The association of rs2233679 in the PIN1 gene promoter with the risk of Coronary Artery Disease in Chinese female individuals.

BACKGROUNDS: Vascular atherosclerosis leads to various cardiovascular and cerebrovascular diseases. Nitric oxide (NO) promotes vasodilatation and prevents Coronary Artery Disease (CAD). Pin1 suppresses NO production by down-regulating the activity of endothelial nitric oxide synthase (eNOS). Whether the genetic polymorphisms of the PIN1 gene (encoding Pin1) are implicated in CAD deserves investigations in human beings. METHODS: A total of 210 CAD patients and control individuals (all females) were enrolled, and their genotypes of rs2233679 (-667C/T, a key SNP in the promoter of PIN1 gene) were sequenced. T-test, chi-square test, odds ratio (OR) and 95% confidence interval (95% CI) were calculated to evaluate Hardy-Weinberg equilibrium, varied genetic distribution and relative CAD risk. RESULTS: The differences in age, BMI, triglyceride, total cholesterol, low-density and high density cholesterol between the CAD and control groups were not significant (all P>0.05), and Hardy-Weinberg equilibrium was observed in the two groups (both P>0.05). The frequency of -667T allele in the CAD group was higher than that in the control group. The genotype -667TT elicited a higher hazardous risk of CAD compared to the genotype -667CC (OR=1.85, 95% CI: 0.75-4.53) as well as the genotypes CC+CT (OR=1.97, 95% CI: 0.86-4.49). CONCLUSIONS: We firstly show that the allele -667T in the PIN1 promoter may elicit a higher CAD-risk than -667C, and the -667TT genotype of PIN1 may be a new genetic biomarker for increased incidence of CAD. These novel observations put forward a new understanding of the PIN1-CAD genetic relationship in humans, potentially contributing to both cardiovascular and cerebrovascular disorders.

Gut microbiome-based medical methodologies for early-stage disease prevention.

Recent advancements highlight the important role of gut microbiome in human health. However, a variety of endogenous and exogenous factors, such as genes, foods, drugs, environmental pollutions, oxidative stress, etc., may interfere with the gut microbiome in vivo and increase risks of digestive system diseases, cardiovascular diseases, neurological diseases, obesity, diabetes, cancers, and so on. Abundant discoveries listed in this work support that changes in the composition of the gut microbiome may be potentially used as sensitive early-stage diagnostic biomarkers and that the gut microbiome could be a promising therapeutic target for systemic prevention of multiple human diseases. Interestingly, the microbial culturomics revolution makes it possible to identify much more species and several new species in the gut microbiome. Several innovative articles published by Science and Nature in 2016 further put forward the feasibility of these perspectives, lay grounds for establishing standardized human gut microbiome compositions, and are particularly important for monitoring dysbiosis of the gut microbiome and for precisely reshaping a dysfunctional gut microbiome. Hypothetically, keeping and reconstructing an optimized gut microbiome would be essential to prevent the occurrence of various human diseases. Hence, these advancements have impressive clinical implications for predicting abnormal healthy status of human beings and for preventing the initiation of systemic disorders at an early stage.

Mfsd2a-based pharmacological strategies for drug delivery across the blood-brain barrier.

The blood-brain barrier (BBB) keeps the central nervous system (CNS) safe from various brain diseases, while the BBB makes it difficult for effective drugs to enter the CNS. Mfsd2a is specifically expressed on the cell membrane of brain-microvascular endothelial cell (BMEC) and is implicated in the delivery of some substances across the BBB. Mfsd2a is the first inhibitor of the transcytosis and the first transporter for lysophosphatidylcholine-docosahexaenoic acid (LPC-DHA) in BMECs. The crucial dual function of Mfsd2a puts forward two kinds of Mfsd2a-based strategies for carrying drugs from blood to the CNS. First, the reversible inhibition of Mfsd2a may temporarily induce a general disinhibition of the transcytosis in BMECs to transport macromolecular drugs across the BBB (Strategy One). Second, Mfsd2a could be used for the transport of some small-molecule drugs chemically coupled to LPC across the BBB (Strategy Two), which is quite similar to the carrier-mediated transport (CMT) via the glucose transporter (GluT1) and the L-type amino acid transporter 1 (LAT1). We here analyze and discuss the clinical significance of the two Mfsd2a-based strategies, including therapeutic potential, available pharmaceuticals, side effects, administration procedures, and disease types. In summary, the regulatory role of Mfsd2a deepens our knowledge of the function of the BBB, potentially contributing to the effective drug delivery in the treatments for neurodegenerative diseases, brain tumors, and life-threatening infections in the CNS.

