intratumoral survivin mRNA therapy could induce antitumor T cell response and inhibit tumor growth of colon cancer. Depletion of CD8+ T cells could significantly inhibit survivin mRNA-induced antitumor effects. RT-qPCR and ELISA analysis indicated that survivin mRNA treatment led to increased expression of receptor activator nuclear factor-κB ligand (RANKL). In vitro experiment showed that MDSCs could be induced from mouse bone marrow cells by RANKL and RANKL-induced MDSCs could produce high level of ROS. STAT3 inhibitor stattic suppressed activation of STAT3 and NF-κB signals, thereby inhibiting expansion of RANKL-induced MDSCs. Combination therapy of survivin mRNA and stattic could significantly enhance antitumor T cell response, improve long-term survival and reduce immunosuppressive tumor microenvironment compared to each monotherapy. In addition, combined therapy resulted in a significantly reduced level of tumor cell proliferation and an obviously increased level of tumor cell apoptosis in CT26 colon cancer-bearing mice, which could be conducive to inhibit the tumor growth and lead to immune responses to released tumor-associated antigens. These studies explored intratumoral mRNA therapy and mRNA-based combined therapy to treat colon cancer and provide a new idea for cancer therapy.

PGD2/DP1 axis promotes liver regeneration by secreting Wnt2 in Kupffer cells in mice.

BACKGROUND AND AIMS: The liver possesses a remarkable regenerative capacity in response to injuries or viral infections. Various growth factors and cytokines are involved in regulating liver regeneration. Prostaglandin (PG) D2, a pro-resolution lipid mediator, is the most abundant hepatic prostanoid. However, the role of PGD2 in the injury-induced liver regeneration remains unclear. APPROACH AND RESULTS: Two-thirds partial hepatectomy (70% PH), massive hepatectomy (85% resection), and carbon tetrachloride-induced chronic injury were performed in mice to study the mechanisms of live regeneration. Hepatic PGD2 production was elevated in mice after PH. Global deletion of D prostanoid receptor (DP) 1, but not DP2, slowed PH-induced liver regeneration in mice, as evidenced by lower liver weight to body weight ratio, less Ki67+ hepatocyte proliferation, and G2/M phase hepatocytes. Additionally, DP1 deficiency specifically in resident Kupffer cells (KCs), and not in endothelial cells or hepatic stellate cells, retarded liver regeneration in mice post-PH. Conversely, the overexpression of exogenous DP1 in KCs accelerated liver regeneration in mice. Mechanistically, DP1 activation promoted Wnt2 transcription in a PKA/CREB-dependent manner in resident KCs and mediated hepatocyte proliferation through Frizzled8/ß-catenin signaling. Adeno-associated virus vector serotype 8 (AAV8)-mediated Frizzled8 knockdown in hepatocytes attenuated accelerated liver regeneration in KC-DP1 transgenic mice post-PH. Treatment with the DP1 receptor agonist BW245C promotes PH-induced liver regeneration in mice. CONCLUSIONS: DP1 activation mediates crosstalk between KCs and hepatocytes through Wnt2, and facilitates liver regeneration. Hence, DP1 may serve as a novel therapeutic target in acute and chronic liver diseases.

Nanotherapeutics targeting autophagy regulation for improved cancer therapy.

The clinical efficacy of current cancer therapies falls short, and there is a pressing demand to integrate new targets with conventional therapies. Autophagy, a highly conserved self-degradation process, has received considerable attention as an emerging therapeutic target for cancer. With the rapid development of nanomedicine, nanomaterials have been widely utilized in cancer therapy due to their unrivaled delivery performance. Hence, considering the potential benefits of integrating autophagy and nanotechnology in cancer therapy, we outline the latest advances in autophagy-based nanotherapeutics. Based on a brief background related to autophagy and nanotherapeutics and their impact on tumor progression, the feasibility of autophagy-based nanotherapeutics for cancer treatment is demonstrated. Further, emerging nanotherapeutics developed to modulate autophagy are reviewed from the perspective of cell signaling pathways, including modulation of the mammalian target of rapamycin (mTOR) pathway, autophagy-related (ATG) and its complex expression, reactive oxygen species (ROS) and mitophagy, interference with autophagosome-lysosome fusion, and inhibition of hypoxia-mediated autophagy. In addition, combination therapies in which nano-autophagy modulation is combined with chemotherapy, phototherapy, and immunotherapy are also described. Finally, the prospects and challenges of autophagy-based nanotherapeutics for efficient cancer treatment are envisioned.

