Multimorbidity of chronic diseases is one of the most common health issues among older adults, and the resulting demand for long-term medical care and management imposes a considerable burden on healthcare systems. Muscle strength, a core indicator of overall health status, is closely associated with the risk of developing multimorbidity of chronic diseases in older adults. Decline in muscle strength not only increases the risk of multimorbidity of chronic diseases but also interacts with it to exacerbate disease burden. In older adults with existing multimorbidity of chronic diseases, muscle strength decline can impair physical function and quality of life, leading to a vicious cycle of disease progression and physical disability. Strength training can help prevent multimorbidity, with potential mechanisms including the promotion of anti-inflammatory effects and enhancement of mitochondrial energy metabolism. This review summarizes the impact of muscle strength decline on multimorbidity of chronic diseases in older adults and the effectiveness and potential mechanisms of exercise interventions, providing evidence to delay muscle strength decline, prevent the occurrence and progression of multimorbidity of chronic diseases, and improve quality of life in older adults.
Humans ; Aged ; Chronic Disease/prevention & control* ; Muscle Strength/physiology* ; Multimorbidity ; Quality of Life ; Resistance Training ; Exercise Therapy ; Exercise ; Sarcopenia

Parkinson's disease (PD), a chronic and common neurodegenerative disease, is characterized by the progressive loss of dopaminergic neurons in the dense part of the substantia nigra and abnormal aggregation of alpha-synuclein. Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by chronic insulin resistance and deficiency in insulin secretion. Extensive evidence has confirmed shared pathogenic mechanisms underlying PD and T2DM, such as oxidative stress caused by insulin resistance, mitochondrial dysfunction, inflammation, and disorders of energy metabolism. Conventional drugs for treating T2DM, such as metformin and glucagon-like peptide-1 receptor agonists, affect nerve repair. Even drugs for treating PD, such as levodopa, can affect insulin secretion. This review summarizes the relationship between PD and T2DM and related therapeutic drugs from the perspective of insulin signaling pathways in the brain.
Humans ; Parkinson Disease/drug therapy* ; Diabetes Mellitus, Type 2/pathology* ; Signal Transduction/physiology* ; Receptor, Insulin/metabolism* ; Animals ; Insulin Resistance/physiology* ; Insulin/metabolism*

Therapeutic resistance in cancer is responsible for numerous cancer deaths in clinical practice. While target mutations are well recognized as the basis of genetic resistance to targeted therapy, nontarget mutation resistance (or nongenetic resistance) remains poorly characterized. Despite its complex and unintegrated mechanisms in the literature, nongenetic resistance is considered from our perspective to be a collective response of innate or acquired resistant subpopulations in heterogeneous tumors to therapy. These subpopulations, e.g., cancer stem-like cells, cancer cells with epithelial-to-mesenchymal transition, and drug-tolerant persisters, are protected by their resistance traits at cellular and molecular levels. This review summarizes recent advances in the research on resistant populations and their resistance traits. NOTCH signaling, as a central regulator of nongenetic resistance, is discussed with a special focus on its canonical maintenance of resistant cancer cells and noncanonical regulation of their resistance traits. This novel view of canonical and noncanonical NOTCH signaling pathways is translated into our proposal of reshaping therapeutic strategies targeting NOTCH signaling in resistant cancer cells. We hope that this review will lead researchers to study the canonical and noncanonical arms of NOTCH signaling as an integrated resistant mechanism, thus promoting the development of innovative therapeutic strategies.
Neoplasms/metabolism* ; Receptors, Notch/metabolism* ; Disease Resistance/physiology* ; Signal Transduction/physiology* ; Humans ; Drug Resistance, Neoplasm/physiology* ; Molecular Targeted Therapy/methods*

