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The outreach of healthcare services is a challenge to remote areas with affected populations. Fortunately, remote health monitoring (RHM) has improved the hospital service quality and has proved its sustainable growth. However, the absence of security may breach the health insurance portability and accountability act (HIPAA), which has an exclusive set of rules for the privacy of medical data. Therefore, the goal of this work is to design and implement the adaptive Autonomous Protocol (AutoPro) on the patient’s remote healthcare (RHC) monitoring data for the hospital using fully homomorphic encryption (FHE). The aim is to perform adaptive autonomous FHE computations on recent RHM data for providing health status reporting and maintaining the confidentiality of every patient. The autonomous protocol works independently within the group of prime hospital servers without the dependency on the third-party system. The adaptiveness of the protocol modes is based on the patient’s affected level of slight, medium, and severe cases. Related applications are given as glucose monitoring for diabetes, digital blood pressure for stroke, pulse oximeter for COVID-19, electrocardiogram (ECG) for cardiac arrest, etc. The design for this work consists of an autonomous protocol, hospital servers combining multiple prime/local hospitals, and an algorithm based on fast fully homomorphic encryption over the torus (TFHE) library with a ring-variant by the Gentry, Sahai, and Waters (GSW) scheme. The concrete-ML model used within this work is trained using an open heart disease dataset from the UCI machine learning repository. Preprocessing is performed to recover the lost and incomplete data in the dataset. The concrete-ML model is evaluated both on the workstation and cloud server. Also, the FHE protocol is implemented on the AWS cloud network with performance details. The advantages entail providing confidentiality to the patient’s data/report while saving the travel and waiting time for the hospital services. The patient’s data will be completely confidential and can receive emergency services immediately. The FHE results show that the highest accuracy is achieved by support vector classification (SVC) of 88% and linear regression (LR) of 86% with the area under curve (AUC) of 91% and 90%, respectively. Ultimately, the FHE-based protocol presents a novel system that is successfully demonstrated on the cloud network.

The COVID-19 outbreak significantly impacted global health, resulting in widespread infections and fatalities. In response, the World Health Organization (WHO) launched the Preparedness and Resilience for Emerging Threats (PRET) program, focusing on respiratory pathogens, to prepare for future pandemics and achieve sustainable well-being around the world. Moreover, the WHO also encouraged countries to establish a National Action Plan for Health Security (NAPHS) to address various disasters and threats. Therefore, governments should develop the necessary systems aligned with NAPHS while maintaining compliance with PRET. Thus, to maintain global health and wellness, a platform for sharing medical data on highly contagious diseases worldwide, free from interference from individual countries, is critical for effective border control. In this paper, we introduce an efficient approach, i.e., a two-layer decentralized blockchain architecture. Our mechanism streamlines integration between national sovereignty and the WHO, enabling the secure and supervised exchange of pandemic data via a single global blockchain and multiple local blockchains. This blockchain framework has strong potential to enhance nations’ ability to prepare for and respond to future pandemics, ensuring the safety and health of their citizens. The bottom-layer local chains facilitate the collection of pandemic immunity data within their own countries, and the upper-layer global chain, with the assistance of the WHO, facilitates the worldwide exchange of these data if needed. Given the characteristics of decentralization and transparency in blockchain technology, and the WHO’s oversight, no government should worry that sensitive medical data will be manipulated or abused by superpowers on the global blockchain. It also highlights the importance of global collaboration in preventing and controlling contagious diseases. Furthermore, the performance of this system is assessed based on several sets of real-world data and requirements. We demonstrate that this global information-sharing mechanism can improve international health safety, provided it is supported by feasible and reasonable resources to handle transactional demands around the world.

Magnolol is a lignan with anti-inflammatory activity identified in Magnolia officinalis. Ulcerative colitis (UC), one of the types of inflammatory bowel disease (IBD), is a disease that causes inflammation and ulcers in the colon. To investigate the effect of magnolol in dextran sulfate sodium (DSS)-induced experimental UC model, male C57 mice were treated with 2% DSS drinking water for 5 consecutive days followed by intragastric administration with magnolol (5, 10 and 15 mg/kg) daily for 7 days. The results showed that magnolol significantly attenuated disease activity index, inhibited colonic shortening, reduced colonic lesions and suppressed myeloperoxidase (MPO) activity. Moreover, colonic pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) induced by colitis were dramatically decreased by magnolol. To further unveil the metabolic signatures upon magnolol treatment, mass spectrometry-based metabolomic analysis of the small molecular metabolites in mice serum were performed. Compared with controls, abnormality of serum metabolic phenotypes in DSS-treated mice were effectively reversed by different doses of magnolol. In particular, magnolol treatment effectively elevated the serum levels of tryptophan metabolites including kynurenic acid (KA), 5-hydroxyindoleacetic acid, indoleacetic acid (IAA), indolelactic acid and indoxylsulfuric acid, which are potential aryl hydrocarbon receptor (AHR) ligands to impact colitis. These findings suggest that magnolol exerts anti-inflammatory effect on DSS-induced colitis and its underlying mechanisms are associated with the restoring of tryptophan metabolites that inhibit the colonic inflammation.

