Expanding the therapeutic potential of Salvia miltiorrhiza: a review of its pharmacological applications in musculoskeletal diseases.

Salvia miltiorrhiz, commonly known as "Danshen" in Chinese medicine, has longstanding history of application in cardiovascular and cerebrovascular diseases. Renowned for its diverse therapeutic properties, including promoting blood circulation, removing blood stasis, calming the mind, tonifying the blood, and benefiting the "Qi", recent studies have revealed its significant positive effects on bone metabolism. This potential has garnered attention for its promising role in treating musculoskeletal disorders. Consequently, there is a high anticipation for a comprehensive review of the potential of Salvia miltiorrhiza in the treatment of various musculoskeletal diseases, effectively introducing an established traditional Chinese medicine into a burgeoning field. AIM OF THE REVIEW: Musculoskeletal diseases (MSDs) present significant challenges to healthcare systems worldwide. Previous studies have demonstrated the high efficacy and prospects of Salvia miltiorrhiza and its active ingredients for treatment of MSDs. This review aims to illuminate the newfound applications of Salvia miltiorrhiza and its active ingredients in the treatment of various MSDs, effectively bridging the gap between an established medicine and an emerging field. METHODS: In this review, previous studies related to Salvia miltiorrhiza and its active ingredients on the treatment of MSD were collected, the specific active ingredients of Salvia miltiorrhiza were summarized, the effects of Salvia miltiorrhiza and its active ingredients for the treatment of MSDs, as well as their potential molecular mechanisms were reviewed and discussed. RESULTS: Based on previous publications, Salvianolic acid A, salvianolic acid B, tanshinone IIA are the representative active ingredients of Salvia miltiorrhiza. Their application has shown significant beneficial outcomes in osteoporosis, fractures, and arthritis. Salvia miltiorrhiza and its active ingredients protect against MSDs by regulating different signaling pathways, including ROS, Wnt, MAPK, and NF-κB signaling. CONCLUSION: Salvia miltiorrhiza and its active ingredients demonstrate promising potential for bone diseases and have been explored across a wide variety of MSDs. Further exploration of Salvia miltiorrhiza's pharmacological applications in MSDs holds great promise for advancing therapeutic interventions and improving the lives of patients suffering from these diseases.

MDIG-mediated H3K9me3 demethylation upregulates Myc by activating OTX2 and facilitates liver regeneration.

The mineral dust-induced gene (MDIG) comprises a conserved JmjC domain and has the ability to demethylate histone H3 lysine 9 trimethylation (H3K9me3). Previous studies have indicated the significance of MDIG in promoting cell proliferation by modulating cell-cycle transition. However, its involvement in liver regeneration has not been extensively investigated. In this study, we generated mice with liver-specific knockout of MDIG and applied partial hepatectomy or carbon tetrachloride mouse models to investigate the biological contribution of MDIG in liver regeneration. The MDIG levels showed initial upregulation followed by downregulation as the recovery progressed. Genetic MDIG deficiency resulted in dramatically impaired liver regeneration and delayed cell cycle progression. However, the MDIG-deleted liver was eventually restored over a long latency. RNA-seq analysis revealed Myc as a crucial effector downstream of MDIG. However, ATAC-seq identified the reduced chromatin accessibility of OTX2 locus in MDIG-ablated regenerating liver, with unaltered chromatin accessibility of Myc locus. Mechanistically, MDIG altered chromatin accessibility to allow transcription by demethylating H3K9me3 at the OTX2 promoter region. As a consequence, the transcription factor OTX2 binding at the Myc promoter region was decreased in MDIG-deficient hepatocytes, which in turn repressed Myc expression. Reciprocally, Myc enhanced MDIG expression by regulating MDIG promoter activity, forming a positive feedback loop to sustain hepatocyte proliferation. Altogether, our results prove the essential role of MDIG in facilitating liver regeneration via regulating histone methylation to alter chromatin accessibility and provide valuable insights into the epi-transcriptomic regulation during liver regeneration.

A draft human pangenome reference.

Here the Human Pangenome Reference Consortium presents a first draft of the human pangenome reference. The pangenome contains 47 phased, diploid assemblies from a cohort of genetically diverse individuals1. These assemblies cover more than 99% of the expected sequence in each genome and are more than 99% accurate at the structural and base pair levels. Based on alignments of the assemblies, we generate a draft pangenome that captures known variants and haplotypes and reveals new alleles at structurally complex loci. We also add 119 million base pairs of euchromatic polymorphic sequences and 1,115 gene duplications relative to the existing reference GRCh38. Roughly 90 million of the additional base pairs are derived from structural variation. Using our draft pangenome to analyse short-read data reduced small variant discovery errors by 34% and increased the number of structural variants detected per haplotype by 104% compared with GRCh38-based workflows, which enabled the typing of the vast majority of structural variant alleles per sample.