Covid-19 pandemic has caused hundreds of thousands deaths and millions of infections and continued spreading violently. Although researchers are racing to find or develop effective drugs or vaccines, no drugs from modern medical system have been proven effective and the high mutant rates of the virus may lead it resistant to whatever drugs or vaccines developed following modern drug development procedure. Current evidence has demonstrated impressive healing effects of several Chinese medicines (CMs) for Covid-19, which urges us to reflect on the role of CM in the era of modern medicine. Undoubtedly, CM could be promising resources for developing drug candidates for the treatment of Covid-19 in a way similar to the development of artemisinin. But the theory that builds CM, like the emphasis of driving away exogenous pathogen (virus, etc.) by restoring self-healing capacity rather than killing the pathogen directly from the inside and the 'black-box' mode of diagnosing and treating patients, is as important, yet often ignored, an treasure as CM herbs and should be incorporated into modern medicine for future advancement and innovation of medical science.
Antiviral Agents/therapeutic use* ; COVID-19/therapy* ; Disease Outbreaks ; Drug Development/standards* ; Drug Resistance, Viral/genetics* ; Drug Therapy, Combination ; Drugs, Chinese Herbal/therapeutic use* ; Humans ; Medicine, Chinese Traditional/trends* ; Mutation Rate ; Pandemics ; Phytotherapy/methods* ; SARS-CoV-2/physiology*

Nonalcoholic fatty liver disease (NAFLD) and type 2 Diabetes Mellitus (T2DM) are highly prevalent diseases and are closely associated, with NAFLD being present in the majority of T2DM patients. In Asian traditional medicine, Mori Cortex is widely used for the treatment of diabetes and hyperlipidemia. However, whether it has a therapeutic effect on T2DM associated with NAFLD is still unknown. The present study showed that the oral treatment with Mori Cortex extract (MCE; 10 g·kg·d) lowered the blood lipid levels and reversed insulin resistance (IR) in high fat-diet/streptozotocin-induced type 2 diabetes in rats. The expression levels of sterol receptor element-binding protein-1c (SREBP-1c) and carbohydrate-responsive element binding protein (ChREBP), which are involved in steatosis in NAFLD rats, were measured in the liver samples. MCE decreased the protein and mRNA expression levels of SREBP-1c and ChREBP. In conclusion, down-regulation of SREBP-1c and ChREBP might contribute to the protective effect of MCE on hepatic injury and IR in the rats with T2DM associated with NAFLD.
Alanine Transaminase ; blood ; Animals ; Aspartate Aminotransferases ; blood ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ; genetics ; Diabetes Mellitus, Type 2 ; blood ; chemically induced ; drug therapy ; metabolism ; Diet, High-Fat ; adverse effects ; Disease Models, Animal ; Down-Regulation ; drug effects ; Insulin ; blood ; Insulin Resistance ; physiology ; Lipid Metabolism ; drug effects ; genetics ; Liver ; drug effects ; physiopathology ; Male ; Morus ; Non-alcoholic Fatty Liver Disease ; blood ; chemically induced ; drug therapy ; metabolism ; Phytotherapy ; Plant Extracts ; pharmacology ; therapeutic use ; Rats ; Rats, Sprague-Dawley ; Streptozocin

OBJECTIVEIn this review, to illustrate the resistance mechanism for pathogen insult, we discussed the role of the intestinal microbiome in promoting resistance to local gastrointestinal tract infections and to respiratory tract infections.

DATA SOURCESThe review was based on data obtained from the published research articles.

STUDY SELECTIONA total of 49 original articles were selected in accordance with our main objective to illustrate the resistance mechanism(s) by which commensal microbiota can contribute to host defense against local and systemic infections.

RESULTSDiverse microorganisms colonize human environmentally exposed surfaces such as skin, respiratory tract, and gastrointestinal tract. Co-evolution has resulted in these microbes with extensive and diverse impacts on multiple aspects of host biological functions. During the last decade, high-throughput sequencing technology developed has been applied to study commensal microbiota and their impact on host biological functions. By using pathogen recognition receptors pathway and nucleotide binding oligomerization domain-like receptors pathway, the commensal microbiome promotes resistance to local and systemic infections, respectively. To protect against the local infections, the microbiome functions contain the following: the competing for sites of colonization, direct production of inhibition molecules or depletion of nutrients needed for pathogens, and priming immune defenses against pathogen insult. At the same time, with the purpose to maintain homeostasis, the commensal bacteria can program systemic signals toward not only local tissue but also distal tissue to modify their function for infections accordingly.