Efficacy of Apagliflozin Plus Pentoxifylline in the Treatment of Early Diabetic Nephropathy and Its Effect on Serum Inflammatory Factors and Immune Function.

Objective: To explore the efficacy of dapagliflozin plus pentoxifylline in the treatment of early diabetic nephropathy and its effect on serum inflammatory factors and immune function. Methods: A total of 90 patients with early diabetic nephropathy who were admitted to Cangzhou Central Hospital from January 2019 to January 2022 were recruited and randomized (1:1) into a control group and an observation group using the random number table method. The control group was treated with dapagliflozin, and the observation group was treated with pentoxifylline plus dapagliflozin. The effectiveness of urinary α (1) microglobulin (α 1-mg) was determined by immunoturbidimetric method, and urinary ß (2) microglobulin (ß 2-mg) was determined. Urine creatinine was determined enzymatically, and the urinary microprotein albumin creatinine ratio (mAlb/Cr) was calculated. The levels of inflammatory factors [interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α)] were detected. Before and after treatment, 3 mL of venous blood was drawn from the two groups of patients, and serum CD4+, CD8+, and CD4+/CD8+ levels were detected. The incidence of adverse reactions between the two groups was calculated. Results: Dapagliflozin plus pentoxifylline was associated with a higher effective rate than dapagliflozin alone (96.67% vs 81.67%) (RR 0·80 [95% CI 0·61-0.98]; P = .021). Dapagliflozin plus pentoxifylline led to lower renal function parameters versus dapagliflozin alone, in favor of the observation group (RR 0.67 [95% CI 0.66-0.88]; P = .032). After treatment, the serum levels of IL-6 and TNF-α in patients treated with dapagliflozin plus pentoxifylline were lower than counterparts treated with dapagliflozin (RR 0.62 [95% CI 0.51-0.78]; P = .037). After treatment, CD4+ and CD4+/CD8+ in the two groups were increased compared with baseline parameters, and the level of CD8+ was decreased ; the increase and decrease were greater in the observation group than in the control group (RR 0.70 [95% CI 0.71-0.96]; P = .044) (RR 0.53 [95% CI 0.41-0.78]; P = .033). The two groups demonstrated similar safety profiles with no statistical difference observed in the incidence of adverse reactions between the two groups (RR 0.73 [95% CI 0.73-1.08]; P = .051). Conclusion: Dapagliflozin plus pentoxifylline might be a promising alternative in the treatment of patients with early diabetic nephropathy, it significantly mitigates the body's inflammatory response, enhances immune function, attenuates the main clinical symptoms, with a high safety profile.

Nanomaterial-mediated modulation of the cGAS-STING signaling pathway for enhanced cancer immunotherapy.

Despite the current promise of immunotherapy, many cancer patients still suffer from challenges such as poor immune response rates, resulting in unsatisfactory clinical efficacy of existing therapies. There is an urgent need to combine emerging biomedical discoveries and innovations in traditional therapies. Modulation of the cGAS-STING signalling pathway represents an important innate immunotherapy pathway that serves as a crucial DNA sensing mechanism in innate immunity and viral defense. It has attracted increasing attention as an emerging target for cancer therapy. The recent advancements in nanotechnology have led to the significant utilization of nanomaterials in cancer immunotherapy, owing to their exceptional physicochemical properties such as large specific surface area and efficient permeability. Given the rapid development of cancer immunotherapy driven by the cGAS-STING activation, this study reviews the latest research progress in employing nanomaterials to modulate this signaling pathway. Based on the introduction of the main activation mechanisms of cGAS-STING pathway, this review focuses on nanomaterials that mediate the agonists involved and effectively activate this signaling pathway. In addition, combination nanotherapeutics based on the activation of the cGAS-STING signaling pathway are also discussed, including emerging strategies combining nanoformulated agonists with chemotherapy, radiotherapy as well as other immunomodulation in tumor targeting therapy. STATEMENT OF SIGNIFICANCE: Given the rapid development of cancer immunotherapy driven by the cGAS / STING activation, this study reviews the latest research advances in the use of nanomaterials to modulate this signaling pathway. Based on the introduction of key cGAS-STING components and their activation mechanisms, this review focuses on nanomaterials that can mediate the corresponding agonists and effectively activate this signaling pathway. In addition, combination nanotherapies based on the activation of the cGAS-STING signaling pathway are also discussed, including emerging strategies combining nanoformulated agonists with chemotherapy, radiotherapy as well as immunomodulation in cancer therapy,.