Ulcerative colitis (UC) is a common chronic remitting disease but without satisfactory treatment. Alternative medicine berberine has received massive attention for its potential in UC treatment. Conventional therapies with the addition of berberine are becoming attractive as novel therapies in UC. In the present study, we investigated the preclinical activity of a conventional oral 5-aminosalicylic acid (5-ASA) therapy plus berberine in experimental colitis. A subclinical dose of 5-ASA (200 mg/kg/day) alone or 5-ASA plus berberine (20 mg/kg/day) was orally administered for 30 days to C57BL/6 mice with colitis induced by three cycles of 2% dextran sulfate sodium (DSS). The disease severity, inflammatory responses, drug accumulation and potential toxicity of colitis mice were examined. The results showed that comparing to 5-ASA alone, 5-ASA plus berberine more potently ameliorated DSS-induced disease severity, colon shortening, and colon histological injury. Further, the up-regulation in mRNA level of colonic TNF-α as well as NFκB and JAK2 phosphorylation caused by DSS were more pronouncedly reversed in animals treated with the combination therapy than those treated with 5-ASA alone. Moreover, the addition of berberine to 5-ASA more significantly inhibited lymphocyte TNF-α secretion of DSS mice than 5-ASA alone. In the meanwhile, no extra drug accumulation or potential toxicity to major organs of colitis mice was observed with this combination treatment. In summary, our studies provide preclinical rationale for the addition of berberine to 5-ASA as a promising therapeutic strategy in clinic by reducing dose of standard therapy.

Hyperlipidemia and hepatic steatosis afflict over 75% of patients with type 2 diabetes, causing diabetic dyslipidemia. (CP) leaf is a herbal tea which has long been consumed by the Chinese population, particularly people suffering from obesity and diabetes. CP appears to exhibit a hypolipidemic effect in lipid loaded mice (Kurihara et al., 2003), although the detailed mechanisms and active ingredients for this hypolipidemic effect have not yet been answered. In this study, we investigated the beneficial effects of CP and predicted the mechanisms by utilizing lipidomics, serum-pharmacochemistry and network pharmacology approaches. Our results revealed that serum and hepatic levels of total triglyceride (TG), total cholesterol (T-CHO), low-density lipoproteins (LDL) and high-density lipoproteins (HDL), as well as 30 lipids including cholesterol ester (CE), diglyceride (DG), phosphatidylethanolamine (PE), phosphatidylcholine (PC), and sphingomyelin (SM) in CP-treated mice were improved in comparison with untreated diabetic mice. In parallel, 14 phytochemical compounds of CP were determined in mice serum after CP administration. Mechanistically, the network pharmacology analysis revealed the predicted targets of CP's active ingredients ALOX12, APP, BCL2, CYP2C9, PTPN1 and linked lipidome targets PLD2, PLA2G(s), and PI3K(s) families could be responsible for the CP effects on diabetic dyslipidemia. In conclusion, this study revealed the beneficial effects of CP on diabetic dyslipidemia are achieved by reducing accumulation of hepatic lipid droplets and regulating circulatory lipids in diabetic mice, possibly through PI3K signaling and MAPK signaling pathways. GRAPHICAL ABSTRACTWork flow of the evaluation of the effects and mechanisms of leaves tea on dyslipidemia in diabetic mice.

Leaves of Cyclocarya paliurus are a sweet tea traditionally used to treat obesity and diabetes in China. However, its protective mechanisms against hyperglycemia remains unclear. Here, we demonstrate that the extract of C. paliurus leaves significantly decreased body loss, food intake and blood glucose level, and increased blood insulin level, β-cell number and insulin-producing β cells in high-fat diet-low dose STZ-induced diabetic mice. In vivo and in vitro studies also showed the extract of C. paliurus leaves significantly inhibited pancreatic β cell apoptosis by suppressing the expression of caspase 8, caspase 9 and cleaved caspase-3, as well as Bax/Bcl-2 ratio, down-regulating p38, ERK and JNK phosphorylation, and up-regulating Akt phosphorylation. These effects were significantly enhanced by inhibitor p-38 or ERK or JNK, and counteracted by inhibitor of PI3K. In addition, the extract of C. paliurus leaves also significantly improved hepatic steatosis, nephropathy and cardiac hypertrophy of diabetic mice. Taken together, these results provide the insight into the effects of C. paliurus leaves on pancreatic β cell preservation in standing glucolipotoxicity. Therefore, C. paliurus tea leaves may be used as a new remedy for diabetes through enhancing pancreatic β cell preservation by inhibiting β cell apoptosis.

