Cancer Research Articles

Long-term outcome of invasive pure micropapillary breast cancer compared with invasive mixed micropapillary and invasive ductal breast cancer: a matched retrospective study.

Data on the prognostic impact of the micropapillary component in breast cancer are limited. The purpose of this study was to investigate the clinicopathological characteristics and long-term outcomes of pure and mixed invasive micropapillary breast cancer (IMPC) patients compared to invasive ductal cancer (IDC) patients. This retrospective study analysed all IMPC and IDC patients treated at the European Institute of Oncology (IEO) between 1997 and 2019. The overall cohort of IMPC patients was divided in two groups, pure and mixed IMPC. Each patient with mixed or pure IMPC was matched with one patient with IDC, based on year of surgery, age, pT, pN, and molecular subtype. A total of 30,115 IDC, 120 pure IMPC and 150 mixed IMPC patients were considered eligible. Compared to IDC, pure and mixed IMPC patients presented a higher rate of locally advanced disease (pT2-T3, pN2-N3), vascular invasion, and Luminal B subtype. After matching, pure and mixed IMPC showed a significant higher rate of vascular invasion compared to IDC patients (p < 0.001). Invasive disease-free survival was better in IDC compared to pure IMPC patients (p = 0.11). Long-term overall survival was significantly worse in pure IMPC group compared to IDC group (p = 0.004), being instead similar between mixed IMPC vs matched IDC (p = 0.07). These real-world data reported the worse prognosis of pure IMPC compared to IDC, highlighting the peculiar prognostic value of the micropapillary subtype itself in the decision-making process of IMPC management. An accurate pre-surgical diagnostic evaluation and a multidisciplinary approach are pivotal to best personalize its treatment.

Impact of Artificial Intelligence-Based Autosegmentation of Organs at Risk in Low- and Middle-Income Countries

Radiation therapy (RT) processes require significant human resources and expertise, creating a barrier to rapid RT deployment in low- and middle-income countries (LMICs). Accurate segmentation of tumor targets and organs at risk (OARs) is crucial for optimal RT. This study assessed the impact of artificial intelligence (AI)-based autosegmentation of OARs in 2 LMICs. Ten patients, comprising 5 head and neck (HN) cancer patients and 5 prostate cancer patients, were randomly selected. Planning computed tomography images were subjected to autosegmentation using an Food and Drug Administration-approved AI software tool and manual segmentation by experienced radiation oncologists from 2 LMIC RT clinics. The control data, obtained from a large academic institution in the United States, consisted of contours obtained by an experienced radiation oncologist. The segmentation time, DICE similarity coefficient (DSC), Hausdorff distance, and mean surface distance were evaluated. AI significantly reduced segmentation time, averaging 2 minutes per patient, compared with 57 to 84 minutes for manual contouring in LMICs. Compared with the control data, the AI pelvic contours provided better agreement than did the LMIC manual contours (mean DSC of 0.834 vs 0.807 in LMIC1 and 0.844 vs 0.801 in LMIC2). For HN contours, AI provided better agreement for the majority of OAR contours than manual contours in LMIC1 (mean DSC: 0.823 vs 0.821) or LMIC2 (mean DSC: 0.792 vs 0.748). Neither the AI nor LMIC manual contours had good agreement with the control data (DSC < 0.600) for the optic nerves, chiasm, and cochlea. AI-based autosegmentation generates OAR contours of comparable quality to manual segmentation for both pelvic and HN cancer patients in LMICs, with substantial time savings.

Cancer and Autoimmune Diseases as Two Sides of Chronic Inflammation - and the Method of Therapy.

Chronic inflammation is associated with a prolonged increase in various inflammatory factors. According to clinical data, it can be linked with both cancer and autoimmune diseases in the same patients. This raises the critical question of how chronic inflammation relates to seemingly opposing diseases - tumors, in which there is immunosuppression, and autoimmune diseases, in which there is over-activation of the immune system. In this review, we consider chronic inflammation as a prerequisite for both immune suppression and an increased likelihood of autoimmune damage. We also discuss potential disease-modifying therapies targeting chronic inflammation, which can be helpful for both cancer and autoimmunity. On the one hand, pro-inflammatory factors persisting in the areas of chronic inflammation stimulate the production of anti-inflammatory factors due to a negative feedback loop, eliciting immune suppression. On the other hand, chronic inflammation can bring the baseline immunity closer to the threshold level required for triggering an autoimmune response using the bystander activation of immune cells. Focusing on the role of chronic inflammation in cancer and autoimmune diseases may open prospects for more intensive drug discovery for chronic inflammation.