Pin1-based diagnostic and therapeutic strategies for breast cancer.

Pin1 is the only known cis-to-trans isomerase that recognizes the phosphorylated pThr/pSer-Pro motifs in many signaling molecules, playing unique roles in the pathogenesis of breast cancer. First, Pin1 is prevalently over-expressed in kinds of breast cancer cell lines and tissues, such as MDA-MB-231 cell, MCF-7 cell, Her2+, ERα+, and basal-like breast cancer subtypes. Second, Pin1 amplifies many oncogenic signaling pathways, inhibits multiple tumor suppressors, promotes the angiogenesis and metastasis of breast cancer cells, and enhances the resistance of breast cancer cells to anti-tumor medicines. Third, inhibiting Pin1 blocks most of these detrimental effects in a great number of breast cancer cell lines. These findings suggest Pin1 as a promising diagnostic biomarker as well as an efficient therapeutic target for breast cancer. It is strongly expected that a Pin1-positive subtype of breast cancers should be extremely concerned and that the therapeutic efficacy of Pin1 inhibitors on breast cancer patients should be evaluated as soon as possible. Nonetheless, Pin1-based therapeutic strategies for breast cancer still deserve some debates. Hence, we give the predictions of several important issues, such as application precondition, side effects, and personalized medication, when Pin1 inhibitors are used in the breast cancer therapy. These proposals are meaningful for the further development of Pin1-based diagnostic and therapeutic strategies in order to conquer breast cancer.

A preliminary identification of PIN1 SNP linkage in patients with coronary heart disease from Handan, China.

Our aim was to perform an initial assessment of the polymorphic patterns of the PIN1 gene in patients with coronary heart disease (CHD). The PIN1-encoded protein (Pin1) suppresses eNOS-NO signaling and may impair cardiovascular function. Blood collection, DNA extraction, PCR amplification and gene sequencing were performed for thirty CHD participants living in central China, focusing on nine single nucleotide polymorphisms (SNPs). Their genetic linkages were revealed and their allele frequencies were compared with SNP data from the NCBI. Three major linkage patterns were identified: [1.rs2287839-5.rs2233682], [3.rs2233679-4.rs1077220-8.rs2287838] and [6.rs889162-7.rs2010457], suggesting correlated involvement in CHD and possible simultaneous genetic origin in ancient times. The frequencies of six SNPs are consistent with the NCBI data, while the frequencies of three SNPs (2.rs2233678, 4.rs1077220 and 9.rs4804461) are not consistent with the NCBI. Especially, the 3.rs2233679-4.rs1077220 linkage is different from other populations worldwide and may be an interesting genetic characteristic of Chinese CHD patients. Predictably, 1.rs2287839, 2.rs2233678, 3.rs2233679 and 5.rs2233682 may be strongly associated with CHD risk, although this requires future verification. The PIN1 SNP linkages lay a new genetic foundation for discovering novel molecular mechanisms of CHD and for exploring PIN1-based targeted treatment of CHD with nitric oxide regulatory therapies in clinical practice.

Promising hen egg-derived proteins/peptides (EDPs) for food engineering, natural products and precision medicines.

Hen eggs (HEs) provide valuable nutrients for humans, including proteins, carbohydrates, lipids and vitamins. Recent studies revealed a number of novel egg-derived proteins/peptides (EDPs), and EDPs may play a crucial role in food industry and medical therapy. First, these EDPs were purified from the enzyme-catalyzed hydrolysates of egg proteins and were characterized by biochemical assays such as gel electrophoresis, HPLC, mass spectrometry, proteomic and peptideomic analysis, etc. Second, some EDPs can be used as nontoxic bio-preservatives and functional nutraceuticals for replacing harmful sodium nitrite, inhibiting foodborne pathogens, promoting metal-ion absorption and improving meat-product quality, and these new features will be widely used in the field of food production. Third, novel medical properties of EDPs comprise anti-oxidative, anti-microbial, anti-inflammatory and anti-nociceptive activities, which will benefit prevention of cardiovascular diseases, cancers, diabetic mellitus, immune disorders, etc. In summary, this review gives a real insight into the novel nutritional, biological and medical functions of EDPs, predictably facilitating the applications of EDPs in production of nutritive supplements, functional nutraceuticals and therapeutic medicines.

PIN1, a perspective on genetic biomarker for nonalcoholic fatty liver disease (NAFLD).