CONCLUSIONSCommensal bacteria play an essential role in protecting against infections, shaping and regulating immune responses, and maintaining host immune homeostasis.

Disease Resistance ; Humans ; Infection ; microbiology ; Intestines ; microbiology ; Symbiosis ; physiology

Toll-like receptor 5 (TLR5) is responsible for the recognition of bacterial flagellin in vertebrates. In the present study, the first TLR5 gene in duck was cloned. The open reading frame (ORF) of duck TLR5 (dTLR5) cDNA is 2580 bp and encodes a polypeptide of 859 amino acids. We also cloned partial sequences of myeloid differentiation factor 88, 2'-5'-oligoadenylate synthetase (OAS), and myxovirus resistance (Mx) genes from duck. dTLR5 mRNA was highly expressed in the bursa of Fabricius, spleen, trachea, lung, jejunum, rectum, and skin; moderately expressed in the muscular and glandular tissues, duodenum, ileum, caecum, and pancreas; and minimally expressed in the heart, liver, kidney, and muscle. DF-1 or HeLa cells transfected with DNA constructs encoding dTLR5 can activate NF-kappaB leading to the activation of interleukin-6 (IL-6) promoter. When we challenged ducks with a Herts33 Newcastle disease virus (NDV), mRNA transcription of the antiviral molecules Mx, Double stranded RNA activated protein kinase (PKR), and OAS was up-regulated in the liver, lung, and spleen 1 and 2 days post-inoculation.
2',5'-Oligoadenylate Synthetase/genetics/metabolism ; Animals ; Cell Line ; *Cloning, Molecular ; Ducks ; Gene Expression Regulation/*physiology ; Humans ; Immunity, Innate ; Myeloid Differentiation Factor 88/genetics/metabolism ; Myxovirus Resistance Proteins/genetics/metabolism ; Newcastle Disease/metabolism ; Newcastle disease virus/classification ; RNA, Messenger/genetics/metabolism ; Species Specificity ; Toll-Like Receptor 5/genetics/*metabolism

BACKGROUNDObesity is a common risk factor for several diseases. Obesity related hormone and increased insulin resistance (IR) may contribute to the effects of obstructive sleep apnoea on cardiovascular consequences. We investigated ghrelin and IR in non-diabetic apnoeic patients with stable coronary heart disease and assessed the effects of continuous positive airway pressure (CPAP).

METHODSPlasma ghrelin, glucose and insulin were measured in 22 patients with CPAP and 22 matched controls without CPAP at baseline and three months. Indexes including homeostasis model assessment IR (HOMA IR), HOMA S and HOMA β were calculated for the assessment of IR, insulin sensitivity and pancreatic β cell function.

RESULTSAt three months follow-up, plasma ghrelin levels and HOMA IR in CPAP group were significantly decreased (P=0.002 and 0.046, respectively) while those in control group increased significantly (P=0.012 and 0.009, respectively). Significant moderate correlations were found between ghrelin vs. HOMA IR and ghrelin vs. HOMA S after CPAP, however, for those without CPAP, no significant associations were observed.

CONCLUSIONSShort-term effective continuous positive airway pressure had a significant effect on lowering plasma ghrelin levels and IR, but not body fat. Further large scale and longer term studies are warranted to corroborate these findings.