CircZNF215 promotes tumor growth and metastasis through inactivation of the PTEN/AKT pathway in intrahepatic cholangiocarcinoma.

BACKGROUND: Increasing evidence shows that circular RNAs (circRNAs), a novel class of noncoding RNAs, play a crucial role in the development of cancers, including intrahepatic cholangiocarcinoma (iCCA). Nevertheless, their functions and exact mechanisms in iCCA progression and metastasis are still unclear. Ipatasertib is a highly selective inhibitor of AKT that inhibits tumor growth by blocking the PI3K/AKT pathway. In addition, phosphatase and tensin homolog (PTEN) can also inhibit the activation of the PI3K/AKT pathway, but it is not clear whether the cZNF215-PRDX-PTEN axis plays a role in the antitumor activity of ipatasertib. METHODS: We identified a new circRNA (circZNF215, termed cZNF215) through high-throughput circRNA sequencing (circRNA-seq). In addition, RT‒qPCR, immunoblot assay, RNA pull-down assay, RNA immunoprecipitation (RIP) assay, and fluorescence in situ hybridization assay (FISH) were used to investigate the interaction of cZNF215 with peroxiredoxin 1 (PRDX1). Coimmunoprecipitation (Co-IP) assays and duolink in situ proximity ligation assays (PLAs) were conducted to analyze the effects of cZNF215 on the interaction between PRDX1 and PTEN. Finally, we tested the potential effects of cZNF215 on the antitumor activity of ipatasertib with in vivo experiments. RESULTS: We found that cZNF215 expression was obviously upregulated in iCCA tissues with postoperative metastases and was correlated with iCCA metastasis and poor outcome in patients with iCCA. We further revealed that overexpression of cZNF215 promoted iCCA cell growth and metastasis in vitro and in vivo, while cZNF215 knockdown had the opposite effect. Mechanistic studies suggested that cZNF215 competitively interacted with PRDX1, which blocked the association between PRDX1 and PTEN, subsequently leading to oxidation-induced inactivation of the PTEN/AKT pathway and finally contributing to iCCA progression and metastasis. Additionally, we also revealed that silencing cZNF215 in iCCA cells had the potential to enhance the antitumor effect of ipatasertib. CONCLUSIONS: Our study demonstrates that cZNF215 facilitates iCCA progression and metastasis by regulating the PTEN/AKT pathway and may serve as a novel prognostic predictor in patients with iCCA.

Circular RNAs in cholangiocarcinoma.

Cholangiocarcinoma (CCA) is the most common primary biliary malignancy with an adverse prognosis. Although its incidence is relatively low, early diagnosis is difficult due to the lack of specific symptoms. Current treatment options for CCA are limited, resulting in a low curative rate. Circular RNAs (circRNAs) have become a new research hotspot in recent years, and they are frequently dysregulated in CCA and may become therapeutic targets and prognostic biomarkers of CCA. Accumulating evidence has demonstrated that numerous dysregulated circRNAs are vital players in the etiopathogenesis of CCA. Aberrant expression of specific circRNAs was correlated with unfavourable clinical characteristics in CCA. Many studies have found that circRNAs are involved in the progression and development of CCA through various mechanisms, including competitive inhibition of miRNAs via the competing endogenous RNA (ceRNA) network, interaction with RNA-binding proteins (RBPs), activation of cancer-related signalling pathways, and regulation of proteins and peptides. Additionally, some circRNAs are involved in the inflammatory microenvironment of CCA and play a crucial role in chemotherapy drug resistance. Thus, they are essential for the early diagnosis and prediction of CCA, and more attention should be given to the roles and mechanisms of circRNAs in CCA. In this review, we summarize the abnormal expression of circRNAs in CCA and the specific inflammatory microenvironment involved, as well as the roles and mechanisms of circRNAs in the occurrence and development of CCA. We also review the latest knowle dge on circRNAs in CCA and discuss the challenges associated with the introduction of circRNAs into clinical practice and their potential clinical value.

FLASH radiotherapy: A promising new method for radiotherapy.

