Previous studies have shown that a traditional Chinese herbal medicine, Yinyangdayu decoction, and repetitive transcranial magnetic stimulation (rTMS) are both effects treatment methods for depression. This study is designed to observe the combined clinical efficacy of Yinyangdayu decoction and rTMS with magnetic stimulation at the taichong point (LR03) in the treatment of depression.

Based on the real-world study, 204 patients with depressive disorder will be recruited and randomized into 3 groups (control group, treatment group 1, and treatment group 2). The control group will receive rTMS only (1 HZ, 1,800 pulses, 100% threshold). Treatment group 1 will receive rTMS + magnetic stimulation at LR03 (the left side, 1 HZ, 1,800 pulses, 100% threshold), and treatment group 2 will be given rTMS + Yinyangdayu decoction (200 mL, 2 times/day). The treatment course will last for 8 weeks, and relevant rating scales will be assessed at baseline, week 4, and week 8 to evaluate the efficacy.

This study might optimize the TCM comprehensive treatment scheme of depression, integrated with Western and traditional Chinese medicine.

Chinese Clinical Trial Registry, ChiCTR1900027443. Registered on 13 November 2019, www.chictr.org.cn

Naringenin is an anti-inflammatory flavonoid that has been studied in chronic liver disease. The mechanism specific to its antifibrosis activity needs further investigation This study was to focused on the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) pathway in hepatic stellate cells and clarified the antifibrosis mechanism of naringenin.

The relationship between the cGAS-stimulator of interferon genes (STING) pathway and liver fibrosis was analyzed using the Gene Expression Omnibus database. Histopathology, immunohistochemistry, fluorescence staining, Western blotting and polymerase chain reaction were performed to assess gene and protein expression levels associated with the cGAS pathway in clinical liver tissue samples and mouse livers. Molecular docking was performed to evaluate the relationship between naringenin and cGAS, and western blotting was performed to study the expression of inflammatory factors downstream of cGAS in vitro.

Clinical database analyses showed that the cGAS-STING pathway is involved in the occurrence of chronic liver disease. Naringenin ameliorated liver injury and liver fibrosis, decreased collagen deposition and cGAS expression, and inhibited inflammation in carbon tetrachloride (CCl4)-treated mice. Molecular docking found that cGAS may be a direct target of naringenin. Consistent with the in vivo results, we verified the inhibitory effect of naringenin on activated hepatic stellate cells (HSCs). By using the cGAS-specific agonist double-stranded (ds)DNA, we showed that naringenin attenuated the activation of cGAS and its inflammatory factors affected by dsDNA. We verified that naringenin inhibited the cGAS-STING pathway, thereby reducing the secretion of inflammatory factors by HSCs to ameliorate liver fibrosis.

Interrupting the cGAS-STING pathway helped reverse the fibrosis process. Naringenin has potential as an antihepatic fibrosis drug.

Acute-on-chronic liver failure (ACLF) is a clinical syndrome that develops in patients with chronic liver diseases following a precipitating event and associated with a high mortality rate due to systemic multiorgan failure. Establishing a suitable and stable animal model to precisely elucidate the molecular basis of ACLF pathogenesis is essential for the development of effective early diagnostic and treatment strategies. In this context, this article provides a concise and inclusive review of breakthroughs in ACLF animal model development.

The pandemic of Coronavirus Disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2), represents an unprecedented threat to health and the world economy. According to the scientific background and preliminary clinical trials, ozone therapy (OT) may help as complementary therapy in prophylaxis, treatment, and in the recovery of convalescents. During the COVID-19 pandemic, the number of registered clinical trials using OT on COVID-19 represented an increment of 36% compared to the total number of previously recorded clinical studies. At present, papers that report an intervention in COVID-19 patients total 25. Four trials have been done in prophylaxis, there are 3 manuscripts enrolled convalescents, and there is 1 meta-analysis. Manuscripts with outcomes, indexed in the MedLine database, represent 73%. The most widely used routes of administration for the intervention in COVID-19 patients are ozonated saline solution and major autohemotherapy. Preliminary results are encouraging, indicating that OT reduces inflammation indices, decreases the time of assisted respiration, decreases C-reactive protein, improves oxygen saturation, could decrease mortality, and makes polymerase chain reaction tests negative in shorter periods. When trained medical doctors follow the correct protocols and use certified devices, the improvements that have been reported allow the patients to recover more quickly. However, it is considered that larger clinical studies are needed.