Serum VEGF, high-sensitivity CRP, and cystatin-C assist in the diagnosis of type 2 diabetic retinopathy complicated with hyperuricemia.

Elevated serum uric acid (UA) level is related to type 2 diabetic retinopathy (DR). Vascular endothelial growth factor (VEGF), high-sensitivity C-reactive protein (hs-CRP), and cystatin C (Cys-C) have involvement in type 2 DR complicated with hyperuricemia (HUA) (HUDR), and we explored their clinical values in HUDR. Type 2 DR patients were allocated into HUDR/DR groups, with type 2 diabetes mellitus (T2DM) patients as the control group. Serum VEGF and inflammation markers hs-CRP, and Cys-C levels were assessed by ELISA and immunoturbidimetry. The correlations between serum UA level and VEGF/hs-CRP/Cys-C were analyzed by Pearson tests, diagnostic values of VEGF/hs-CRP/Cys-C were analyzed by receiver operating characteristic curves, and the independent risk factors in HUDR were analyzed by logistic multivariate regression. Serum VEGF/hs-CRP/Cys-C level differences among the T2DM/DR/HUDR groups were statistically significant, with the levels in HUDR > DR > T2DM. Serum UA level in HUDR patients was positively correlated with serum VEGF/hs-CRP/Cys-C. Serum VEGF/hs-CRP/Cys-C assisted in HUDR diagnosis, with their combination showing the greatest diagnostic value. UA/FPG/HbA1C/VEGF/hs-CRP/Cys-C were independent risk factors for HUDR. The incidence of proliferative DR was increased in HUDR patients. Collectively, serum VEGF, hs-CRP, and Cys-C levels in HUDR patients were increased, and HUA might promote DR progression.

Understanding the Heat Transfer Performance of Zeolitic Imidazolate Frameworks upon Gas Adsorption by Molecular Dynamics Simulations.

Metal-organic frameworks (MOFs) with ultrahigh specific surface area and porosity have emerged as promising nanoporous materials for gas separation, storage, and adsorption-driven thermal energy conversion systems such as adsorption heat pumps. However, an inadequate understanding of the thermal transport of MOFs with adsorbed gases hampers the thermal management of such systems in practical applications. In this work, an in-depth investigation on the mechanistic heat transfer performance of three topological zeolitic imidazolate frameworks (ZIFs) upon hydrogen, methane, and ethanol adsorption was carried out by molecular dynamics simulations. It is revealed that the trade-off between the additional heat transfer pathway and phonon scattering resulting from adsorbed gases determines the thermal conductivity of ZIFs. It is found that the increased thermal conductivity with the increased number of adsorbed gases is correlated with the overlap energy between the vibrational density of states of gases and Zn atoms, suggesting the additional heat transfer pathways formed between gas molecules and frameworks. Moreover, the gas spatial distribution and diffusion also impose remarkable impacts on the heat transfer performance. Both the homogeneous gas distribution and the fast gas diffusion are conducive to form effective heat transfer pathways, leading to enhanced thermal conductivity. This study provides molecular insight into the mechanism of the improved thermal conductivity of ZIFs upon gas adsorption, which may pave the way for effective thermal management in MOF-related applications.

Does mild flexion of the femoral prosthesis in total knee arthroplasty result in better early postoperative outcomes?