Blood Glucose ; Case-Control Studies ; Continuous Positive Airway Pressure ; methods ; Coronary Artery Disease ; blood ; Female ; Ghrelin ; blood ; Humans ; Insulin ; blood ; Insulin Resistance ; physiology ; Male ; Middle Aged ; Sleep Apnea, Obstructive ; therapy

The p38 mitogen-activated protein kinase (MAPK) plays an evolutionarily conserved role in the cellular response to microbial infection and environmental stress. Activation of p38 is mediated through phosphorylation by upstream MAPKK, which in turn is activated by MAPKKK. In the Caenorhabditis elegans, the p38 MAPK (also called PMK-1) signaling pathway has been shown to be required in its resistance to bacterial infection. However, how different upstream MAP2Ks and MAP3Ks specifically contribute to the activation of PMK-1 in response to bacterial infection still is not clearly understood. By using double-stranded RNA-mediated interference (RNAi) and genetic mutants of C. elegans, we demonstrate that C. elegans MOM-4, a mammalian TAK1 homolog, is required for the resistance of C. elegans to a P. aeruginosa infection. We have also found that the MKK-4 of C. elegans is required for P. aeruginosa resistance, but not through the regulation of DLK-1. In summary, our results indicate that different upstream MAPKKKs or MAPKKs regulate the activation of PMK-1 in response to P. Aeruginosa.
Animals ; Caenorhabditis elegans ; enzymology ; genetics ; immunology ; microbiology ; Caenorhabditis elegans Proteins ; genetics ; metabolism ; Disease Resistance ; Enzyme Activation ; MAP Kinase Kinase 1 ; metabolism ; MAP Kinase Signaling System ; Membrane Proteins ; deficiency ; genetics ; metabolism ; Mutation ; Pseudomonas Infections ; enzymology ; Pseudomonas aeruginosa ; physiology ; RNA Interference ; p38 Mitogen-Activated Protein Kinases ; metabolism

OBJECTIVE: To examine the plasma adiponectin concentration in coronary heart disease (CHD) patients combined with abnormal glucose metabolism, and to explore the clinical significance of adiponectin. METHODS: Eighty-seven hospitalized CHD patients confirmed by coronary angiography from August 2009 to April 2010 at Xiangya Hospital were enrolled and divided into 3 groups according to their glucose metabolic state: 31 patients were selected as a simple CHD group, 28 were selected as a CHD combined with impaired glucose tolerance group (CHD+IGT group), and the other 28 as a CHD combined with diabetes mellitus group (CHD+DM group). The 31 healthy subjects who got health checkup at the same time were enrolled as a normal control group (NC group). Plasma adiponectin was measured by enzyme linked immunosorbent assay. The height, weight,waistline and blood pressure of all the subjects were checked, and the fasting blood glucose (FBG), insulin, lipids, high-sensitivity C-reactive protein (hs-CRP), free fatty acids (FFA), the liver function and the renal function were checked as well. The body mass index and the homeostasis model were assessed for insulin resistance. RESULTS: 1) Plasma adiponectin in the CHD group, the CHD+IGT group, and the CHD+DM group was all lower than that in the NC group (P<0.05); 2) Compared with the CHD group, the plasma adiponectin in the CHD+DM group was the lowest, followed by the CHD+IGT group, and there was significant difference in the 3 groups (P<0.05); 3) Plasma adiponectin level was positively related with the high density lipoprotein cholesterol-C (HDL-C) (r=0.483, P<0.01), while it was negatively related with the hs-CRP and Gensini score (r=-0.489, P<0.05;r=-0.252, P<0.05). CONCLUSION Plasma adiponectin concentration is reduced in the CHD patients, and significantly reduced in CHD patients combined with abnormal glucose metabolism. Plasma adiponectin concentration decreases significantly with the severity of abnormal glucose metabolism. CHD and the abnormal glucose metabolism are important influence factors for plasma adiponectin. That plasma adiponectin level significantly decreases may be the superimposed results of CHD and abnormal glucose metabolism. Plasma adiponectin combined with HDL-C, hs-CRP and Gensini score may provide the reference in the judgement of the severity of CHD patients with abnormal glucose metabolism.
Adiponectin ; blood ; Aged ; Coronary Disease ; blood ; complications ; metabolism ; Diabetes Mellitus, Type 2 ; blood ; complications ; Female ; Humans ; Insulin Resistance ; physiology ; Male ; Middle Aged