Among the treatments for malignant tumors, radiotherapy is of great significance both as a main treatment and as an adjuvant treatment. Radiation therapy damages cancer cells with ionizing radiation, leading to their death. However, radiation-induced toxicity limits the dose delivered to the tumor, thereby constraining the control effect of radiotherapy on tumor growth. In addition, the delayed toxicity caused by radiotherapy significantly harms the physical and mental health of patients. FLASH-RT, an emerging class of radiotherapy, causes a phenomenon known as the 'FLASH effect', which delivers radiotherapy at an ultra-high dose rate with lower toxicity to normal tissue than conventional radiotherapy to achieve local tumor control. Although its mechanism remains to be fully elucidated, this modality constitutes a potential new approach to treating malignant tumors. In the present review, the current research progress of FLASH-RT and its various particular effects are described, including the status of research on FLASH-RT and its influencing factors. The hypothetic mechanism of action of FLASH-RT is also summarized, providing insight into future tumor treatments.

Uncommon Cause of Right Upper Quadrant Pain Treated by Laparoscopic Surgery: A Case Report.

Introduction: Right upper quadrant pain is a very common symptom of cholecystitis. Right upper quadrant pain caused by fish bone perforation of the stomach wall is rare. Case Presentation: We report a 42-year-old woman who was admitted to our hospital with "1-month history of dull progressive right upper quadrant pain radiating to the back." Computed tomography of the abdomen revealed a linear, high-density body between the stomach wall and the liver. On history, the patient stated she had eaten a bony fish a month prior but did not note any significant pain at the time. Laparoscopy revealed a fish bone 2 cm in length half on the surface of the caudate lobe of the liver, and no perforation of the gastrointestinal tract was found. The postoperative course was uncomplicated, and the patient was discharged home on day 3 after surgery. Conclusion: The case of right upper quadrant pain caused by the fish bone is very rare. Radiological examinations play a significant role in the diagnosis of fish bone ingestion. Laparoscopic surgery is technically feasible and safe for the treatment of patients with fish bone ingestion.

The role and mechanism of noncoding RNAs in regulation of metabolic reprogramming in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Metabolic reprogramming is considered to be an important hallmark of cancer. Emerging studies have demonstrated that noncoding RNAs (ncRNAs) are closely associated with metabolic reprogramming of HCC. NcRNAs can directly regulate the expressions or functions of metabolic enzymes or indirectly regulate the metabolism of HCC cells through some vital signaling pathways. Until now, the mechanisms of HCC development and progression remain largely unclear, and understanding the regulatory mechanism of ncRNAs on metabolic reprogramming of HCC may provide an important basis for breakthrough progress in the treatment of HCC. In this review, we summarize the ncRNAs involved in regulating metabolic reprogramming of HCC. Specifically, the regulatory roles of ncRNAs in glucose, lipid and amino acid metabolism are elaborated. In addition, we discuss the molecular mechanism of ncRNAs in regulation of metabolic reprogramming and possible therapeutic strategies that target the metabolism of cancer cells by modulating the expressions of specific ncRNAs.

CircNFIB inhibits tumor growth and metastasis through suppressing MEK1/ERK signaling in intrahepatic cholangiocarcinoma.

BACKGROUND: Considerable evidence shows that circular RNAs (circRNAs) play an important role in tumor development. However, their function in intrahepatic cholangiocarcinoma (ICC) metastasis and the underlying mechanisms are incompletely understood. METHODS: circNFIB (hsa_circ_0086376, termed as cNFIB hereafter) was identified in human ICC tissues through circRNAs sequencing. The biological role of cNFIB was determined in vitro and in vivo by gain or loss of functional experiments. Fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP) and RNA pull-down assays were conducted to analyze the interaction of cNFIB with dual specificity mitogen-activated protein kinase kinase1 (MEK1). Duolink in situ proximity ligation assay (PLA) and coimmunoprecipitation (co-IP) assay were used to investigate the effects of cNFIB on the interaction between MEK1 and mitogen-activated protein kinase 2 (ERK2). Finally, a series of in vitro and in vivo experiments were performed to explore the influences of cNFIB on the anti-tumor activity of trametinib (a MEK inhibitor). RESULTS: cNFIB was significantly down-regulated in human ICC tissues with postoperative metastases. The loss of cNFIB was highly associated with aggressive characteristics and predicted unfavorable prognosis in ICC patients. Functional studies revealed that cNFIB inhibited the proliferation and metastasis of ICC cells in vitro and in vivo. Mechanistically, cNFIB competitively interacted with MEK1, which induced the dissociation between MEK1 and ERK2, thereby resulting in the suppression of ERK signaling and tumor metastasis. Moreover, we found that ICC cells with high levels of cNFIB held the potential to delay the trametinib resistance. Consistently, in vivo and in vitro studies demonstrated that cotreatment with trametinib and lentivirus vector encoding cNFIB showed greater inhibitory effect than isolated trametinib treatment. CONCLUSIONS: Our findings identified that cNFIB played a key role in ICC growth and metastasis by regulating MEK1/ERK signaling. Given the efficacy of cNFIB modulation on ICC suppression and trametinib sensitivity, cNFIB appears to be a potential therapeutic molecule for ICC treatment.