BACKGROUND: The purpose of this study was to measure the femoral prosthesis flexion angle (FPFA) in total knee arthroplasty (TKA) using three-dimensional reconstruction, and to assess the differences in early clinical efficacy between patients with different degrees of flexion. METHODS: We conducted a prospective cohort study. From June 2019 to May 2021, 113 patients admitted for TKA due to osteoarthritis of the knee were selected. The patients' postoperative knee joints were reconstructed in three dimensions according to postoperative three-dimensional computed tomography (CT) scans. The FPFA was measured, and the patients were divided into 4 groups: anterior extension group (FPFA < 0°), mildly flexed group (0° ≤ FPFA < 3°), moderately flexed group (3° ≤ FPFA < 6°) and excessively flexed group (6° ≤ FPFA). The differences in the Knee Society Score (KSS), knee Range of Motion (ROM), and visual analogue scale (VAS) scores were measured and compared between the four groups at each postoperative time point. RESULTS: Postoperative KSS, ROM, and VAS were significantly improved in all groups compared to the preoperative period. At 1 year postoperatively, the ROM was significantly greater in the mildly flexed group (123.46 ± 6.51°) than in the anterior extension group (116.93 ± 8.05°) and the excessively flexed group (118.76 ± 8.20°) (P < 0.05). The KSS was significantly higher in the mildly flexed group (162.68 ± 12.79) than in the other groups at 6 months postoperatively (P < 0.05). The higher KSS (174.17 ± 11.84) in the mildly flexed group was maintained until 1 year postoperatively, with a statistically significant difference (P < 0.05). No significant difference in VAS scores was observed between groups at each time point. CONCLUSIONS: A femoral prosthesis flexion angle of 0-3° significantly improved postoperative knee mobility, and patients could obtain better Knee Society Scores after surgery, which facilitated the postoperative recovery of knee function. TRIAL REGISTRATION: ChiCTR2100051502, 2021/09/24.

ACE inhibitory activity and salt-reduction properties of umami peptides from chicken soup.

Angiotensin-I-converting enzyme (ACE) inhibitory activity and salt-reduction properties of umami peptides identified in chicken soup were investigated. The ACE inhibition rate of TPLVDR (91.22%) and AEINKILGN (81.26%) was significantly higher than other umami peptides, and their semi-inhibitory concentration was 0.017 mM and 0.034 mM, respectively. After in vitro digestion, the inhibitory activity of AEINKILGN and TPLVDR decreased, but the original sequences were still detected. The docking results showed that AEINKILGN and TPLVDR mainly interacted with Zn2+ and key sites (His353, Lys511and Glu411) in the active pockets of ACE through hydrogen bonds, which was crucial to the ACE inhibitory activity. Based on response surface methodology and sensory analysis, saltiness and palatability models were established to investigate the salt-reduction effect. The optimal level of AEINKILGN was about 1.16 mg/mL in 0.44% salt solution. And the TPLVDR was applicable to the low salt solution (0.1-0.2%) at a concentration from 0.23 to 0.29 mg/mL.

Identification and virtual screening of novel umami peptides from chicken soup by molecular docking.

By combining python script invocation, the batch processing of molecular docking was achieved to screen 20 potential umami peptides out of the 208 peptides identified in chicken soup. Nine peptides were dominated by umami taste according to sensory analysis, among which PPQEAAQF (2.56) has the highest umami intensity, followed by AEEHVEAVN (2.43) and NEFGYSNR (2.19). The threshold of nine peptides ranged from 0.08 mM to 0.58 mM. In 0.35 % MSG, the effective threshold of umami-enhancing effect of LPLQD was 0.24 mM. In addition, the molecular docking results indicated that His71, Ser107, and Asp147 of taste receptor type 1 member 1, and Asn68, Asp216, His387, and Ala302 of taste receptor type 1 member 3 play critical roles in the binding with umami peptides by forming hydrogen bonds and hydrophobic force. Thus, the combination of molecular docking and python script invocation was effective and economical for umami peptides screening.

Causal association between colorectal cancer and Alzheimer's disease: a bidirectional two-sample mendelian randomization study.

Background: Colorectal cancer and Alzheimer's disease are both common life-threatening diseases in the elderly population. Some studies suggest a possible inverse relationship between colorectal cancer and Alzheimer's disease, but real-world research is subject to many biases. We hope to clarify the causal relationship between the two through a bidirectional two-sample Mendelian randomization study. Methods: In our study, we used genetic summary data from large-scale genome-wide association studies to investigate the relationship between colorectal cancer and Alzheimer's disease. Our primary analysis employed the inverse-variance weighted method and we also used complementary techniques, including MR-Egger, weighted median estimator, and Maximum likelihood. We applied simex adjustment to the MR-Egger results. We also utilized the MRlap package to detect potential sample overlap and its impact on the bias of the results. In addition, we performed several sensitivity and heterogeneity analyses, to ensure the reliability of our results. Results: The combined effect size results of the inverse-variance weighted method indicate that colorectal cancer may decrease the incidence of Alzheimer's disease, with an odds ratio (OR) of 0.846 (95% CI: 0.762-0.929). Similar results were observed using other methods such as MR-Egger, weighted median estimator, and Maximum likelihood. On the other hand, Alzheimer's disease may slightly increase the incidence of colorectal cancer, with an OR of 1.014 (95% CI: 1.001-1.027). However, the results of one subgroup were not significant, and the results from MRlap indicated that sample overlap introduced bias into the results. Therefore, the results of the reverse validation are not reliable. The F-statistic for all SNPs was greater than 20. Four SNPs related to the outcome were excluded using Phenoscanner website but the adjustment did not affect the overall direction of the results. The results of these statistics were further validated by MR-PRESSO, funnel plots, leave-one-out analyses, Cochran's Q, demonstrating the reliability of the findings. Conclusion: According to the findings of this Mendelian randomization study, there appears to be a causal association between colorectal cancer and Alzheimer's disease. These results could have important implications for clinical practice in terms of how colorectal cancer and Alzheimer's disease are treated. To better understand the relationship between these two diseases, more research and screening are needed in clinical settings.