OBJECTIVE: A novel genetic and molecular basis of nonalcoholic fatty liver disease (NAFLD) was explored. STUDY DESIGN: A 38-year-old male, who has no bad living and dietary habits, was diagnosed as NAFLD. The potential pathogenic role of Pin1 was evaluated by enzyme-linked immunosorbent (ELISA) assay and single nucleotide polymorphism (SNP) sequencing. RESULTS: ELISA determined a six-time higher concentration of plasma Pin1 compared to our previous data. Nine PIN1 SNPs were sequenced and classified according to their NAFLD-pathogenic risks, suggesting that rs2233678 and rs2287839 may be the most important genotypes that result in Pin1 overexpression and NAFLD development. CONCLUSION: In summary, this work explores a novel basis for early-onset NAFLD and highlights that elevated plasma Pin1 may predict NAFLD risk at early stage. Hypothetically, inhibiting Pin1 may benefit NAFLD prevention in the future.

A post-surgical adjunctive hypoxic therapy for myocardial infarction: Initiate endogenous cardiomyocyte proliferation in adults.

Myocardial infarction (MI) is a major threat to health worldwide, but today's methods for recovering heart function are limited, which is due largely to the deficient proliferative capacity of adult cardiomyocytes in the human body. To successfully overwhelm this deficiency, we propose a promising hypoxic therapy and highlight its unique role in directly eliciting endogenous myocardial regeneration in vivo. In the hypothesis, sufficient oxygen could be a restrictive factor of myocardial growth, whereas a moderate hypoxia might stimulate cardiomyocyte proliferation and enhance myocardial regeneration, heart weight and cardiac function recovery. The potential involvements of the hypoxia inducible factor-1 (HIF-1) and its downstream oncogenic signalings were hypothesized and evaluated in detail. Notably, the hypoxic treatment may initiate spontaneous proliferation of pre-existing cardiomyocytes in adult human body, which cannot (or hardly) be achieved by current MI-therapeutic approaches such as cardiovascular drugs, cardiac surgeries and aerobic exercise. The hypoxic therapy will lead to lower surgical risks compared with tissue regeneration in vitro and putative cardiac transplantation. With optimized moderately-low oxygen concentration, available therapeutic frequency and cycles, and controllable side effects, the hypoxic therapy will be a non-invasive, non-surgical, low-cost and low-risk approach to promoting myocardial regeneration in vivo and recovering cardiac function for MI patients who have large-area myocardial necrosis, in addition to other current MI-therapeutic methodologies.

Review fantastic medical implications of 3D-printing in liver surgeries, liver regeneration, liver transplantation and drug hepatotoxicity testing: A review.

The epidemiological trend in liver diseases becomes more serious worldwide. Several recent articles published by International Journal of Surgery in 2018 particularly emphasized the encouraging clinical benefits of hepatectomy, liver regeneration and liver transplantation, however, there are still many technical bottlenecks underlying these therapeutic approaches. Remarkably, a few preliminary studies have shown some clues to the role of three-dimensional (3D) printing in improving traditional therapy for liver diseases. Here, we concisely elucidated the curative applications of 3D-printing (no cells) and 3D Bio-printing (with hepatic cells), such as 3D-printed patient-specific liver models and devices for medical education, surgical simulation, hepatectomy and liver transplantation, 3D Bio-printed hepatic constructs for liver regeneration and artificial liver, 3D-printed liver tissues for evaluating drug's hepatotoxicity, and so on. Briefly, 3D-printed liver models and bioactive tissues may facilitate a lot of key steps to cure liver disorders, predictably bringing promising clinical benefits. This work further provides novel insights into facilitating treatment of hepatic carcinoma, promoting liver regeneration both in vivo and in vitro, expanding transplantable liver resources, maximizing therapeutic efficacy as well as minimizing surgical complications, medical hepatotoxicity, operational time, economic costs, etc.

Anatomical, animal, and cellular evidence for Zika-induced pathogenesis of fetal microcephaly.