Laparoscopic Pancreaticoduodenectomy Versus Conventional Open Approach for Patients With Pancreatic Duct Adenocarcinoma: An Up-to-Date Systematic Review and Meta-Analysis.

BACKGROUND: To compare perioperative and oncological outcomes of pancreatic duct adenocarcinoma (PDAC) after laparoscopic versus open pancreaticoduodenectomy (LPD vs. OPD), we performed a meta-analysis of currently available propensity score matching studies and large-scale retrospective cohorts to compare the safety and overall effect of LPD to OPD for patients with PDAC. METHODS: A meta-analysis was registered at PROSPERO and the registration number is CRD42021250395. PubMed, Web of Science, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases were searched based on a defined search strategy to identify eligible studies before March 2021. Data on operative times, blood loss, 30-day mortality, reoperation, length of hospital stay (LOS), overall morbidity, Clavien-Dindo ≥3 complications, postoperative pancreatic fistula (POPF), blood transfusion, delayed gastric emptying (DGE), postpancreatectomy hemorrhage (PPH), and oncologic outcomes (R0 resection, lymph node dissection, overall survival, and long-term survival) were subjected to meta-analysis. RESULTS: Overall, we identified 10 retrospective studies enrolling a total of 11,535 patients (1,514 and 10,021 patients underwent LPD and OPD, respectively). The present meta-analysis showed that there were no significant differences in overall survival time, 1-year survival, 2-year survival, 30-day mortality, Clavien-Dindo ≥3 complications, POPF, DGE, PPH, and lymph node dissection between the LPD and OPD groups. Nevertheless, compared with the OPD group, LPD resulted in significantly higher rate of R0 resection (OR: 1.22; 95% CI 1.06-1.40; p = 0.005), longer operative time (WMD: 60.01 min; 95% CI 23.23-96.79; p = 0.001), lower Clavien-Dindo grade ≥III rate (p = 0.02), less blood loss (WMD: -96.49 ml; 95% CI -165.14 to -27.83; p = 0.006), lower overall morbidity rate (OR: 0.65; 95% CI 0.50 to 0.85; p = 0.002), shorter LOS (MD = -2.73; 95% CI -4.44 to -1.03; p = 0.002), higher 4-year survival time (p = 0.04), 5-year survival time (p = 0.001), and earlier time to starting adjuvant chemotherapy after surgery (OR: -10.86; 95% CI -19.42 to -2.30; p = 0.01). CONCLUSIONS: LPD is a safe and feasible alternative to OPD for patients with PDAC, and compared with OPD, LPD seemed to provide a similar OS. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/#recordDetails.

Robotic Versus Laparoscopic Distal Pancreatectomy for Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-Analysis.

BACKGROUND: Robotic distal pancreatectomy (RDP) and laparoscopic distal pancreatectomy (LDP) are the two principal minimally invasive surgical approaches for patients with pancreatic body and tail adenocarcinoma. The use of RDP and LDP for pancreatic ductal adenocarcinoma (PDAC) remains controversial, and which one can provide a better R0 rate is not clear. METHODS: A comprehensive search for studies that compared robotic versus laparoscopic distal pancreatectomy for PDAC published until July 31, 2021, was conducted. Data on perioperative outcomes and oncologic outcomes (R0-resection and lymph node dissection) were subjected to meta-analysis. PubMed, Cochrane Central Register, Web of Science, and EMBASE were searched based on a defined search strategy to identify eligible studies before July 2021. RESULTS: Six retrospective studies comprising 572 patients (152 and 420 patients underwent RDP and LDP) were included. The present meta-analysis showed that there were no significant differences in operative time, tumor size, and lymph node dissection between RDP and LDP group. Nevertheless, compared with the LDP group, RDP results seem to demonstrate a possibility in higher R0 resection rate (p<0.0001). CONCLUSIONS: This systematic review and meta-analysis suggest that RDP is a technically and oncologically safe and feasible approach for selected PDAC patients. Large randomized and controlled prospective studies are needed to confirm this data. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/#recordDetails, identifier [CRD42021269353].