The Effect of Coronavirus Pandemic on the Treatment of Gynecological and Breast Cancers

Introduction: During the COVID-19 pandemic, various groups, including women with cancer, were affected as a high-risk group in terms of disease diagnosis and treatment. Despite the importance of therapeutic changes in cancers, such as breast and gynecological cancer, there is no comprehensive study in this regard that also refers to the coronavirus. The need for a deep understanding of the impact of coronavirus on the treatment plan of this group of patients caused the researcher to design and implement this study that aims to investigate the treatment challenge among cancer patients during the COVID-19 pandemic. Materials and methods: To answer the study question, a comprehensive search was carried out in databases, such as PubMed, Web of Science Core Collection, and Scopus, using keywords, including cancer, gynecologic cancer, breast cancer, treatment, delay, and modification. Full-texted, English language and original articles were included in this study. Results: In total, 27 articles were selected for the study. The findings of this study revealed that COVID-19 greatly affects the treatment of gynecology and breast cancer. These patients experience delay or modification of cancer treatment. Increased time between diagnosis and treatment, delay, change or cancellation of surgery and change in treatment plan are the most important changes in cancer treatment during the COVID-19 pandemic. Conclusion: The COVID-19 pandemic has had a significant impact on various aspects of gynecology and breast cancer care worldwide. In the current pandemic, there has been a significant delay in the diagnosis and treatment of gynecological and breast cancer, which, due to its higher morbidity and mortality, has made the condition more difficult for cancer patients and treatment teams.

The Role of Circular RNA in the Pathogenesis of Chemotherapy-Induced Cardiotoxicity in Cancer Patients: Focus on the Pathogenesis and Future Perspective.

Cardiotoxicity is a serious challenge cancer patients face today. Various factors are involved in cardiotoxicity. Circular RNAs (circRNAs) are one of the effective factors in the occurrence and prevention of cardiotoxicity. circRNAs can lead to increased proliferation, apoptosis, and regeneration of cardiomyocytes by regulating the molecular pathways, as well as increasing or decreasing gene expression; some circRNAs have a dual role in cardiomyocyte regeneration or death. Identifying each of the pathways related to these processes can be effective on managing patients and preventing cardiotoxicity. In this study, an overview of the molecular pathways involved in cardiotoxicity by circRNAs and their effects on the downstream factors have been discussed.

Alternative therapy for lymphoma with febrile neutropenia using traditional Chinese medicine: A case report

IntroductionFebrile neutropenia is a common complication in patients undergoing chemotherapy for hematologic malignancies and is associated with significant morbidity and mortality. Primary granulocyte colony-stimulating factor (G-CSF) prophylaxis is consistently associated with a notable reduction in the risk of febrile neutropenia. However, the use of G-CSF in patients who are already neutropenic from chemotherapy remains controversial. Studies have shown that 12.9% of cancer patients incorporate traditional Chinese medicine (TCM) to alleviate chemotherapy side effects in Taiwan; thereby providing an alternative management strategy for neutropenic fever in cancer patients. Case presentationThis is an 18-year-old female with newly diagnosed precursor T-lymphoblastic lymphoma. After chemotherapy, the patient developed febrile neutropenia. Despite the use of antibiotics and G-CSF, the febrile neutropenia persisted for two months. Approximately ten days after the initiation of traditional Chinese medicine decoction with the strategy of tonifying the spleen and stomach, clearing yin fire, and uplifting yang, her absolute neutrophil count (ANC) had gradually increased. Additionally, after two weeks of treatment, her fever subsided. The patient continued with chemotherapy and was discharged in stable condition. DiscussionAntibiotic use aligns with the TCM perspective of an “attack” approach. Conversely, our TCM decoction was designed to raise the ANC by tonifying the spleen and stomach, clearing Yin Fire, and uplifting Yang. Li Dongyuan, one of the four great masters of the Jin Yuan Dynasty, created the formula: Bupiwei Shengyang Sanhuo Decoction that is notable in this regard. The herbs in our decoction have shown hematopoietic and myelosuppression-alleviating effect. For many patients who do not respond adequately to G-CSF alone, integrative treatments involving both TCM and Western medicine can offer additional therapeutic benefits by increasing blood cell counts.