Several recent articles published by Brain and Development in 2016 demonstrated some rare, but innovative, genetic mechanisms for microcephaly. This concise mini-review presented another novel pathogenic mechanism for microcephaly, which has actually been a worldwide medical challenge since the World Health Organization (WHO) defined the outbreak of the Zika virus (ZIKV) as an International Public Health Emergency on 1 Feb, 2016. As a recent noteworthy clinical phenomenon, the ZIKV outbreak was accompanied by a dramatically increased number of microcephalus fetuses. However, no direct evidence supporting the suspected pathogenic effects of ZIKV on fetal microcephaly was shown previously before 2016. Herein, we evaluated the most important human pathological, animal developmental, and neuro-cytotoxic findings released in 2016, and highlighted the original experimental evidence that strengthens the potential link between ZIKV and the high incidence of microcephaly in new-born babies. Because killing mosquitoes via insecticides is currently the only effective way to suppress ZIKV-induced disorders, the animal and cellular models described in this mini-review are very beneficial to anti-ZIKV drug development and vaccine assessment.

Focus on the therapeutic efficacy of 3BNC117 against HIV-1: In vitro studies, in vivo studies, clinical trials and challenges.

3BNC117, which was discovered in 2011, is a broadly neutralizing antibody (bNAb) and specifically neutralizes the human immunodeficiency virus type-1 (HIV-1) by targeting the CD4-binding site. This is the first comprehensive review that focuses on the role of 3BNC117 in the prevention of HIV-1 and acquired immune deficiency syndrome (AIDS). Briefly, 3BNC117 neutralizes many HIV/SHIV strains in vitro, blocks HIV-1 acquisition in animal models via a pre-exposure prophylaxis, alleviates HIV-1-associated viremia via a post-exposure therapeutic effect, prevents the establishment of latent HIV-1 reservoirs, and induces both humoral and cellular anti-HIV immune responses in vivo. The outcomes of Phase I and Phase IIa clinical trials in 2015 and 2016 showed the safety, tolerability, and therapeutic efficacy of 3BNC117 in HIV-1-infected human individuals. Nevertheless, anti-3BNC117 antibodies and HIV-1 strains resistant to 3BNC117 pose clinical challenges to immunotherapy with 3BNC117, so potential strategies for optimizing the potency of 3BNC117 are suggested here. Predictably, HIV-1 prevention and AIDS treatment will benefit from combinational immunotherapies with 3BNC117 and other pharmaceuticals (bNAbs, antiretroviral medicines, viral inducers, etc.) in the near future.

The AAV-mediated and RNA-guided CRISPR/Cas9 system for gene therapy of DMD and BMD.

Mutations in the dystrophin gene (Dmd) result in Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), which afflict many newborn boys. In 2016, Brain and Development published several interesting articles on DMD treatment with antisense oligonucleotide, kinase inhibitor, and prednisolone. Even more strikingly, three articles in the issue 6271 of Science in 2016 provide new insights into gene therapy of DMD and BMD via the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9). In brief, adeno-associated virus (AAV) vectors transport guided RNAs (gRNAs) and Cas9 into mdx mouse model, gRNAs recognize the mutated Dmd exon 23 (having a stop codon), and Cas9 cut the mutated exon 23 off the Dmd gene. These manipulations restored expression of truncated but partially functional dystrophin, improved skeletal and cardiac muscle function, and increased survival of mdx mice significantly. This review concisely summarized the related advancements and discussed their primary implications in the future gene therapy of DMD, including AAV-vector selection, gRNA designing, Cas9 optimization, dystrophin-restoration efficiency, administration routes, and systemic and long-term therapeutic efficacy. Future orientations, including off-target effects, safety concerns, immune responses, precision medicine, and Dmd-editing in the brain (potentially blocked by the blood-brain barrier) were also elucidated briefly. Collectively, the AAV-mediated and RNA-guided CRISPR/Cas9 system has major superiorities compared with traditional gene therapy, and might contribute to the treatment of DMD and BMD substantially in the near future.

Pin1 in cardiovascular dysfunction: A potential double-edge role.

BACKGROUNDS: Our lab focused on the structural and functional properties of Pin1, which is the only known cis-trans isomerase regulating pSer/pThr-Pro motifs in proteins and facilitates various signaling pathways. We are lucky enough to read the article, contributed by Costantino et al. in your esteemed journal, on the role of Pin1 in diabetes-induced vascular dysfunction. Pin1 regulates the production of nitric oxide (NO), which is a key physiological stimulator of blood vessels and promotes vascular relaxation responses significantly. However, the regulation of cardiovascular diseases by Pin1 is somewhat controversial. METHODS AND RESULTS: We compared the recent studies that support the down-regulation, as well as up-regulation, of NO production by Pin1 and tried to explore the underlying molecular mechanisms. We especially compared the different regulations of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) by Pin1, which is potentially the major reason leading to the controversial role of Pin1. Interestingly, the regulation of both eNOS and iNOS by Pin1 involves a double-edge effect, positively and negatively, contributing to paradoxical Pin1 functions in different animal models and cell lines. The extremely complex Pin1-regulated signaling networks might further exacerbate distinct cellular responses in vivo and influence NO production. CONCLUSIONS: Pin1 plays a dual role, both positive and negative, in regulating NO production and in mediating the pathogenesis of cardiovascular diseases. Pin1 functions may vary a lot under different circumstances. Future investigations should focus on eNOS as well as iNOS in order to increase authenticity and accuracy of results.