Hepatitis B virus (HBV) biomarkers have been used for a better categorization of patients, even though the lack of simple algorithms and the impact of genotypes limit their application. Our aim was to assess the usefulness of noninvasive markers for the identification of HBV inactive carriers (ICs) in a single-point evaluation and to design a predictive model for their identification.

This retrospective-prospective study included 343 consecutive HBeAg-negative individuals. Clinical, analytical, and virological data were collected, and a liver biopsy was performed if needed. Subjects were classified at the end of follow-up as ICs, chronic hepatitis B and gray zone.A predictive model was constructed, and validated by 1000-bootstrap samples.

After 39 months of follow-up, 298 subjects were ICs, 36 were chronic hepatitis B CHB, and nine were gray zone. Eighty-nine (25.9%) individuals required a liver biopsy. Baseline HBV DNA hazard ratio (HR) 6.0, p<0.001), HBV core-related antigen (HBcrAg) (HR 6.5, p<0.001), and elastography (HR 4.6, p<0.001) were independently associated with the IC stage. The ACE score (HBV DNA, HBcrAg, elastography), obtained by bootstrapping, yielded an area under the receiver operating characteristics (AUROC) of 0.925 (95% CI: 0.880–0.970, p<0.001) for identification of ICs. The AUROC for genotype D was 0.95, 0.96 for A, 0.90 for E, and 0.88 for H/F. An ACE score of <1 had a positive predictive value of 99.5%, and a score ≤12 points had a diagnostic accuracy of 93.8%.

Low baseline HBV DNA, HBcrAg, and liver stiffness were independently associated with the IC phase. A score including those variables identified ICs at a single-point evaluation, and might be applied to implement less intensive follow-up strategies.

Three-dimensional (3D) printing has provided individuals in various industries with a tool to bring their creations to life. The medical field is no stranger to 3D printing, which has been utilized in various applications since its inception. The various additive technologies currently available to elucidate the differences between them will be discussed briefly. The current applications of 3D printing in medicine could be divided into applications in medical education, patient care, equipment modification or fabrication, and research. The various applications in these categories are described with examples of upcoming research and technology that may be available in the near future. Despite the benefits of 3D printing, challenges remain, and technology improvements are required before there will be more adoption in the medical field. The technology is growing rapidly and evolving, and more 3D printing applications will be seen in the future.

Lasting LPS stimulation changes macrophages toward the M2 phenotype therefore resulting in immunodepression. Melatonin can improve sleep, adjust the time difference, regulate immunity, and anti-tumor. This study is to observe whether melatonin can induce M2 macrophage apoptosis to reverse lasting LPS-induced immunodepression for lung cancer prevention and explore the possible mechanism.

The effects of LPS alone or in combination with melatonin on macrophage phenotypes were assessed by surface markers, morphological changes, cytokines, autophagy, and autophagic efflux. The anti-cancer effect was evaluated in the lung carcinogenic model and lung cancer allograft model. Melatonin-related targets and pathways were predicted by network pharmacology.