Gender differences affect the location of the patellar tendon attachment site for tibial rotational alignment in total knee arthroplasty.

PURPOSE: This study was carried out to investigate the accuracy of referring different locations of the patellar tendon attachment site and the geometrical center of the osteotomy surface for tibial rotational alignment and observe the influences of gender differences on the results. METHODS: Computed tomography scans of 135 osteoarthritis patients (82 females and 53 males) with varus deformity was obtained to reconstruct three-dimensional (3D) models preoperatively. The medial boundary, medial one-sixth, and medial one-third of the patellar tendon attachment site were marked on the tibia. These points were projected on the tibial osteotomy plane and connected to the geometrical center (GC) of the osteotomy plane or the middle of the posterior cruciate ligament (PCL) to construct six tibial rotational axes (Akagi line, MBPT, MSPT1, MSPT2, MTPT1 and MTPT2). The mismatch angle between the vertical line of the SEA projected on the proximal tibial osteotomy surface and six different reference axes was measured. In additional, the effect of gender differences on rotational alignment for tibial component were assessed. RESULTS: Relative to the SEA, rotational mismatch angles were - 1.8° ± 5.1° (Akagi line), - 2.5° ± 5.3° (MBPT), 2.8° ± 5.3° (MSPT1), 4.5° ± 5.4° (MSPT2), 7.3° ± 5.4° (MTPT1), and 11.6° ± 5.8° (MTPT2) for different tibial rotational axes in all patients. All measurements differed significantly between the male and female. The tibial rotational axes with the least mean absolute deviation for the female or male were Akagi line or MSPT, respectively. There was no significant difference in whether the GC of the osteotomy surface or the midpoint of PCL termination was chosen as the posterior anatomical landmark when the medial boundary or medial one-sixth point of the patellar tendon attachment site was selected as the anterior anatomical landmark. CONCLUSION: When referring patellar tendon attachment site as anterior anatomical landmarks for tibial rotational alignment, the influence of gender difference on the accuracy needs to be taken into account. The geometric center of the tibial osteotomy plane can be used as a substitute for the middle of the PCL termination when reference the medial boundary or medial one-sixth of the patellar tendon attachment site.

Stress distribution patterns during the gait cycle in patients with anterior femoral notching following total knee replacement.

BACKGROUND: Anterior femoral notching (AFN) is a severe complication of total knee replacement (TKR), which in a percentage of patients may lead to fractures after surgery. The purpose of this study was to investigate the stress distribution in patients with AFN and the safety depth of AFN during the gait cycle. METHODS: We performed a finite element (FE) analysis to analyse the mechanics around the femur during the gait cycle in patients with AFN. An adult volunteer was selected as the basis of the model. The TKR models were established in the 3D reconstruction software to simulate the AFN model during the TKR process, and the 1 mm, 2 mm, 3 mm, 4 mm, and 5 mm AFN models were established, after which the prosthesis was assembled. Three key points of the gait cycle (0°, 22°, and 48°) were selected for the analysis. RESULTS: The stress on each osteotomy surface was stable in the 0° phase. In the 22° phase, the maximum equivalent stress at 3 mm was observed. In the 48° phase, with the increase in notch depth, each osteotomy surface showed an overall increasing trend, the stress range was more extended, and the stress was more concentrated. Moreover, the maximum equivalent force value (158.3 MPa) exceeded the yield strength (115.1 MPa) of the femur when the depth of the notch was ≥ 3 mm. CONCLUSIONS: During the gait cycle, if there is an anterior femoral cortical notch ≥ 3 mm, the stress will be significantly increased, especially at 22° and 48°. The maximum equivalent stress exceeded the femoral yield strength and may increase the risk of periprosthetic fractures.