Patient-reported sexual health outcomes of cervical cancer patients treated with definitive chemoradiation and MRI-guided brachytherapy

BackgroundSexual health is an important survivorship issue in cervical cancer. We assessed patient-reported sexual health outcomes and correlations with oncologist-assessed vaginal toxicity (VT). MethodsThis was a prospective, cross-sectional study of stage IB-IVA cervical cancer patients treated with definitive chemoradiation, who completed a socio-demographic questionnaire and the following patient-reported-outcomes (PROs): Female Sexual Function Index (FSFI), Female Sexual Distress Scale-Revised (FSDS-R), Menopause Rating Scale (MRS), Hospital Anxiety and Depression Scale (HADS). VT was assessed using the CTCAE v4.0. Sociodemographic, clinical data, PROs and VT were summarized using descriptive statistics; correlations were evaluated using linear regression analyses. ResultsBetween August 2018 and April 2022, 73 patients were analyzed. Median age was 49 (range 25–81), 57.5% had vaginal involvement at diagnosis and 76.9% were partnered. Sexual dysfunction (FSFI score ≤ 26), sexual distress (FSDS-R ≥ 11), severe menopausal symptoms (MRS ≥ 17), anxiety (HAD-Anxiety >7) and depression (HAS-Depression >7) were reported in 86.3%, 54.5%, 36.2%, 46.6% and 24.7%, respectively. Grade 2+ VT was reported in 27.4%. No significant associations were found between PROs and VT. On multivariable analysis, non-partnered status, use of hormone replacement therapy, and International Commission on Radiation Units and Measurements – rectovaginal dose (ICRU-RV) >65Gy were associated with worse sexual health (p < 0.005). ConclusionCervical cancer patients self-report high rates of sexual distress, dysfunction and menopause symptoms. Discordance between oncologist-assessed VT and PROs highlights the importance of evaluating the patient's experience. Proactive treatment of menopausal symptoms and attention to radiotherapy doses to the vagina should be considered.

Probiotics as an Adjunct Approach to the Prevention and Treatment of Colon Cancer: A Review

Abstract:: One out of every six people in the world is suffering from cancer disease. The major causes of cancer are high consumption of tobacco, high body mass index, and alcoholic beverages with low intake of a healthy diet and limited physical activity. Colon cancer is one of the leading causes of cancer-related morbidity worldwide. In the past few years, probiotics have drawn a lot of interest as potential preventive and therapeutic anticancer agents. This literature review addressed both human and animal research that has explored the association between probiotics and colon cancer. Probiotic administration has remarkable potential for the prevention and treatment of colon cancer through various mechanisms such as inhibiting the growth of cancer cells via apoptosis, improving immune activity, restoring gut microbiota, improving intestinal barrier properties, synthesizing anticarcinogenic compounds, and degrading carcinogenic compounds. Therefore, probiotics emerge as an adjunct therapy, holding the potential to significantly reduce the risk of colorectal cancer.

Quercetin has a protective impact on human umbilical vein endothelial cells against tungsten carbide cobalt nanoparticle-induced cytotoxicity, oxidative stress, apoptosis

Oxidative stress is a pivotal factor in the pathogenesis of various cancer diseases. In fact, oxidative DNA damage is described as the type of damage probably to occur in cancer cells. This study examined the protective impact of the polyphenolic compound quercetin on human umbilical vein endothelial (HUVEC) cells against tungsten carbide cobalt nanoparticles (WC-Co NPs)-induced oxidative stress, cytotoxicity, and apoptosis. One of the most often used models for studying endothelial cells in vitro is the human umbilical vein epithelial cell. Scanning electron microscope (SEM) and transmission electron microscopy (TEM) were used to measure the size of the NPs prior to WC-Co NPs treatment. WC-Co NPs had a polygonal form and measured 45.26 ± 1 nm in size. Using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT),neutral red uptake(NRU) and lactate dehydrogenase (LDH) assays, the cytotoxicity of WC-Co NPs on HUVECs cells was assessed. The cytotoxicity of NPs increased in a concentration-dependent way. The MTT result was used to calculate the median inhibitory concentration (IC50) for HUVEC cells at 24 h, which came out to be 23.14 μg/ml. Intracellular reactive oxygen species(ROS) and lipid peroxidation(LPO) levels were elevated at 17 g/ml WC-Co NPs and then reduced in HUVECs cells upon immediate exposure to 150 µM quercetin (QR). Using JC-1 staining, the loss of mitochondrial membrane potential(MMP) in control, WC-Co NPs alone and WC-Co NPs plus QR exposed cell were evaluated. In HUVECs cells, maximum apoptotic cells were seen at increasing NPs concentrations. Based on the impacts of NPs on HUVECs cells, the data suggests that QR may work on the process of scavenging ROS, which is responsible for DNA repair. Consequently, the above findings highlight the significance of these QR as defenses against DNA damage brought on by oxidative stress, which frequently happens in a number of cancer disorders.