Single LPS stimulation polarized macrophages to M1 phenotype, whereas LPS stimulation lasting for 7d polarized macrophages to M2 phenotype. However, combination treatment of lasting LPS and 10 µM melatonin inhibited the polarization of macrophages towards an M2-like phenotype and exerted a continuous antitumor effect. In the urethane-induced lung carcinoma model, long-lasting LPS administration (>4 times) facilitated macrophage polarization toward the M2 phenotype and promoted lung carcinogenesis, which was abrogated by macrophage depletion, while melatonin alone or in combination with lasting LPS could decrease M2-like macrophages and prevented carcinogenesis. In the Lewis lung cancer allograft model, melatonin decreased M2 macrophages and promoted the tumor-suppressing effect of short-term LPS administration (<4 times). Network pharmacology indicated that melatonin regulates macrophages by targeting the multi-protein network.

Melatonin as a key maintainer of macrophage phenotype can induce LPS-stimulated M2 macrophage apoptosis to reverse system immunodepression for lung cancer prevention.

Emerging evidence has demonstrated that abnormal body composition may potentiate the development of frailty, whereas little work focuses on the role of divergent adipose tissue. Therefore, we aimed to determine the potential contribution of adipose tissue distribution to multidimensional frailty in decompensated cirrhosis.

We conducted a retrospective cohort study. Divergent adipose tissues were assessed by computed tomography-derived subcutaneous adipose tissue index (SATI), visceral adipose tissue index (VATI) and total adipose tissue index (TATI), respectively. Frailty was identified by our validated self-reported Frailty Index. Multiple binary logistic models incorporating different covariates were established to assess the relationship between adipose tissue distribution and frailty.

The study cohort comprised 245 cirrhotic patients with 45.3% being male. The median Frailty Index, body mass index (BMI) and model for end-stage liver disease (MELD) score were 0.11, 24.3 kg/m2 and 8.9 points, respectively. In both men and women, patients who were frail exhibited lower levels of SATI in comparison with nonfrail patients. SATI inversely correlated with Frailty Index in the entire cohort (rs=−0.1361, p=0.0332). Furthermore, SATI or TATI was independently associated with frail phenotype in several multiple logistic regression models adjusting for age, BMI, presence of ascites, sodium, Child-Pugh class or MELD score in isolation.

In the context of decompensated cirrhosis, low SATI and concomitant TATI were associated with higher risk of being frail. These findings highlight the importance to further apply tissue-specific tools of body composition in place of crude metric like BMI.

The goal of this study was to investigate the mechanism by which the long noncoding RNA MALAT1 inhibited hepatocyte proliferation in acute liver injury (ALI).

Lipopolysaccharide (LPS) was used to induce an ALI cellular model in HL7702 cells, in which lentivirus vectors containing MALAT1/EZH2/GFER overexpression or knockdown were introduced. A series of experiments were performed to determine their roles in liver injury, oxidative stress injury, and cell biological processes. The interaction of MALAT1 with EZH2 and enrichment of EZH2 and H3K27me3 in the GFER promoter region were identified. Rats were treated with MALAT1 knockdown or GFER overexpression before LPS induction to verify the results derived from the in vitro assay.

MALAT1 levels were elevated and GFER levels were reduced in ALI patients and the LPS-induced cell model. MALAT1 knockdown or GFER overexpression suppressed cell apoptosis and oxidative stress injury induced cell proliferation, and reduced ALI. Functionally, MALAT1 interacted directly with EZH2 and increased the enrichment of EZH2 and H3K27me3 in the GFER promoter region to reduce GFER expression. Moreover, MALAT1/EZH2/GFER was activated the AMPK/mTOR signaling pathway.

Our study highlighted the inhibitory role of reduced MALAT1 in ALI through the modulation of EZH2-mediated GFER.

Carissa edulis (Apocynaceae) is a wild fruit species highly consumed by Cameroonian populations because of its many biological effects. However, few studies so far have addressed the nutritional, antioxidant, and physicochemical properties of this plant.

Juice and cake powders obtained from C. edulis fruits were examined for their contents in macronutrients, micronutrients, and phenolic compounds through conventional methods. Then, the in vitro antioxidant properties were assessed using the 1,1-diphenyl-2-picrylhydrazyl radical scavenging, total reducing power, and the total antioxidant capacity assays.