Salubrinal Protects Against Cisplatin-Induced Cochlear Hair Cell Endoplasmic Reticulum Stress by Regulating Eukaryotic Translation Initiation Factor 2α Signalling.

Objective: Cisplatin is a broad-spectrum anti-tumour drug commonly used in clinical practice. However, its ototoxicity greatly limits its clinical application, and no effective method is available to prevent this effect. Endoplasmic reticulum stress (ERS) is reportedly involved in cisplatin ototoxicity, but the exact mechanism remains unclear. Therefore, this study aimed to investigate the role of eukaryotic translation initiation factor 2α (eIF2α) signalling and its dephosphorylation inhibitor salubrinal in cisplatin ototoxicity. Methods: We evaluated whether salubrinal could protect against cisplatin-induced damage in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells and mouse cochlear explants. By knocking down eIF2α, we elucidated the vital role of eIF2α in cisplatin-induced damage in HEI-OC1 cells. Whole-mount immunofluorescent staining and confocal microscopy of mouse cochlear explants and HEI-OC1 cells were performed to analyse cisplatin-induced damage in cochlear hair cells and the auditory cell line. Results: Data suggested salubrinal attenuated cisplatin-induced hair cell injury by inhibiting apoptosis. In addition, salubrinal significantly reduced ERS levels in hair cells via eIF2α signalling, while eIF2α knockdown inhibited the protective effect of salubrinal. Significance: Salubrinal and eIF2α signalling play a role in protecting against cisplatin-induced ototoxicity, and pharmacological inhibition of eIF2α-mediated ERS is a potential treatment for cisplatin-induced damage in the cochlea and HEI-OC1 cells.

[Accuracy of patellar tendon at the attachment as anatomic landmark for rotational alignment of tibial component].

Objective: To investigate the accuracy of the modified Akagi line which referenced the patellar tendon at the attachment and the geometrical center point of the tibial osteotomy surface for tibial rotational alignment. Methods: Between July 2021 and December 2021, 72 patients who underwent three-dimension (3D) CT for varus osteoarthritis knees were enrolled. Among 72 patients, 18 were male and 54 were female with a mean age of 64.9 years (range, 47-84 years). The preoperative hip-knee-ankle angle ranged from 0° to 26°, with a mean of 9.3°. CT images were imported into Mimics 21.0 medical image control system to establish 3D models of the knees. The prominent point of lateral epicondyle and the medial epicondylar sulcus were identified in femoral 3D models to construct the surgical transepicondylar axis and the vertical line of its projection [anteroposterior (AP) axis]. In tibial 3D models, the patellar tendon at the attachment was used as anatomical landmarks to construct rotational alignment for tibial component, including the line connecting the medial border of the patellar tendon at the attachment (C) and the middle (O) of the posterior cruciate ligament insertion (Akagi line), the line connecting the point C and the geometric center (GC) of the tibial osteotomy plane [medial border axis of the patellar tendon (MBPT)], the line connecting the medial sixth point of the patellar tendon at the attachment and the point GC [medial sixth axis of the patellar tendon (MSPT)], the line connecting the medial third point of the patellar tendon at the attachment and point O [medial third axis of the patellar tendon 1 (MTPT1)], and the line connecting the medial third point of the patellar tendon at the attachment and point GC [medial third axis of the patellar tendon 2 (MTPT2)]. The angles between the five reference axes and the AP axis were measured, and the distribution of the rotational mismatch angles with the AP axis was counted (≤3°, 3°-5°, 5°-10°, and >10°). Results: Relative to the AP axis, the Akagi line and MBPT were internally rotated (1.6±5.9)° and (2.4±6.9)°, respectively, while MSPT, MTPT1, and MTPT2 were externally rotated (5.4±6.6)°, (7.0±5.8)°, and (11.9±6.6)°, respectively. There were significant differences in the rotational mismatch angle and its distribution between reference axes and the AP axis ( F=68.937, P<0.001; χ 2=248.144, P<0.001). The difference between Akagi line and MBPT showed no significant difference ( P=0.067), and the differences between Akagi line and MSPT, MTPT1, MTPT2 were significant ( P<0.012 5). Conclusion: When the position of the posterior cruciate ligament insertion can not be accurately identified on total knee arthroplasty, MBPT can be used as the modified Akagi line in reference to the geometrical center point of the tibial osteotomy surface to construct a reliable rotational alignment of the tibial component.