The double-edge role of B cells in mediating antitumor T-cell immunity: Pharmacological strategies for cancer immunotherapy.

Emerging evidence reveals the controversial role of B cells in antitumor immunity, but the underlying mechanisms have to be explored. Three latest articles published in the issue 521 of Nature in 2015 reconfirmed the puzzling topic and put forward some explanations of how B cells regulate antitumor T-cell responses both positively and negatively. This paper attempts to demonstrate that different B-cell subpopulations have distinct immunological properties and that they are involved in either antitumor responses or immunosuppression. Recent studies supporting the positive and negative roles of B cells in tumor development were summarized comprehensively. Several specific B-cell subpopulations, such as IgG(+), IgA(+), IL-10(+), and regulatory B cells, were described in detail. The mechanisms underlying the controversial B-cell effects were mainly attributed to different B-cell subpopulations, different B-cell-derived cytokines, direct B cell-T cell interaction, different cancer categories, and different malignant stages, and the immunological interaction between B cells and T cells is mediated by dendritic cells. Promising B-cell-based antitumor strategies were proposed and novel B-cell regulators were summarized to present interesting therapeutic targets. Future investigations are needed to make sure that B-cell-based pharmacological strategies benefit cancer immunotherapy substantially.

Configuration-specific immunotherapy targeting cis pThr231-Pro232 tau for Alzheimer disease.

Tau pathology is the main pathological characteristic of mild cognitive impairment (MCI) and Alzheimer disease (AD), and tau-based therapeutic strategies have great implications in the prevention of MCI and AD. The phosphorylation of threonine 231 preceding proline 232 (pThr231-Pro232) triggers tau hyperphosphorylation, tau aggregation, and tau pathology. Interestingly, the pThr231-Pro232 motif may be in a cis or trans configuration, but several recent studies have firstly indicated that cis, but not trans, pThr231-Pro232 tau is a striking therapeutic target for MCI and AD. Cis pThr231-Pro232 tau appears firstly in MCI and accumulates exclusively in the development of AD. Moreover, cis pThr231-Pro232 tau has low affinity to microtubules, high resistance to dephosphorylation and degradation, and a potent tendency to aggregate. On the contrary, trans pThr231-Pro232 tau has normal physiological activity in vivo. Fortunately, Pin1 is the only known isomerase that catalyzes pThr231-Pro232 tau from the neurotoxic cis to nontoxic trans configuration, which prevents MCI and AD. Nonetheless, as we have mentioned before, Pin1 is frequently inactivated under abnormal physiological conditions in vivo. Therefore, it is necessary to clear cis pThr231-Pro232 tau by immunotherapy when Pin1 is insufficient, in order to avoid the occurrence of MCI and AD.

Hypnosis and music interventions (HMIs) inactivate HIF-1: A potential curative efficacy for cancers and hypertension.

Hypnosis and music interventions (HMIs) have shown positive influence on cancers for nearly 200years, but the underlying mechanisms were rarely explored systematically. The hypothesis suggests a potential curative efficacy of HMIs on cancers by inhibiting hypoxia inducible factor-1 (HIF-1), which is a key mediator of cancer development, especially under hypoxic conditions. HMIs are sufficient to attenuate the pain and anxiety degree of individuals, improve multiple psychological and physiological parameters, and consequently, lead to increased oxygen saturation in vivo. Furthermore, abundant oxygen in vivo inhibits the activation of HIF-1 and potentially blockades kinds of HIF-1-induced oncogenic signaling pathways. The hypothesized efficacy of HMIs is very similar to anti-cancer medicines targeting HIF-1. The implication of the hypothesis in preventing hypertension is also discussed. In summary, the hypothesis clearly suggests the potential involvement of the convenient, safe, non-pharmaceutical, and low-cost HMIs in preventing HIF-1-mediated diseases, including cancers and hypertension.

Pin1 liberates the human immunodeficiency virus type-1 (HIV-1): Must we stop it?