The results showed that cakes displayed significantly higher fat (22.68 ± 2.16 vs 5.06 ± 0.43 g/100 g dry weight (DW)), carbohydrates (39.25 ± 1.16 vs 19.29 ± 0.55 g/100 g DW), protein (1.32 ± 0.56 vs 0.23 ± 0.13 g/100 g DW), zinc, copper, and calcium levels compared to juice. However, their ash (0.28 ± 0.02 vs 0.31 ± 0.02 g/100 g DW), moisture (5.67 ± 0.53 vs 14.40 ± 1.36 g/100 g), carotenoids, and Vitamin C levels were significantly lower. The phenolic content in the juice was generally lower (p < 0.05) than in the cake. Polyphenols, flavonoids tannins, and anthocyanins were respectively the most quantitatively important compounds. On the other hand, the study of the antioxidant activity revealed that the cake had higher antioxidant activities.

Taken all together, the results showed that the cake of the C. edulis fruits has higher nutritional value, bioactive compound levels, and antioxidant potentials than juice which merits further consideration as food supplements.

In this century, viral infections are still a serious threat to the safety of human life and health. Millions of people were infected by viruses every year worldwide, and many of them died from the infections. In recent decades, outbreak pandemics of SARS, influenza, and especially SARS-Cov-2 (nCov-2019) have been witnessed. To protect people from viral infections, vaccine is one of the most important approaches. But to develop a vaccine against a viral infection, the status and its regulation of the human immunity against a viral infection must be explored and known well. As a reference for the protection approach or strategy to control viral infections, based on the reports or publications in recent years, we present our new perspectives about human immunity statuses against viral infection, and conclude the statuses as three basic types: efficient immunity status, non-efficient immunity status and separated immunity status.

Efficacy evaluations with preclinical magnetic resonance imaging (MRI) are uncommon, but MRI in the preclinical phase of drug development provides information that is useful for longitudinal monitoring. The study aim was to monitor the protective effectiveness of silymarin with multiparameter MRI and biomarkers in a thioacetamide (TAA)-induced model of liver injury in rats. Correlation analysis was conducted to assess compare the monitoring of liver function by MRI and biomarkers.

TAA was injected three times a week for 8 weeks to generate a disease model (TAA group). In the TAA and silymarin-treated (TAA-SY) groups, silymarin was administered three times weekly from week 4. MR images were acquired at 0, 2, 4, 6, and 8 weeks in the control, TAA, and TAA-SY groups.

The area under the curve to maximum time (AUCtmax) and T2* values of the TAA group decreased over the study period, but the serological markers of liver abnormality increased significantly more than those in the control group. In the TAA-SY group, MRI and serological biomarkers indicated attenuation of liver function as in the TAA group. However, pattern changes were observed from week 6 to comparable levels in the control group with silymarin treatment. Negative correlations between either AUCtmax or T2* values and the serological biomarkers were observed.

Silymarin had hepatoprotective effects on TAA-induced liver injury and demonstrated the usefulness of multiparametric MRI to evaluate efficacy in preclinical studies of liver drug development.

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death and ranks sixth in terms of incident cases worldwide. The purpose of this study was to develop an effective and sensitive method to distinguish liver cancer tissues from normal tissues in HCC patients. Integrin α6 is a promising cell surface target for molecular imaging of HCC, where it is overexpressed and is a prognostic biomarker. We previously identified an integrin α6-targeted peptide CRWYDENAC (RWY) that has been used for positron emission tomography (PET) imaging of HCC in mouse models.

We labeled the integrin α6-targeted RWY peptide with cyanine 7 (Cy7) to form an optical probe (Cy7-RWY) for near infrared fluorescent (NIRF) and photoacoustic (PA) imaging in HCC. Mice transplanted with subcutaneous HCC-LM3 or orthotopic HCC-H22 cells that overexpressed integrin α6 were intravenously injected with Cy7-RWY and its corresponding Cy7-control. NIRF and PA images of mice were collected from 0 to 48 h after injection.