Liver cancer belongs to Gastrointestinal (GI) malignancies which is a common clinical disease, a thorny public health problem, and one of the major diseases that endanger human health. Molecules from natural products (NPs) or their derivatives play an increasingly important role in various chronic diseases such as GI cancers. The chemical composition of the Alstonia yunnanensis Diels roots was studied using silica column chromatography, gel chromatography, recrystallization, and HPLC, and the compounds were structurally identified by modern spectral analysis using mass spectrometry (MS) and nuclear magnetic resonance ( 1 H-, 13 C-, HMQC-, HMBC-, and 1 H- 1 HCOSY-NMR), ultraviolet and visible spectrum (UV), and electronic Circular Dichroism (ECD). Acetoxytabernosine (AC), an indole alkaloid with antitumor activity, was isolated from Alstonia yunnanensis Diels root. The current study aimed to investigate the influence of AC on the cell proliferation of BEL-7402 and SMMC7721 and to elucidate the underlying mechanism. The absolute configuration of AC was calculated by ECD (electronic circular dichroism). The effects of AC on the viability of different tumor cell lines were studied by the SRB method. The death mode of human hepatoma cells caused by AC was studied by TUNEL cell apoptosis detection and AnnexinV-FITC/PI double staining image. Mitochondrial membrane potential was detected by JC-1. The effects of AC on the expression of apoptosis-related proteins (Caspase9, Caspase3, and Parp-1) in SMMC7721 and BEL-7402 cells were detected by western blot. It was found that the absolute configuration of AC is 19(s), 20(s)-Acetoxytabernosine. AC could induce apoptosis of SMMC7721 and BEL-7402, and block the replication of DNA in the G1 phase. Under the treatment of AC, the total protein expression of apoptosis-related proteins (Caspase9, Caspase3, and Parp-1) significantly decreased in SMMC7721 and BEL-7402. The results suggested that AC induced apoptosis through a caspase-dependent intrinsic pathway in SMMC7721 and BEL-7402, and natural product-based drug development is an important direction in antitumor drug discovery and research.

Early childhood is a critical period for development, and early life stress may increase the risk of gastrointestinal diseases including irritable bowel syndrome (IBS). In rodents, neonatal maternal separation (NMS) induces bowel dysfunctions that resemble IBS. However, the underlying mechanisms remain unclear. Here we show that NMS induces expansion of intestinal stem cells (ISCs) and their differentiation toward secretory lineages including enterochromaffin (EC) and Paneth cells, leading to EC hyperplasia, increased serotonin production, and visceral hyperalgesia. This is reversed by inhibition of nerve growth factor (NGF)-mediated tropomyosin receptor kinase A (TrkA) signalling, and treatment with NGF recapitulates the intestinal phenotype of NMS mice in vivo and in mouse intestinal organoids in vitro. Mechanistically, NGF transactivates Wnt/β-catenin signalling. NGF and serotonin are positively correlated in the sera of diarrhea-predominant IBS patients. Together, our findings provide mechanistic insights into early life stress-induced intestinal changes that may translate into treatments for gastrointestinal diseases. Early life stress has been associated with the occurrence of gastrointestinal diseases later in life, but underlying mechanisms remain poorly understood. Here, Wong et al. show that early life stress leads to expansion of intestinal stem cells and their differentiation into serotonin-producing enterochromaffin cells through crosstalk between NGF and Wnt signalling pathways.

Cumulative inhibition of voltage-gated Na+ channel current (INa) caused by high-frequency depolarization plays a critical role in regulating electrical activity in excitable cells. As discussed in this review paper, exposure to certain small-molecule modulators can perturb INa during high-frequency stimulation, influencing the extent of cumulative inhibition and electrical excitability in excitable cells. Carbamazepine differentially suppressed transient or peak (INa(T)) and late (INa(L)) components of INa. Moreover, the cumulative inhibition of INa(T) during pulse-train stimulation at 40 Hz was enhanced by lacosamide. GV-58 was noted to exert stimulatory effect on INa(T) and INa(L). This stimulated INa was not countered by ω-conotoxin MVIID but was effectively reversed by ranolazine. GV-58′s exposure can slow down INa inactivation elicited during pulse-train stimulation. Lacosamide directly inhibited INa magnitude as well as promoted this cumulative inhibition of INa during pulse-train stimuli. Mirogabalin depressed INa magnitude as well as modulated frequency dependence of the current. Phenobarbital can directly modulate both the magnitude and frequency dependence of ionic currents, including INa. Previous investigations have shown that exposure to small-molecule modulators can perturb INa under conditions of high-frequency stimulation. This ionic mechanism plays a crucial role in modulating membrane excitability, hereby supporting the validity of these findings.