Post-Operative Sleep Endoscopy with Target-Controlled Infusion After Palatopharyngoplasty for Obstructive Sleep Apnea: Anatomical and Polysomnographic Outcomes.

INTRODUCTION: The findings of drug-induced sleep endoscopy (DISE) are not always correlated with the outcome of upper airway surgery for obstructive sleep apnea (OSA), and whether multilevel surgery is truly required in treating multilevel obstruction identified in preoperative DISE remains an issue. We attempted to compare DISE findings before and after palatopharyngoplasty in patients with OSA because changes in DISE may be beneficial to better understand polysomnographic and anatomical outcomes. METHODS: This was a prospective cohort study for 34 patients with moderate to severe OSA who underwent palatopharyngoplasty at a tertiary care center from 2016 to 2018. We recorded the patients' demographic characteristics, procedures, and surgical outcomes and compared the preoperative and postoperative DISE staging patterns. RESULTS: The apnea-hypopnea index (AHI) values of 34 adults improved significantly after surgery (40.6 ± 23.3 versus 25.6 ± 20.6, P < 0.001). The majority of patients, 26/34, had preoperative complete concentric collapse at the velum, and for most (20/26, 77%) there was a change of the collapse pattern into anteroposterior collapse postoperatively. Patients with postoperative velar collapse had higher follow-up AHI values than those who without (27.8 ± 21.9 versus 15.2 ± 7.7, P = 0.023). Patients with preoperative complete tongue base collapse had higher follow-up AHI values than did those with no or partial collapse (40.6 ± 21.0 versus 21.0 ± 18.6, P = 0.017). Patients with postoperative complete tongue base collapse also had higher follow-up AHI values than the others (42.7 ± 22.1 versus 18.5 ± 15.4, P = 0.001). CONCLUSION: Palatopharyngoplasty could change the collapse pattern at the velum in most patients. Preoperative and postoperative complete tongue base collapse and postoperative velar collapse identified in TCI-DISE were associated with relatively poor outcomes.

Perioperative and short-term oncological outcomes following laparoscopic versus open pancreaticoduodenectomy after learning curve in the past 10 years: a systematic review and meta-analysis.

BACKGROUND: To compare perioperative and short-term oncologic outcomes of laparoscopic pancreaticoduodenectomy (LPD) to open pancreaticoduodenectomy (OPD) using data from large-scale retrospective cohorts and randomized controlled trials (RCTs) in the last 10 years. METHODS: A meta-analysis to assess the safety and feasibility of LDP and OPD registered with PROSPERO: (CRD42020218080) was performed according to the PRISMA guidelines. Studies comparing LPD with OPD published between January 2010 and October 2020 were included; only clinical studies reporting more than 30 cases for each operation were included. Two authors performed data extraction and quality assessment independently. The primary endpoint was operative times, blood loss, and 90 days mortality. Secondary endpoints included reoperation, length of hospital stay (LOS), morbidity, Clavien-Dindo ≥3 complications, postoperative pancreatic fistula (POPF), blood transfusion, delayed gastric emptying (DGE), postpancreatectomy hemorrhage (PPH), and oncologic outcomes (R0-resection, lymph node dissection). RESULTS: Overall, the final analysis included 15 retrospective cohorts and 3 RCTs comprising 12,495 patients (2,037 and 10,458 patients underwent LPD and OPD). It seems OPD has more lymph nodes harvested but no significant differences [weighted mean difference (WMD): 1.08; 95% confidence interval (CI): 0.02 to 2.14; P=0.05]. Nevertheless, compared with OPD, LPD was associated with a higher R0 resection rate [odds ratio (OR): 1.26; 95% CI: 1.10-1.44; P=0.0008] and longer operative time (WMD: 89.80 min; 95% CI: 63.75-115.84; P<0.00001), patients might benefit from lower rate of wound infection (OR: 0.36; 95% CI: 0.33-0.59; P<0.0001), much less blood loss (WMD: -212.25 mL; 95% CI: -286.15 to -138.14; P<0.00001) and lower blood transfusion rate (OR: 0.58; 95% CI: 0.43-0.77; P=0.0002) and shorter LOS (WMD: -1.63 day; 95% CI: -2.73 to -0.51; P=0.004). No significant differences in 90-day mortality, overall morbidity, Clavien-Dindo ≥3 complications, reoperation, POPF, DGE and PPH between LPD and OPD. CONCLUSIONS: Our study suggests that after learning curve, LPD is a safe and feasible alternative to OPD as it provides similar perioperative and acceptable oncological outcomes when compared with OPD.