Both NIRF and PA signals started to accumulate in the tumor 2 h after injection of Cy7-RWY and peaked at 24 h.

Cy7-RWY is a promising optical probe for NIRF and PA imaging of HCC in mice, and has potential clinical application for HCC detection.

The aim was to evaluate the efficacy and safety of Yanggan Jian (YGJ) in HBV-infected patients with decompensated cirrhosis.

This randomized, double-blind controlled trial enrolled 160 patients with HBV-related decompensated cirrhosis who were already receiving or about to start antiviral therapy. Patients were randomly assigned to receive YGJ or placebo for 24 weeks, and were followed-up to 36 weeks. The primary outcome was the proportion of patients with a ≥2 point reduction in Child-Turcotte-Pugh (CTP) score from baseline at week 24. Secondary outcomes were CTP class and score, serum liver function indices, mortality, incidence of hepatocellular carcinoma and variceal bleeding.

The proportion of patients with a CTP score reduction ≥2 was significantly greater in the YGJ than in the placebo group (p=0.009); the percentage of patients with CTP class C was significantly less than that in the placebo group (p<0.05), and the YGJ group had a significantly greater mean change from baseline in CTP score at week 24 (p=0.034). The improvement in measured values and change from baseline of prothrombin time, serum albumin, platelets, cholinesterase, international normalized ratio, and activated partial thromboplastin time were significantly better with YGJ than with placebo. Between-group differences in cumulative rates of variceal bleeding, hepatocellular carcinoma, death, or the frequency of any adverse event (AE), AEs related to treatment, or discontinuation because of AEs were not significant.

YGJ significantly improved CTP scores and hepatic synthetic and reserve function in patients with HBV-related decompensated cirrhosis, and was safe and well tolerated.

After a period of more than 50 years, numerous evidences have led to the exploration of the cyclic control core of cells, which sequentially comprise of genomes (G), transcriptomes (T) and proteomes (P). In the previous reports of the investigators on spatiotemporal cell biology, a novel theory system was introduced and reported, and the cyclic control core was named, the “GTP core”. Indeed, the GTP core controls all events in cells based on the spatiotemporal cell biology. In the present study, the schematic regulation of the GTP core based on the spatiotemporal cell biology was further discussed and summarized, in order to improve and perfect this novel theory system. It is hoped that these perspectives would lead to the further discussion and exploration of this area by other researchers worldwide.

Liver organ shortage remains a major health burden in the US, with more patients being waitlisted than the number of liver transplants (LTs) performed. This study investigated US national and regional trends in living donor LT (LDLT) and identified factors associated with recipient survival.

We retrospectively analyzed LDLT recipients and donors from the United Network Organ Sharing/Organ Procurement Transplant Network database from 1998 until 2019 for clinical characteristics, demographic differences, and survival rate. National and regional trends in LDLT, recipient outcomes, and predictors of survival were analyzed.

Of the 223,571 candidates listed for an LT, 57.5% received an organ, of which only 4.2% were LDLTs. Annual adult LDLTs first peaked at 412 in 2001 but experienced a significant decline to 168 by 2009. LDLTs then gradually increased to 445 in 2019. Region 2 had the highest LDLT numbers (n=919), while region 1 had the highest proportion (11.1%). Overall, post-LT mortality was 21.4% among LDLT recipients. Post-LDLT survival rates after 1-, 5-, and 10-years were 92%, 87%, and 70%, respectively. Interval analysis (2004–2019) showed that patients undergoing LDLT in recent years had lower mortality than in earlier years (hazard ratio=0.81, 95% confidence interval=0.75–0.88).

Following a substantial decline after a peak in 2001, the number of adult LDLTs steadily increased from 2011 to 2019. However, LDLTs still constitute the minority of the transplant pool in the US. Life-saving policies to increase the use of LDLTs, particularly in regions of high organ demand, should be implemented.