Circ_0006089 facilitates gastric cancer progression and oxaliplatin resistance via miR-217/NRP1

BackgroundOxaliplatin (OXA) is a vital tool in the chemotherapy of gastric cancer (GC) patients. Circular RNAs (circRNAs) are a group of non-coding RNAs that have been associated with tumorigenesis. Nevertheless, the function of circRNAs in OXA resistance of GC is unknown. MethodsCirc_0006089/miR-217/NRP1 were elucidated through qRT-PCR in GC OXA-tolerant tissues and cell lines. OXA half-inhibitory concentration (IC50) was quantified by MTT assay. RNA pull-down and luciferase reporter tests were applied to characterize the interaction between circ_0006089 and miR-217, miR-217 and NRP1 in GC cells. ResultsThe findings disclosed that circ_0006089 and NRP1 was heightened whereas miR-217 was dramatically declined in OXA-tolerant GC tissues and cell lines. OXA resistance was reduced and the proliferation, migration and invasion ability of OXA cells were diminished after silencing circ_0006089. In addition, circ_0006089 raised OXA resistance by sponging miR-217. Further studies revealed that miR-217 bound to NRP1 and weakened OXA resistance. In addition, it was found that circ_0006089 accelerated GC progression and OXA resistance by upregulating NRP1 expression via sponging miR-217. ConclusionCirc_0006089 regulated OXA resistance in GC cells through miR-217/NRP1 axis, implying it was a promising biomarker for GC therapy.

ASO Author Reflections: It Does Not Matter Whether Radical Prostatectomy is Performed in High-Risk Localized Disease or at the Oligometastatic Stage.

Radical prostatectomy (RP) alone has traditionally been considered insufficient for patients with high-risk localized prostate cancer (HRPC) owing to the frequent need for adjuvant salvage radiotherapy or androgen deprivation therapy (ADT) following surgery. Previously, systemic therapy, such as ADT, was the standard treatment for metastatic prostate cancer (PC) patients; RP was not considered viable for these patients. However, since 2015, there has been a recognition that metastatic PC patients can be categorized based on the extent of their metastases, leading to the consideration of RP for some metastatic cases. In recent years, the concept of cytoreductive RP has gained traction; studies suggest that it may improve survival rates in metastatic PC patients through mechanisms, such as tumor debulking and enhancement of the immune response. A meta-analysis of retrospective studies has shown that cytoreductive RP is associated with higher cancer-specific survival rates at 1-year, 3-year, and 5-year intervals compared with systemic therapy alone. In our study, which followed HRPC and oligometastatic PC patients for an average of 46 months, we observed biochemical recurrence in 17.8% of HRPC and 13% of oligometastatic patients, with overall survival rates of 96.4% and 87%, respectively. Although prospective or randomized studies are still lacking, current retrospective studies, including our own, suggest promising outcomes for RP in HRPC and oligometastatic patients. With the increasing prevalence of robotic surgery, improved pelvic anatomy observation, and growing surgical confidence, the realization of prospective randomized study results may not be far off.

Sinensetin inhibits the movement ability and tumor immune microenvironment of non-small cell lung cancer through the inactivation of AKT/β-catenin axis.