Efficacy of epalrestat combined with alprostadil for diabetic nephropathy and its impacts on renal fibrosis and related factors of inflammation and oxidative stress.

OBJECTIVE: To explore the efficacy of epalrestat (Ep) combined with alprostadil (Alp) in the treatment of diabetic nephropathy (DN) and its impacts on renal fibrosis (RF) and inflammation and oxidative stress (OS)-related factors. METHODS: In this retrospective study, 120 patients with DN treated in the Cangzhou Central Hospital from January 2020 to January 2021 were selected as the research subjects. Among them, 80 cases treated with Ep combined with Alp were assigned to group A, and the rest 40 patients treated with Alp only were assigned to group B. The two groups were compared with respect to the following items: serum OS indexes (malondialdehyde, MDA; superoxide dismutase, SOD; total antioxidant capacity, TAOC), inflammatory factors (tumor necrosis factor-α, TNF-α; interleukin-2, IL-2), RF index transforming growth factor-ß1 (TGF-ß1), urinary protein indexes (urinary albumin excretion, UAE; serum albumin, ALB), blood glucose (fasting blood glucose, FBG), fasting C-peptide, postprandial 2hC peptide levels, overall response rate (ORR) and incidence of adverse reactions. RESULTS: Compared with group B, the levels of MDA, TNF-α, IL-2 and TGF-ß1 were lower, while SOD and TAOC were higher in group A. In addition, ALB was higher, while UAE and FBG were lower in group A as compared with group B. Moreover, group A had a higher ORR and fewer adverse reactions as compared with group B. CONCLUSION: The combined therapy of Ep and Alp is more effective in the treatment of DN. This combination can effectively reduce RF and better alleviate inflammation and OS.

Surface-Enhanced Raman Spectroscopy Analysis of Astragalus Saponins and Identification of Metabolites After Oral Administration in Rats by Ultrahigh-Performance Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry Analysis.

Astragalus mongholicus Bunge (Fabaceae) is an ancient Chinese herbal medicine, and Astragalus saponins are the main active components, which have a wide range of biological activities, such as immunomodulation, antioxidation, and neuroprotection. In this study, silver nanoparticles obtained by sodium borohydride reduction were used as the enhanced substrate to detect astragaloside I (1), astragaloside II (2), astragaloside III (3), astragaloside IV (4), isoastragaloside I (5), and isoastragaloside II (6) in the phloem, xylem, and cork by surface-enhanced Raman spectroscopy (SERS). In the SERS spectrum of Astragalus slices, the characteristic peaks were observed at 562, 671, 732, 801, 836, 950, 1,026, 1,391, and 1,584 cm-1, among which 950 cm-1 and 1,391 cm-1 were strong SERS signals. Subsequently, the metabolites of the six kinds of Astragalus saponins were identified by UPLC/ESI/Q-TOF-MS. Totally, 80, 89, and 90 metabolites were identified in rat plasma, urine, and feces, respectively. The metabolism of saponins mainly involves dehydration, deacetylation, dihydroxylation, dexylose reaction, deglycosylation, methylation, deacetylation, and glycol dehydration. Ten metabolites (1-M2, 1-M11, 2-M3, 2-M12, 3-M14, 4-M9, 5-M2, 5-M17, 6-M3, and 6-M12) were identified by comparison with reference standards. Interestingly, Astragalus saponins 1, 2, 5, and 6 were deacetylated to form astragaloside IV (4), which has been reported to have good pharmacological neuroprotective, liver protective, anticancer, and antidiabetic effects. Six kinds of active Astragalus saponins from different parts of Astragalus mongholicus were identified by SERS spectroscopy. Six kinds of active Astragalus saponins from different parts of Astragalus mongholicus were identified by SERS spectrum, and the metabolites were characterized by UPLC/ESI/Q-TOF-MS, which not only provided a new method for the identification of traditional Chinese medicine but also provided a theoretical basis for the study of the pharmacodynamic substance basis of Astragalus mongholicus saponins.