Oropharyngeal squamous cell carcinomas (OPSCCs) have shown an alarming rate of increase in incidence over the past several decades, markedly in men. In the United States, transcriptionally-active human papillomavirus (HPV), particularly HPV 16, has become the highest contributive agent of OPSCCs, affecting approximately 16,000 people a year. Compared to patients with HPV-negative OPSCCs, patients with HPV-positive OPSCCs exhibit better health responses to chemoradiotherapy and an overall increase in long-term survival. Despite promising treatment options, many OPSCCs are discovered at an advanced stage, and ∼20% of cases will recur after definitive treatment. Therefore, extensive research is ongoing to identify new targets for precision treatment and to stratify tumor prognosis. The aim of this review is to capture the most updated research on HPV-positive OPSCCs, emphasizing their relevance as potential new targets for precision medicine and survival prognosis.

Euphorbiasteroid (EUP) is one of the ingredients of traditional Chinese medicinal plants with anti-inflammatory activity. This study aimed to evaluate the effect of EUP on rheumatoid arthritis (RA).

Cell Counting Kit-8 (CCK8) and 5-Ethynyl-2′-deoxyuridine (EdU) were performed to detect the proliferation of fibroblast-like synoviocytes (FLSs). The expression of cytokines was detected by quantitative real-time polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA). The Transwell system without the gel was utilized to detect the cell migration. The pro-angiogenesis ability of HUVECs was detected by tube formation assay. EUP was introduced into the collagen-induced arthritis (CIA) model to determine its therapeutic effect, as measured by microcomputed tomography (micro-ct) and hematoxylin-eosin (H&E) staining. AKT1 was enriched by network pharmacology and molecular docking techniques. Western blot, immunofluorescence (IF) and RT-qPCR were conducted to detect the effects of EUP on AKT1.

When RA FLSs were treated with EUP, the proliferation of RA FLSs decreased in a dose- and time-dependent manner. Furthermore, the production of inflammatory cytokines, cell migration and proangiogenic ability of RA FLSs were suppressed by the EUP treatment. The in vivo experiments revealed that EUP can significantly reduce the severity of the CIA model by decreasing the paw thickness, arthritis score, cartilage degeneration, joint destruction, and serum inflammatory cytokine level. The network pharmacology and molecular docking predicted AKT1 as the target, in which EUP exerts its effects. The western blot, IF and RT-qPCR identified the toll-like receptor signaling pathway and its key component, AKT1, as potential targets, in which EUP exerts its anti-arthritic effects in RA.

EUP ameliorates the deterioration of RA by inactivating the toll-like receptor signaling pathway via AKT1. Therefore, EUP might hold potential as a treatment medicine for RA.

Diabetic foot ulcers (DFUs) are a significant source of morbidity, and pose great financial burden to the health service. Conventional treatments with dressings are often ineffective. Platelet-rich products have been used in recent years for the treatment of DFUs, with promising results. The present study aims to evaluate the efficacy of plasma rich in growth factors (PRGF) membrane therapy in the treatment of chronic non-healing DFUs, in order to improve wound healing and accelerate the epithelisation of chronic wounds.

A total of six diabetic patients with chronic non-healing foot ulcers were included in the present study. The Endoret procedure was used to isolate the PRGF from blood samples, resulting in the formation of a membrane clot, which was placed over the bed of the ulcer. A portion of the PRGF was also allowed to infiltrate around the ulcer edge. Patients were followed up in clinic at two weekly intervals, until full healing was achieved.

All six patients (mean age: 60 years old) underwent successful treatment with the PGRF membrane. Full epithelisation of the ulcers was achieved for all patients, with a mean duration of eight weeks. No complications were noted throughout the treatment period.

The use of an autologous PRGF membrane is a secure and efficacious surgical treatment for chronic non-healing DFUs. The present study demonstrates that the PRGF fibrin membrane can be used to optimize surface regeneration in DFUs. Additional data and randomized studies are required to establish the effectiveness of this method in treating DFUs.