Although current treatment strategies have improved clinical outcomes of non-small cell lung cancer (NSCLC) patients, side effect and prognosis remain a hindrance. Thus, safer and more effective therapeutical drugs are needed for NSCLC. Sinensetin (Sin) is a flavonoid from citrus fruits, which exhibits antitumor effect on diverse cancers. However, the effect and mechanism of Sin on NSCLC remain unknown. In this study, NSCLC cell lines, and tumor-bearing mice were treated with Sin. The effect and mechanism of Sin were addressed using cell counting kit-8, transwell, enzyme-linked immunosorbent assay, hematoxylin and eosin, immunohistochemistry, and western blot analysis assays in both cell and animal models. Sin reduced the cell viability of A549 and H1299, with the IC50 of 81.46 µM and 93.15 µM, respectively. Sin decreased invaded cell numbers, the expression of N-cadherin and vascular endothelial growth factor A (VEGFA), while increased the E-cadherin level, the cytotoxicity of CD8+ T cells, and the concentration of interferon-γ (IFN-γ), interleukin-2 (IL-2), and tumor necrosis factor-α (TNF-α) in NSCLC cells. Mechanistically, Sin declined the expression of protein kinase B (AKT)/β-catenin pathway, which was restored with the application of SC79, an activator of AKT. The inhibitory role of Sin in NSCLC cell proliferation, invasion, epithelial-mesenchymal transition (EMT) and immune escape was reversed by the management of SC79. In vivo, Sin reduced tumor size and weight, and the expression of N-cadherin, VEGFA, and AKT/β-catenin pathway, but enhanced the level of E-cadherin and IFN-γ. Taken together, Sin suppressed cell growth, invasion, EMT and immune escape via AKT/β-catenin pathway in NSCLC.

Fertility-sparing treatment for endometrial cancer and atypical endometrial hyperplasia patients with progesterone resistance: A retrospective analysis of 61 cases

Fertility-sparing treatment for endometrial cancer and atypical endometrial hyperplasia patients with progesterone resistance: A retrospective analysis of 61 cases

Association Between Changes in Skeletal Muscle Quality and Prognosis in Postoperative Patients with Early Gastric Cancer.

Identifying accurate prognostic factors is crucial for postoperative management of early gastric cancer (EGC) patients. Skeletal muscle quality (SMQ), defined by muscle density on computed tomography (CT) images, has been proposed as a novel prognostic factor. This study compared the prognostic significance of SMQ changes with the well-established factor of body weight (BW) loss in the postoperative EGC setting. This single-center retrospective study included 297 postoperative EGC patients (median age 69 years, 68.4% male) who had preoperative and 1-year-postoperative gastrectomy CT images. SMQ was defined as the modified intramuscular adipose tissue content (mIMAC = skeletal muscle density-subcutaneous fat density on CT images) and the change as ΔmIMAC. Log-rank test, Kaplan-Meier survival, and Cox proportional hazards regression analyses were used to assess the associations between prognosis and either ΔmIMAC or BW change (ΔBW). Prognosis prediction by ΔmIMAC and ΔBW was compared by using the area under the curve (AUC) of the receiver operating characteristic curve. ΔmIMAC was significantly associated with prognosis (log-rank test; P = 0.037), but ΔBW was not (P = 0.243). Prognosis was significantly poorer in the severely decreased mIMAC group than in the preserved group (multivariate Cox proportional hazards regression analysis; P = 0.030) but was unaffected by BW changes (P = 0.697). The AUC indicated a higher prognostic value for ΔmIMAC than ΔBW (ΔmIMAC: AUC = 0.697, ΔBW: AUC = 0.542). One-year post-gastrectomy SMQ changes may be better prognostic EGC predictors than BW changes.

The Long-Term Results of Proximal Gastrectomy for Proximal Gastric Cancer: A Propensity Score Matching Analysis Based on SEER Database.

Proximal gastrectomy (PG) is one of function-preserving gastrectomy (FPG). In this study, we compared the long-term results of proximal gastric cancer (PGC) patients undergoing proximal gastrectomy and total gastrectomy (TG). Patients diagnosed with PGC and receiving PG or TG between 2004 and 2020 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was applied to minimize confounding factors. Kaplan-Meier analysis and log-rank test were used to compare overall survival (OS) and cancer-specific survival (CSS) between the PG and TG groups. Univariate and multivariate Cox regression analyses were performed to identify independent risk factors affecting OS. A total of 3916 patients were recruited according to the inclusion and exclusion criteria, with 2614 undergoing PG and 1302 undergoing TG. After 1:1 PSM matching, 912 pairs of data were included for analysis. Before PSM matching, PG group tended to have better OS and CSS outcomes. However, after PSM matching, both surgical approaches showed similar long-term results. PG for PGC yields comparable long-term outcomes to TG and demonstrates safety in terms of oncologic outcomes.