Acquired immune deficiency syndrome (AIDS) is mainly caused by the human immunodeficiency virus type-1 (HIV-1). To our knowledge, this is the first review focusing on the vital role of Pin1 in the infection of HIV-1 and the development of AIDS. We and others have demonstrated that Pin1, the only known cis-to-trans isomerase recognizing the pThr/pSer-Pro motifs in proteins, plays striking roles in several human diseases. Interestingly, recent evidence gradually indicates that Pin1 regulates several key steps of the life cycle of HIV-1, including the uncoating of the HIV-1 core, the reverse transcription of the RNA genome of HIV-1, and the integration of the HIV-1 cDNA into human chromosomes. Whereas inhibiting Pin1 suppresses all of these key steps and attenuates the replication of HIV-1, at the same time different PIN1 gene variants are correlated with the susceptibility to HIV-1 infection. Furthermore, Pin1 potentially promotes HIV-1 infection by activating multiple oncogenes and inactivating multiple tumor suppressors, extending the life span of HIV-infected cells. These descriptions suggest Pin1 as a promising therapeutic target for the prevention of HIV-1 and highlight the possibility of blocking the development of AIDS by Pin1 inhibitors.

The structural and functional role of the three tryptophan residues in Pin1.

Pin1, the only known isomerase catalyzing phosphorylated pSer/pThr-Pro motifs in proteins, plays unique roles in human diseases notably cancers and Alzheimer's disease. Herein, site-directed mutagenesis was employed to construct the tryptophan mutants of Pin1, including W11L, W34L, and W73L. Spectral methodologies, activity measurement, and proteinase resistance analysis were used to investigate the structural and functional role of the tryptophan residues in Pin1. In general, W11 and W34 are essential to the structure and the function of Pin1, because their mutations influence the structure of WW domain of Pin1, potentially attenuate the binding affinity of Pin1 to substrates, and thus inhibit the enzymatic activity of Pin1. Particularly, W11 mutation results in significantly varied structural features of Pin1 as revealed by fluorescence and circular dichroism (CD) spectroscopies, and decreases the enzymatic activity, thermal stability, and proteinase resistance of Pin1, all of which give an explanation for the high conservation of W11 in vivo. The synchronous fluorescence spectra indicate that W11 and W34 mutations possibly block their energy transfer to Y23 or Y24, suggesting the structural rearrangement in WW domain. By contrast, W73 is of minor importance for the structure and the function of Pin1, because the parameters of W73L observed in several experiments are very similar to wild-type Pin1. These observations are very beneficial for further understanding the structural and functional characteristics of Pin1 and for unveiling the pathogenesis of Pin1-related diseases especially those caused by tryptophan mutations.

Pin1, endothelial nitric oxide synthase, and amyloid-ß form a feedback signaling loop involved in the pathogenesis of Alzheimer's disease, hypertension, and cerebral amyloid angiopathy.

Although the molecular mechanism has not yet been clarified until now, it is very interesting that Alzheimer's disease (AD), hypertension (HTN), and cerebral amyloid angiopathy (CAA) often occur synchronously and possess many similar pathological characteristics. Herein, we hypothesize that a feedback signaling loop, consisted of Pin1, endothelial nitric oxide synthase (eNOS), and amyloid-ß (Aß), may contribute to the interesting pathological phenomenon. First, Pin1 inhibits the production of Aß, and enhances the activity of eNOS. Second, Aß and eNOS form a mutual inhibition system. Third, the well-balanced feedback signaling loop avoids the development of AD, HTN, and CAA by inhibiting the frequent pathological characteristics of these diseases, including Aß deposition in cerebral microvessels and cerebral microbleeds. On one hand, Pin1 and eNOS not only inhibit Aß production but also accelerate Aß clearance, preventing Aß deposition in cerebral microvessels. On the other hand, Pin1 and eNOS promote vasodilatation and prevent the elevation of blood pressure in brain, alleviating the pathology of cerebral microbleeds. However, once the precise balance is disturbed, it may result in Aß deposition, microbleeds, and elevated blood pressure, possibly leading to the synchronous occurrence of AD, HTN, and CAA. The hypothesis updates the current understanding of the molecular linkage among AD, HTN, and CAA, and lays the ground for developing combined prevention, diagnosis, and treatment of these diseases more efficiently and more economically. Interestingly, biotechnical medicines enhancing the activity of Pin1 and/or eNOS may prevent the development of AD, HTN, and CAA, and targeting Aß deposition may alleviate the clinical pathologies of these related diseases.