Clearance of high-risk HPV after large loop excision of the transformation zone of early-stage invasive cervical cancer or adenocarcinoma in situ is highly correlated with the absence of residual cancer

Clearance of high-risk HPV after large loop excision of the transformation zone of early-stage invasive cervical cancer or adenocarcinoma in situ is highly correlated with the absence of residual cancer

Racial disparities in malignant cervical cancer from 2000 to 2020

Racial disparities in malignant cervical cancer from 2000 to 2020

Optimizing classification models for medical image diagnosis: a comparative analysis on multi-class datasets

The surge in machine learning (ML) and artificial intelligence has revolutionized medical diagnosis, utilizing data from chest ct-scans, COVID-19, lung cancer, brain tumor, and alzheimer parkinson diseases. However, the intricate nature of medical data necessitates robust classification models. This study compares support vector machine (SVM), naïve Bayes, k-nearest neighbors (K-NN), artificial neural networks (ANN), and stochastic gradient descent on multi-class medical datasets, employing data collection, Canny image segmentation, hu moment feature extraction, and oversampling/under-sampling for data balancing. Classification algorithms are assessed via 5-fold cross-validation for accuracy, precision, recall, and F-measure. Results indicate variable model performance depending on datasets and sampling strategies. SVM, K-NN, ANN, and SGD demonstrate superior performance on specific datasets, achieving accuracies between 0.49 to 0.57. Conversely, naïve Bayes exhibits limitations, achieving precision levels of 0.46 to 0.47 on certain datasets. The efficacy of oversampling and under-sampling techniques in improving classification accuracy varies inconsistently. These findings aid medical practitioners and researchers in selecting suitable models for diagnostic applications.

Inflammation as a shared mechanism of chronic stressrelated disorders with potential novel therapeutic targets.

Stress is a subjective experience that varies across individuals depending on their sensitivity, resilience, and length of exposure to stressors. Stress may be categorised as acute (positive stress) or chronic (negative stress). Acute stress is advantageous for the human body, but chronic stress results in changes in cardiovascular, neuroendocrine, autonomic, and immunological functions, eventually causing different illnesses. The specific process relating stress to chronic stress associated diseases is still a topic of continuing debate. Inflammation has been recognised as a new and fascinating physiological mechanism that connects chronic stress and its associated illnesses. This article explored the relationships between chronic stress, inflammation, and chronic illnesses, including depression, cancer, and cardiovascular disease. This article also emphasises on various possible therapeutic targets for the management of chronic stressrelated illnesses by targeting inflammation, namely lipoxins and alpha7 nicotinic receptors. These therapeutic targets may be useful in developing new and safe therapies for the management of chronic stressrelated dysfunctions.

Berberine: A Multi-Target Natural PCSK9 Inhibitor with the Potential to Treat Diabetes, Alzheimer's, Cancer and Cardiovascular Disease.

Berberine is a natural product with a wide range of pharmacological effects. It has antimicrobial, anti-cancer, anti-inflammatory, anti-hyperlipidemic, neuroprotective, and cholesterollowering properties, among others. It has been used in traditional Chinese and Ayurvedic medicine for 3000 years and is generally well-tolerated with few side effects. Its main drawback is low oral bioavailability, which has hindered widespread clinical use. However, recent interest has surged with the emergence of evidence that berberine is effective in treating cancer, diabetes, Alzheimer's disease, and cardiovascular disease via multiple mechanisms. It enhances insulin sensitivity and secretion by pancreatic β-cells in Type 2 Diabetes Mellitus in addition to reducing pro-inflammatory cytokines such as IL-6, IL-1β, TLR4 and TNF-α. These cytokines are elevated in Alzheimer's disease, cardiovascular disease, and diabetes. Reductions in pro-inflammatory cytokine levels are associated with positive outcomes such as improved cognition, reduced cardiovascular events, and improved glucose metabolism and insulin sensitivity. Berberine is a natural PCSK9 inhibitor, which contributes to its hypolipidemic effects. It also increases low-density lipoprotein receptor expression, reduces intestinal cholesterol absorption, and promotes cholesterol excretion from the liver to the bile. This translates into a notable decrease in LDL cholesterol levels. High LDL cholesterol levels are associated with increased cardiovascular disease risk. Novel synthetic berberine derivatives are currently being developed that optimize LDL reduction, bioavailability, and other pharmacokinetic properties.